TREATMENT OF SCLERODERMA

BACKGROUND

Scleroderma is a disease resulting from microvascular pathology, immune and inflammatory activation with excessive fibrosis that causes hardening and tightening of skin and connective tissues. A particularly devastating consequence of the illness is over-production of collagen in the skin and organ tissues. Scleroderma manifests as a variety of symptoms that decrease quality of life, such as hardening and tightening of patches of skin, shiny skin, restricted movement due to hardness in skin, hair loss, white lumps under the skin due to calcium deposition, exaggerated responses to cold temperatures and emotional stress, numbness in finger and/or toe, pain in finger and/or toe, changes in color in finger and/or toe, digestive system, acid reflux, restricted movement of food through the digestive tract, malnutrition, fatigue, and anxiety. Over time, Scleroderma patients often present with other comorbidities, such as secondary Raynaud's syndrome, endothelial dysfunction, gastrointestinal disorders, dyspnea (i.e., shortness of breath), calcinosis, cardiac dysfunction, and kidney dysfunction. Scleroderma is often divided into categories known as “limited” or “diffuse” disease, which refers, e.g., to the degree and pattern of skin involvement. Both types can present with organ and vascular involvement. Disease-modifying anti-rheumatic drug treatments, such as mycophenolate and methotrexate are used to treat scleroderma, but have limited effect and morbidity and mortality with the disease remains high. Recent approved antifibrotic drugs such as nintedenib have had an impact in Scleroderma patients affected with lung fibrosis and reduce the annual decline in lung function but have little impact on overall disease modification nor the vascular pathology of the disease, Thus the medical need for disease-modifying treatments that can reduce the poorly treated common disease symptoms and overall morbidity and mortality remains high. It is considered an orphan indication and rare disease with approximately 150,000 patients in the United States.

SUMMARY

Described herein are methods and compositions that include the use of dual N-type and L-type calcium channel blockers selective for the N-type calcium channel that can also, in some embodiments, possess selective sodium channel blocker activity (e.g., Nav 1.7 sodium channel blocker activity), transient receptor potential vanilloid-1 ion channel (TRP-v1) blocker activity, reduce the release of Interleukin-1 (IL-1), decrease P2X7R activity, decrease serum uric acid levels, decrease thrombospondin, and decrease TGF-β as well. for the treatment of scleroderma in a subject.

Scleroderma is notoriously difficult to treat, with existing drugs (such as calcium channel blockers which are directed at improving only the Raynaud's symptoms and attacks that most patients experience) having the potential for serious side effects that are, without wishing to be bound by theory, believed to be at least in part the result of unselective (e.g., non-discriminate or low selectivity) calcium channel inhibition.

Based on these considerations, N-selective dual N- and L-type calcium channel inhibition can be useful to treat diseases and disorders that are associated with dysregulation of blood flow and sympathetic nervous system overactivity, including those featuring symptoms of neuropathic pain and vasoconstriction, such as scleroderma. Dual N-type and L-type calcium channel blockers selective for the N-type calcium channel can also inhibit, e.g., the Nav 1.7 sodium channel, decrease TRPV-1 activity which is increased in neuropathic pain states, and reduce IL-1 production. This can be useful in the treatment of scleroderma and many comorbidities associated with scleroderma, such as endothelial dysfunction, gastrointestinal disorders, and calcinosis.

It is understood that, in contrast to L-type calcium channel blockade, dual N-type and L-type calcium channel blockade selective for the N-type calcium channel can decrease sympathetic activity, as well as dilate both arterioles and the venous system, resulting in less adverse events than patients treated with dual L and N-calcium channel antagonists with lower levels of N type calcium channel selectivity (such as, e.g., a lack of peripheral edema caused by lesser dilation of the venous system). It is therefore postulated that this may enable dosing of a dual N-type and L-type calcium channel blockers selective for the N-type calcium channel at higher levels than non-N selective calcium channel blockers, thus increasing potency at producing disease modifying effects. In addition, dual L-type and N-channel type calcium channel blockade selective for the N-type calcium channel is believed to stimulate the release of NO and endothelial nitric oxide synthase (eNOS) expression, which are critical for normal endothelial function. Further, N-type calcium channels are more widely located in the body than L-type channels, and have been identified in the nervous system, heart, kidney, venules, and the endothelium. In the spine, N-type channels are located pre-synaptically and regulate sympathetic nerve activity; these channels may involve suppression of both arteriole and venule constriction in the fingers and toes that occur in secondary Raynaud's syndrome in subjects having scleroderma.

A beneficial effect of L-type calcium channel inhibition is the dilation of the arteries in smooth muscle, causing an increase in arterial diameter, referred to as vasodilation. However, L-type calcium channel inhibition induces a homeostatic reflex mechanism in which norepinephrine is produced. The norepinephrine induces vasoconstriction, as well as elevating heart rate, and thus partially offsets the vasodilating effects of the L-type calcium channel inhibition. A useful complementary effect of N-type calcium channel inhibition is the decrease of norepinephrine release and sympathetic outflow pre-synaptically in the spinal cord at the level of the dorsal root ganglion, which can counteract the homeostasis mechanism triggered by blockade of the L-type calcium channel. It is believed that dual N-type and L-type calcium channel blockers selective for the N-type calcium channel are able to achieve an optimal balance of N- vs. L-type calcium channel inhibition to realize these effects.

Additional advantages include an increase in bone density in certain subjects (e.g., subjects afflicted with osteoporosis), beneficial renal effects, and improvement in vascular modeling which has been shown to reduce the progression of arterial disease with long term use. The beneficial renal effects are understood to be an effect of reduced renal constriction and improved blood flow in the kidney.

Cilnidipine is understood to exert an optimum balance of selective N- vs. L-type calcium channel inhibition (which can have a 5 fold to 50-fold to 100-fold to 1600 fold selectivity for N-type calcium channel over L-type calcium channel), which can make it surprisingly effective at treating neuropathic pain and vasoconstriction, particularly when they occur concurrently, such as in Raynaud's syndrome. The potential role of cilnidipine and dual N-type and L-type calcium channel blockers selective for the N-type calcium channels in treating Raynaud's syndrome has not been recognized. Cilnidipine also has activity against the Nav 1.7 sodium channel, which may further contribute to its efficacy in the treatment of Raynaud's syndrome. See WO 2021/178903, which is incorporated by reference herein in its entirety.

Phosphodiesterase inhibitors have been explored for treatment in patients having, e.g., neuropathic pain and/or vasoconstriction; however, at the doses that have been explored in these studies, common side effects occur such as headache, flushing, and dyspepsia and occasionally hypotension when used concurrently with nitrates.

Additional advantages of dual N-type and L-type calcium channel blockers selective for the N-type calcium channel include, for example:

- Improvement in endothelial function and endothelial concentrations of nitric oxide by improving blood flow, reducing pain that is, e.g., a consequence of reduced blood flow.
- Improvement in cardiac and left ventricle functioning resulting in reduction of pain due, e.g., to ischemia.
- Improvement in the incidence and severity of atherosclerosis including reducing pain caused, e.g., by a reduction in blood flow, and reducing the overall incidence of atherosclerotic-related events.
- Decrease in overall sympathetic nervous system activity and plasma concentration of norepinephrine, which can decrease pain due to net arteriole dilation and decrease in sympathetically mediated pain syndromes.
- Improvement in overall autonomic functioning, which may improve gut function in patients whose gut function (e.g., competency of the lower esophageal sphincter and peristalsis and gastric emptying), is compromised due to impaired autonomic function as occurs in certain disease states (e.g., scleroderma).
- Decrease in oxidative stress and reduction in reactive oxygen species.

Based on these considerations, a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel such as cilnidipine, optionally in combination with a dose of a phosphodiesterase type 5 inhibitor such as tadalafil can be surprisingly useful to treat scleroderma.

Some embodiments provide a method of treating scleroderma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Some embodiments provide a method of treating endothelial dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Some embodiments provide a method of treating diabetic neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Some embodiments provide a method of treating dyspnea in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Some embodiments provide a method of treating a gastrointestinal disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Definitions

As used herein, the terms “about” and “approximately” are used interchangeably, and when used to refer to modify a numerical value, encompass a range of uncertainty of the numerical value of from 0% to 10% of the numerical value.

As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

The terms “treat,” “treating,” and “treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slow the progression of a disease, disorder or condition or of one or more symptoms thereof.

As used herein, the terms “subject” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the disease or disorder is associated with dysregulation of blood flow and sympathetic nervous system overactivity. In some embodiments, the disease or disorder is characterized by neuropathic pain, vasoconstriction, dysesthetic pain, burning pain, body temperature changes of the subject, hyperesthesia, changes in skin or tissue color, edema, changes in skin turgor, ruble, pallor, cyanosis, vasospasm, or any combination thereof. In some embodiments, the disease or disorder is scleroderma. In some embodiments, the disease or disorder is endothelial dysfunction. In some embodiments, the disease or disorder is diabetic neuropathy. In some embodiments, the disease or disorder is dyspnea. In some embodiments, the disease or disorder is a gastrointestinal disorder. In some embodiments, the disease or disorder is renal dysfunction. In some embodiments, the disease or disorder is ulceration of the skin. In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is calcinosis. In some embodiments, the disease or disorder is characterized by microvascular pathology and loss of normal arteriole architecture. In some embodiments, the disease or disorder is a cardiac disorder and can include microvascular coronary artery disease, a conduction defect and tachyarrythmia, autonomic insufficiency, pericardial involvement, and heart failure.

As used herein, the phrase “fixed dosage form” refers to the simultaneous administration of two or more therapeutic agents to a subject in the form of a single composition or dosage.

As used herein, the term “dual N-type and L-type calcium channel blocker selective for the N-type calcium channel” refers to an agent that inhibits both N- and L-type calcium channels, and inhibits the N-type calcium channel to a greater degree than the L-type calcium channel. The terms “dual N-type and L-type calcium channel blocker selective for the N-type calcium channel” and “dual N-type and L-type selective calcium blocker” are used interchangeably herein. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel has at least a 5-fold selectivity for the N-type calcium channel over the L-type calcium channel. For example, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel exhibits at least a 10-fold, at least a 30-fold, at least a 50-fold, at least a 80-fold, at least a 100-fold, at least a 300-fold, at least a 500-fold, at least a 800-fold, at least a 900-fold, or at least a 1000-fold selectivity for the N-type calcium channel over the L-type calcium channel. For example, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel exhibits at least a 50-fold to 100-fold selectivity for the N-type calcium channel over the L-type calcium channel. Examples of dual N-type and L-type calcium channel blocker selective for the N-type calcium channel include, but are not limited to, cilnidipine, Z-160, ralfinamide, CNV2197944, or pharmaceutically acceptable salts thereof.

As used herein, the term “non-N-selective calcium channel blocker” refers to an agent that blocks one or more calcium channels, but either (1) does not block the N-type calcium channel, or (2) blocks the N-type calcium channel, but not selectively over the L-type calcium channel (e.g., selectively blocks the L-type calcium channel over the N-type calcium channel). Examples of non-N-selective calcium channel blockers include, but are not limited to, nifedipine, nicardipine, amlodipine, Z-944, nimodipine, verapamil, diltiazem, felodipine, isradipine, nisoldipine, nitrendipine, and pharmaceutical salts thereof.

As used herein, the term “vasoconstriction” refers to the reduction in diameter of a blood vessel (e.g., an artery, vein, or capillary) resulting in reduced blood flow to the tissue the vasoconstricted blood vessels circulate blood to and from.

As used herein, the term “reducing susceptibility of a subject to cold-induced pain or discomfort” refers to reducing the pathologic response of a subject to experience pain or discomfort when subjected to an environment that lowers the temperature of a body part of the subject. In some embodiments, reducing susceptibility of a subject to cold-induced pain or discomfort can include reducing the likelihood that a subject will experience pain or discomfort when subjected to an environment that lowers the temperature of a body part of the subject. In some embodiments, reducing susceptibility of a subject to cold-induced pain or discomfort can include reducing the magnitude or intensity of pain or discomfort that a subject feels when subjected to an environment that lowers the temperature of a body part of the subject.

As used herein, the term “body temperature” refers to the temperature range of the body in a healthy, awake subject under normal conditions of thermoregulation as measured in the mouth, the rectum, the armpit, or the ear. For example, the temperature range in a healthy human subject under normal conditions of thermoregulation is 36.1° C. to 37.8° C.

The term “therapeutically effective amount,” as used herein, refers to a sufficient amount of a chemical entity being administered which will relieve to an extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. When a combination of two or more chemical entities is administered (e.g., a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, and a phosphodiesterase type 5 inhibitor), a therapeutically effective amount of each component of the combination is understood to be the therapeutically effective amount of each component when used in conjunction with the other component, which can be different (e.g., lower) than the therapeutically effective amount of each component when administered alone.

The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term “pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. The term “pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt may not be specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and methanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: transdermal, intranasally, sublingual, intraspinal, or ocular administration.

For purposes of clarification, when a parameter, score, state, condition, or statistic in a subject is increased, decreased, or improved after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor, the increase, decrease, or improvement is, for example, measured, assessed, or obtained in relation to the parameter, score, state, condition, or statistic measured, assessed, or obtained before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor, unless otherwise specified herein. The parameter, score, state, condition, or statistic can be a single measurement, score, or assessment, an average of a plurality of measurements, scores, or assessments, or a daily average of a plurality of measurements, scores, or assessments. Unless otherwise specified herein, measurements, scores, or assessments are typically taken within 1 month (e.g., within 3 weeks, 2 weeks, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, or 6 hours) of the administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor.

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 shows a schematic of a study to assess the safety and efficacy of cilnidipine alone and in combination with tadalafil in subjects having secondary Raynaud's disease.

FIG. 2 shows a schedule of assessments in the double-blind parallel group.

FIG. 3A and FIG. 3B show a schedule of assessments in the double-blind 4-way crossover group.

FIG. 4A and FIG. 4B show a schedule of assessments in the double-blind 2-way crossover group.

FIG. 5 shows a schematic of the study design for the Phase 2B study associated with Example 5.

FIG. 6 shows a schematic of the study design for the Phase 3 study associated with Example 5.

FIG. 7 shows a statistical outcome of Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) questionnaire.

FIG. 8 shows a schedule of assessments for the Phase 2B and Phase 3 study associated with Example 5.

FIG. 9 shows the schematic of the study of Example 5.

DETAILED DESCRIPTION

In one aspect, disclosed herein is a method of treating scleroderma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel (“dual N-type and L-type selective calcium blocker”), and/or a phosphodiesterase type 5 inhibitor. In some embodiments, a dual N-type and L-type selective calcium blocker is administered to the subject. In some embodiments, a dual N-type and L-type selective calcium blocker and a phosphodiesterase type 5 inhibitor are administered to the subject. In some embodiments, a phosphodiesterase type 5 inhibitor is administered to the subject.

In another aspect, disclosed herein is a method of treating scleroderma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor.

Examples of N-type calcium channels include, but are not limited to, the Cav2.2 Type, which has two subunits, Cav 2.2a and Cav2.2b, both of which have an alpha 1 subunit of 2.2 and are affected by N type current.

In some embodiments, the scleroderma is limited scleroderma. In some embodiments, the scleroderma is diffuse scleroderma.

In some embodiments, the treating comprises reducing the frequency of one or more symptoms associated with scleroderma in the subject. In some embodiments, the treating comprises reducing the severity of one or more symptoms associated with scleroderma in the subject. In some embodiments, the treating comprises reducing the duration of one or more symptoms associated with scleroderma in the subject.

Some embodiments provide a method of reducing the frequency, severity, or duration of one or more scleroderma symptoms in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, the symptoms are selected from the group consisting of: hardening and tightening of patches of skin, shiny skin, restricted movement due to hardness in skin, hair loss, white lumps under the skin due to calcium deposition, exaggerated responses to cold temperatures and emotional stress, numbness in finger and/or toe, pain in finger and/or toe, changes in color in finger and/or toe, digestive system, acid reflux, restricted movement of food through the digestive tract, malnutrition, fatigue, anxiety, and any combination thereof.

In some embodiments, the treating comprises reducing fibrosis in the subject. In some embodiments, reducing fibrosis comprises reducing formation of collagen and extracellular matrix proteins in the subject. In some embodiments, the collagen is formed by fibroblasts. In some embodiments, the fibrosis is renal fibrosis or myocardial fibrosis.

In some embodiments, the treating comprises improving vascular function in the subject. In some embodiments, improving vascular function comprises decreasing intima media thickness (IMT), decreasing arterial stiffness, reducing urinary albumin excretion (UAE), reducing plaque in the arteries, or any combination thereof.

In some embodiments, the subject has digital ulcerations. In some embodiments, after administration of the dual N-type and L-type selective calcium blocker, the number and/or severity of the digital ulcerations is reduced.

Some embodiments provide a method of treating cardiac dysfunction and/or improving cardiac function in a subject in need thereof, comprising administering a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor to the subject.

Some embodiments provide a method of treating cardiac dysfunction and/or improving cardiac function in a subject in need thereof, comprising administering a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor to the subject.

In some embodiments, the treating comprises improving cardiac function in the subject. In some embodiments, improving cardiac function in the subject comprises reducing the frequency and/or severity of cardiac arrhythmias; reducing sympathomimetic increases in papillary muscle-developed tension (PMDT); reducing myocardial interstitial norepinephrine level; decreasing aortic pressure; increased aortic, vertebral, and coronary blood flow; reducing myocardial oxygen consumption; reducing blood pressure; or any combination thereof.

In some embodiments, the treating comprises improving renal function in the subject. In some embodiments, improving renal function comprises reducing intrarenal arterial stiffness, improving blood flow to the kidneys, increasing expression levels of podocyte proteins, or any combination thereof.

Some embodiments provide a method of treating renal dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor. In some embodiments, the subject has scleroderma, secondary Raynaud's syndrome, or both.

In some embodiments, starting before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor, the subject was administered an alternative therapy useful to treat the scleroderma at regular intervals; and after administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject, the dosage and/or frequency of the alternative therapy required to treat the subject is reduced. In some embodiments, the alternative therapy is a non-N-selective calcium channel blocker.

Some embodiments provide a method of treating pulmonary fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor. In some embodiments, the subject has scleroderma, secondary Raynaud's syndrome, or both.

Some embodiments provide a method of treating a cardiac disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor. In some embodiments, the subject has scleroderma, secondary Raynaud's syndrome, or both.

In some embodiments, the cardiac disorder is microvascular coronary artery disease, conduction defects and tachyarrythmias, autonomic insufficiency, pericardial involvement, heart failure, or a combination thereof.

Some embodiments provide a method of treating microvascular pathology and/or loss of normal arteriole architecture in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor. In some embodiments, the subject has scleroderma, secondary Raynaud's syndrome, or both.

In some embodiments, the subject has atherosclerosis, an increased adherence of monocytes and/or macrophages in a vessel wall, restenosis, or a combination thereof.

In some embodiments, after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, the atherosclerosis, an increased adherence of monocytes and/or macrophages in a vessel wall, restenosis, or a combination thereof are treated or ameliorated.

In some embodiments, the diabetic neuropathy is small fiber diabetic neuropathy. In some embodiments, the diabetic neuropathy is peripheral neuropathy. In some embodiments, the diabetic neuropathy is autonomic neuropathy. In some embodiments, the diabetic neuropathy is proximal neuropathy. In some embodiments, the diabetic neuropathy is focal neuropathy.

In some embodiments, after administration of the therapeutically effective amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and the second therapeutic agent, the severity, frequency, and/or duration of numbness, sensation of tingling in the feet or hands, sensation of pins and needles, prickling sensations, sensation of burning feet or hands, cold sensations, pinching sensations, stabbing sensations, heightened sensitivity to touch, indigestion, gastroparesis, nausea, vomiting, stomach pain, diarrhea, constipation, muscle weakness, lack of coordination, ulcers and/or infection in a foot, bone and joint pain, hip pain, hypoglycemia unawareness, reduced libido, vision impairment, eye pain, Bell's palsy, or any combination thereof are reduced in the subject.

In some embodiments, the dyspnea is acute dyspnea. In some embodiments, the dyspnea is chronic dyspnea.

In some embodiments, the gastrointestinal disorder is gastroesophageal reflux disease (GERD). In some embodiments, the gastrointestinal disorder is acid reflux. In some embodiments, the method comprises reducing dilation of the lower esophageal sphincter. In some embodiments, the gastrointestinal disorder is irregular peristalsis. In some embodiments, the irregular peristalsis is a motility disorder (e.g., hypermotility or hypomotility). In some embodiments, the irregular peristalsis is reverse peristalsis. In some embodiments, the irregular peristalsis is irregular intestinal peristalsis.

In some embodiments, the gastrointestinal disorder is bloating. In some embodiments, the gastrointestinal disorder is constipation. In some embodiments, the gastrointestinal disorder is diarrhea. In some embodiments, the gastrointestinal disorder is incontinence. In some embodiments, the gastrointestinal disorder is decreased autonomic functioning anorectal function.

Some embodiments provide a method of reducing the frequency of one or more symptoms associated with gastroesophageal reflux disease in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

Some embodiments provide a method of reducing the frequency of one or more symptoms associated with gastroesophageal reflux disease in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

Some embodiments provide a method of reducing the severity of one or more symptoms associated with gastroesophageal reflux disease in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

Some embodiments provide a method of reducing the severity of one or more symptoms associated with gastroesophageal reflux disease in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

Some embodiments provide a method of treating acid reflux in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

Some embodiments provide a method of reducing dilation of the lower esophageal sphincter in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

Some embodiments provide a method of reducing dilation of the lower esophageal sphincter in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor, wherein the subject is a human.

In some embodiments, the subject is identified or diagnosed as having a dilated lower esophageal sphincter. In some embodiments, a dilated lower esophageal sphincter is understood to be dilated to an irregular degree as assessed by a medical professional (e.g., a doctor (e.g., a gastroenterologist), nurse, or nurse practitioner). In some embodiments, the subject identified or diagnosed as having a dilated lower esophageal sphincter is afflicted with nausea and/or reverse peristalsis. In some embodiments, dilation of the lower esophageal sphincter in the subject is reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject.

In some embodiments, the subject is identified or diagnosed as having damaged esophageal tissue. In some embodiments, damage to the esophageal tissue in the subject is reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject. In some embodiments, the subject is identified or diagnosed as having achalasia. In some embodiments, the achalasia in the subject is reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, the autonomic functioning of the subject is improved; wherein the improvement of autonomic functioning in the subject is characterized by a lower reduction in systolic blood pressure in the upper arm of the subject when the subject is subjected to a tilt table test.

In some embodiments, the subject is identified or diagnosed as having acid reflux. In some embodiments, the frequency or severity of the acid reflux in the subject is reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject.

In some embodiments, the subject is identified or diagnosed as having irregular peristalsis. In some embodiments, the incidences of irregular peristalsis in the subject are reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject. In some embodiments, the irregular peristalsis is irregular intestinal peristalsis.

In some embodiments, the incidences of intestinal peristalsis in the subject are reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject.

In some embodiments, the subject has scleroderma. In some embodiments, the scleroderma is limited scleroderma. In some embodiments, the scleroderma is diffuse scleroderma.

In some embodiments, the subject has Raynaud's syndrome. In some embodiments, the Raynaud's syndrome is secondary Raynaud's syndrome.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, one or more symptoms of the Raynaud's syndrome are improved.

In some embodiments, vasoconstriction in the subject is reduced after administering the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject.

In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, CNV2197944, or pharmaceutically acceptable salts thereof. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is cilnidipine or a pharmaceutically acceptable salt thereof.

In some embodiments, the amount of the phosphodiesterase type 5 inhibitor used in the method is less than the therapeutically effective amount of the phosphodiesterase type 5 inhibitor useful to treat scleroderma in a subject when administered in combination with a non-N selective calcium channel blocker. In some embodiments, the amount of the phosphodiesterase type 5 inhibitor used in the method is less than the therapeutically effective amount of the phosphodiesterase type 5 inhibitor useful to treat scleroderma in a subject when administered alone (i.e., when a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is not co-administered to the subject or was not previously administered to the subject within 1 week of administering the phosphodiesterase type 5 inhibitor).

In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 1 mg to about 50 mg (e.g., about 3 mg to about 35 mg, about 5 mg to about 40 mg, about 5 mg to about 25 mg, about 8 mg to about 28 mg, about 12 mg to about 28 mg, about 9 mg to about 21 mg, about 15 mg to about 25 mg, about 17 mg to about 23 mg, about 8 mg to about 12 mg, about 25 mg to about 35 mg, about 28 mg to about 32 mg, about 15 mg to about 35 mg, about 8 mg, about 10 mg, about 12 mg, about 18 mg, about 20 mg, about 22 mg, about 25 mg, about 30 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 40 mg, or about 50 mg). In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 5 mg to about 40 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 5 mg to about 25 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 9 mg to about 21 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 10 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 20 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 30 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 32 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 33 mg. In some embodiments, the dosage of the dual N-type and L-type selective calcium blocker is about 35 mg.

In some embodiments, the dosage of the phosphodiesterase type 5 inhibitor is about 1 mg to about 50 mg (e.g., about 2 mg to about 40 mg, about 8 mg to about 40 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 12 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 17 mg, about 20 mg, or about 25 mg). In some embodiments, the dosage of the phosphodiesterase type 5 inhibitor is about 2 mg to about 8 mg. In some embodiments, the dosage of the phosphodiesterase type 5 inhibitor is about 5 mg.

In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is administered orally. In some embodiments, the phosphodiesterase type 5 inhibitor is administered orally.

In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered separately, sequentially, or simultaneously.

In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of tachycardia, headaches, flushing, increased heart rate, flushing, decreased renal blood flow, myalgia, chest pain, heart palpitation, and/or pedal enema than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the scleroderma.

In some embodiments, the non-N-selective calcium channel blocker is selected from the group consisting of: nifedipine, nicardipine, amlodipine, Z-944, nimodipine, verapamil, diltiazem, felodipine, isradipine, nisoldipine, and nitrendipine.

In some embodiments, a reduction in the Raynaud's condition scale is measured in the subject. In some embodiments, the reduction in the Raynaud's condition scale is at least about 25%.

In some embodiments, a reduction in the Raynaud's severity scale is measured in the subject.

In some embodiments, a reduction in the average weekly pain score is measured in the subject.

In some embodiments, an increase in the temperature of a body part as measured by thermography is observed in the subject. In some embodiments, the body part is an index finger.

In some embodiments, an improvement in the SF-12 index of functional wellbeing is measured in the subject.

In some embodiments, an improvement in Scleroderma Health Assessment Questionnaire (SHAQ®) is measured in the subject.

In some embodiments, a reduction in the Reactive Hyperemia Index as measured by Endo PAT is measured in the subject.

In some embodiments, an improvement in endothelial function as measured by Endo PAT is measured in the subject.

In some embodiments, nitric oxide levels in the endothelium are increased as measured by Endo PAT in the subject.

In some embodiments, an improvement (e.g., at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 32%, or about 35% improvement) in the finger ulcer visual analog scale (VAS) is measured or assessed in the subject.

In some embodiments, an improvement (e.g., at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or about 49% improvement) in the Raynaud's visual analog scale (VAS) is measured or assessed in the subject.

In some embodiments, an improvement in breathing is determined in the subject as measured by increased oxygen saturation in the blood of the subject.

In some embodiments, an improvement in breathing (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or about 67% improvement) is determined in the subject as measured by the breathing visual analog scale (VAS).

In some embodiments, an improvement in the Standard Disability Index (e.g., an at least 9%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, about 9% improvement, or about 50% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the Alternative Disability Index (e.g., at least 10%, at least 20%, at least 30%, at least 40%, or about 42% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the SHAQ Intestinal Difficulty score (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 45% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the SHAQ Breathing Difficulty score (also referred to herein as the “breathing difficulty parameter of the SHAQ”) (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 73%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 73% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the SHAQ Raynaud's Difficulty score (e.g., at least 5%, at least 10%, at least 15%, at least 17%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 49%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, about 35%, or about 49% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the SHAQ Burden of Finger Ulcers score (also referred to herein as “burden of finger ulcers parameter of the Scleroderma Health Assessment Questionnaire (SHAQ)”) (e.g., at least 5%, at least 10%, at least 15%, at least 17%, at least 20%, at least 25%, at least 30%, at least 34%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, about 17%, or about 34% improvement) is measured or assessed in the subject.

In some embodiments, an improvement in the SHAQ Overall Scleroderma Disease Severity (also referred to herein as the “overall disease severity scale in the Scleroderma Health Assessment Questionnaire (SHAQ)”) is measured or assessed in the subject. In some embodiments, an improvement (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, about 32%, or about 63% improvement) in overall scleroderma disease severity is measured or assessed in the visual analog scale of overall disease severity in the subject. In some embodiments, an improvement of at least 30% in overall scleroderma disease severity is measured or assessed in the visual analog scale of overall disease severity in the subject. In some embodiments, an improvement of at least 60% in overall scleroderma disease severity is measured or assessed in the visual analog scale of overall disease severity in the subject.

In some embodiments, an improvement in scleroderma disease severity is measured or assessed in the subject. In some embodiments, an improvement (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or about 63% improvement) in scleroderma disease severity is measured or assessed in the visual analog scale of overall disease severity in the subject.

In some embodiments, an improvement in the Overall Scleroderma Disease Activity Score is measured or assessed in the subject. In some embodiments, an improvement of at least 5% (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) in the Overall Scleroderma Disease Activity Score is measured or assessed in the subject. In some embodiments, the improvement in the Overall Scleroderma Disease Activity Score is measured using the Scleroderma Disease Activity Instrument developed by the Scleroderma Clinical Trials Consortium (see, for example, Example 6B).

In some embodiments, an improvement in the scleroderma disease associated damage score is measured or assessed in the subject. In some embodiments, an improvement of at least 5% (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) in the scleroderma disease associated damage in the subject. In some embodiments, the improvement in the scleroderma disease associated damage score is measured using the Systemic Sclerosis Damage Activity Assessment developed by the Scleroderma Clinical Trials Consortium (see, for example, Example 6A).

In some embodiments, the subject has Raynaud's syndrome. In some embodiments, the Raynaud's syndrome is also treated.

In some embodiments, the Raynaud's syndrome is secondary Raynaud's syndrome. In some embodiments, the subject has lupus (e.g., systemic lupus erythematosus (SLE)), scleroderma, scleroderma with interstitial lung disease, rheumatoid arthritis, atherosclerosis, cryoglobulinemia, polycythemia, dermatomyositis, polymyositis, Sjögren's syndrome, or any combination thereof. In some embodiments, the subject has scleroderma. In some embodiments, the subject has scleroderma and the Raynaud's syndrome is secondary Raynaud's syndrome.

The combination of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is understood to improve the underlying pathological processes associated with, e.g., scleroderma and Raynaud's syndrome (e.g., secondary Raynaud's syndrome). For example, the treating comprises dilating arterioles, dilating venules, increasing production of nitrous oxide, reducing norepinephrine, improving endothelial function, inhibiting calcitonin gene-related neuropeptide (CGRP), reducing inflammation, or any combination thereof in the subject.

In some embodiments, before administering the dual N-type and L-type selective calcium blocker or the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject, the subject is diagnosed with scleroderma. In some embodiments, before administering the dual N-type and L-type selective calcium blocker or the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject, the subject is diagnosed with Raynaud's syndrome (e.g., secondary Raynaud's syndrome). In some embodiments, before administering the dual N-type and L-type selective calcium blocker or the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject, the subject is diagnosed with Raynaud's syndrome (e.g., secondary Raynaud's syndrome) and scleroderma.

In some embodiments, the subject also has interstitial lung disease. In some embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) the interstitial lung disease is treated. In some embodiments, the method further comprises administering an agent selected from the group consisting of: a calcineurin inhibitor, cyclophosphamide, nintedanib, methotrexate, mycophenolate, a glucocorticoid (e.g., prednisone, dexamethasone, and hydrocortisone), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), D-penicillamine, a diuretic, omeprazole, bosentan, epoprostenol, enalapril, Lisinopril, captopril, or any combination thereof. For example, the method further comprises administering nintedanib. In some embodiments, the method further comprises administering a calcineurin inhibitor, a non-steroidal anti-inflammatory drug, or both. In some embodiments, treating interstitial lung disease in the subject comprises increasing Forced Vital Capacity (FVC), increasing percent of predicted value, increasing diffusing capacity of the lung for carbon monoxide (DLCO), increasing total lung capacity (TLC) or any combination thereof. For further information, see Caron, M. et al; Eur. Resp. Review; 2018 27: 170102 which is incorporated by reference herein in its entirety.

In some embodiments, the treating comprises improving lung function in the subject. In some embodiments, improving lung function in the subject comprises increasing blood oxygen saturation. In some embodiments, increasing blood oxygen saturation comprises increasing one measurement or an average of a plurality of measurements of blood oxygen saturation by at least about 1% (e.g., at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 8%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, or at least about 40%) after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to one measurement or an average of a plurality of measurements of blood oxygen saturation taken before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, when a plurality of measurements is taken before and after administration, they are taken over the same period of time (e.g., the same number of days).

Some embodiments provide a method of treating skin ulcerations in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, the subject has skin ulcerations. In some embodiments, the skin ulcerations are digital ulcerations. In some embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)), the number and/or severity of the skin ulcerations (e.g., digital ulcerations) is reduced. In some embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)), one or more skin ulcerations (e.g., digital ulcerations) in the subject exhibits healing. In some embodiments, the subject exhibits an improvement in skin ulcer (e.g., digital ulcer) severity after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the improvement comprises a reduction in a score provided by the visual analog scale (VAS). In some embodiments, one score or an average of a plurality of scores is reduced by at least about 0.25% (e.g., at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 8%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%) after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to one score or an average of a plurality of scores taken before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, when a plurality of scores are obtained before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor, at least one (e.g., at least two, at least three, at least 5, at least 10, or at least 20) digital ulcers fully heal. Further information on the measurement of digital ulcer severity using VAS is in the Examples.

In some embodiments, the method further comprises administering vitamin C and/or vitamin E to the subject.

In some embodiments, the treating comprises improving cardiac function in the subject. In some embodiments, improving cardiac function in the subject comprises reducing the frequency and/or severity of cardiac arrhythmias; reducing sympathomimetic increases in papillary muscle-developed tension (PMDT); reducing myocardial interstitial norepinephrine level; decreasing aortic pressure; increased aortic, vertebral, and/or coronary blood flow; reducing myocardial oxygen consumption; reducing blood pressure; atrial remodeling; or any combination thereof.

In some embodiments, the treating comprises alleviating one or more symptoms associated with scleroderma in the subject. In some embodiments, the treating comprises alleviating one or more symptoms associated with Raynaud's syndrome (e.g., secondary Raynaud's syndrome) in the subject. In this context, alleviating one or more symptoms associated with the disease or disorder can, for example, comprise reducing the severity, duration, and/or frequency of the symptoms when compared to (1) the severity, duration, and/or frequency of the one or more symptoms in the subject before start of the treatment (e.g., before administration of the one or more therapeutic agents, and wherein the severity, duration, and/or frequency of the one or more symptoms before administration of the one or more therapeutic agents can, for example, be evaluated by a single measurement or assessment, or an average of a plurality of measurements or assessments taken, e.g., over the course of a 2 week period, a 7 day period, a 6 day period, a 5 day period, a 4 day period, a 3 day period, a 2 day period, or a 1 day period (e.g., a 7 day period)), wherein, for example, the reduction in severity, duration, and/or frequency of the symptoms is measured about 1 hour after treatment (e.g., after about 2 hours, 4 hours, 6 hours, 8 hours, 16 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 1.5 weeks, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, or 1 year of treatment); (2) the severity, duration, and/or frequency of the one or more symptoms experienced by a subject after the subject was administered a placebo; and/or (3) the severity, duration, and/or frequency of the one or more symptoms experienced by a subject after the subject was administered an alternative treatment such as a non-N selective calcium channel blocker alone, a combination of a non-N selective calcium channel blocker and a phosphodiesterase type 5 inhibitor, or a phosphodiesterase type 5 inhibitor alone. In some embodiments, the reduction in severity, duration, and/or frequency of the symptoms is greatest within 2 days (e.g., within 1.5 days, within 1 day, within 20 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 2 hours, or within 1 hour after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor))). In some embodiments, the reduction in severity, duration, and/or frequency of the symptoms is greatest within 8 hours after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor.

In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of the one or more symptoms of scleroderma and/or Raynaud's syndrome than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the secondary Raynaud's syndrome. In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of the one or more symptoms of scleroderma and/or Raynaud's syndrome than when administered a therapeutically effective amount of a phosphodiesterase type 5 inhibitor alone.

In some embodiments, the treating comprises reducing the frequency of one or more symptoms associated with Raynaud's syndrome (e.g., secondary Raynaud's syndrome) in the subject.

In some embodiments, the treating comprises reducing the duration of one or more symptoms associated with secondary Raynaud's syndrome in the subject.

In some embodiments, the treating comprises reducing the severity of one or more symptoms associated with secondary Raynaud's syndrome in the subject.

In another aspect, disclosed herein is a method of reducing the frequency of one or more symptoms associated with scleroderma in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, a dual N-type and L-type selective calcium blocker and a phosphodiesterase type 5 inhibitor are administered to the subject. In some embodiments, a dual N-type and L-type selective calcium blocker is administered to the subject. In some embodiments, a phosphodiesterase type 5 inhibitor is administered to the subject. In some embodiments, reducing the frequency of one or more symptoms associated with scleroderma comprises measuring a reduction in the average frequency (e.g., average daily frequency) of the one or more symptoms measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to the average frequency (e.g., average daily frequency) of the one or more symptoms measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) taken over the same time period (e.g., 7 days). In some embodiments, the frequency of the one or more symptoms associated with scleroderma is reduced by at least 5%, for example, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% (e.g., at least 25%; e.g., at least 40%; e.g., at least 45%). In some embodiments, the frequency of one or more symptoms associated with scleroderma in the subject is reduced by at least 25%. In some embodiments, the subject experiences no symptoms (e.g., no observable or reported symptoms) after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)).

Some embodiments provide a method of reducing the duration of one or more symptoms associated with scleroderma in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In another aspect, disclosed herein is a method of reducing the duration of one or more symptoms associated with scleroderma in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

In some embodiments, a dual N-type and L-type selective calcium blocker and a phosphodiesterase type 5 inhibitor are administered to the subject. In some embodiments, a dual N-type and L-type selective calcium blocker is administered to the subject. In some embodiments, a phosphodiesterase type 5 inhibitor is administered to the subject. In some embodiments, reducing the duration of one or more symptoms associated with scleroderma comprises reducing the collective duration of the one or more symptoms of scleroderma measured over a timespan (i.e., duration of time) divided by the number of occurrences of the one or more symptoms that occur during the timespan after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to the collective duration of the one or more symptoms of scleroderma divided by the number of occurrences of the one or more symptoms over the same timespan before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the timespan is from about 1 day to about 1 month, for example, from about 1 day to about 3 weeks, from about 1 day to about 2 weeks, from about 1 day to about 10 days, from about 1 day to about 7 days, from about 4 days to about 10 days, from about 5 days to about 9 days, from about 6 days to about 8 days, or about 7 days. In some embodiments, the duration of the one or more symptoms is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In some embodiments, the duration of the one or more symptoms associated with scleroderma in the subject is reduced by at least 20%.

In some embodiments, the treating comprises reducing the severity of one or more symptoms associated with scleroderma in the subject. In some embodiments, reducing the severity of the one or more symptoms associated with scleroderma comprises measuring a reduction in the visual analog scale (VAS) 0-10 cm. In some embodiments, reducing the severity of the one or more symptoms associated with scleroderma comprises measuring a reduction in a score provided by the visual analog scale. In some embodiments, the reduction in the score provided by the visual analog scale comprises a reduction in a single score or the average of a plurality of scores measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to a single score or the average of a plurality of scores measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, when a plurality of scores is obtained before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, the score is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In some embodiments, the score is reduced by at least 20%.

In some embodiments, the subject has lupus, scleroderma, scleroderma with interstitial lung disease, rheumatoid arthritis, atherosclerosis, cryoglobulinemia, polycythemia, dermatomyositis, polymyositis, Sjögren's syndrome, or any combination thereof. In some embodiments, the subject has scleroderma. In some embodiments, the Raynaud's syndrome is secondary Raynaud's syndrome. In some embodiments, the subject has scleroderma and the Raynaud's syndrome is secondary Raynaud's syndrome.

In some embodiments, the symptoms are selected from the group consisting of: pain, anemia, fatigue, change in coloration of the skin, cyanosis, reperfusion, deoxygenation of the blood, digital ulcerations, reduced temperature in one or more parts of the body, changes in the endothelium of a blood vessel, swelling, impaired vision, or any combination thereof. In some embodiments, the symptom is pain.

In some embodiments, the method comprises reducing pain or discomfort caused by a reduction of body temperature in a subject, wherein the reduction of body temperature in the subject is caused by an exposure of the subject to air having a temperature of less than 25° C.

In some embodiments, the reduction of body temperature in the subject is caused by an exposure of the subject to air having a temperature of less than 20° C., for example, less than 20° C., less than 15° C., less than 10° C., less than 5° C., less than 0° C., less than −5° C., less than −10° C., or less than −5° C. In some embodiments, the reduction of body temperature in the subject is caused by an exposure of the subject to air having a temperature of less than 10° C. In some embodiments, the pain or discomfort that is reduced occurs during the exposure of the subject to air having a temperature of less than 25° C.

In some embodiments, the reduction of body temperature in the subject is followed by a restoration to the normal body temperature in the subject, and the pain or discomfort that is reduced occurs after restoration to the normal body temperature in the subject.

In some embodiments, the reduction of body temperature in the subject comprises reduction in the temperature of a region of the body of the subject. In some embodiments, the reduction of body temperature in the subject comprises a reduction in the temperature of a finger of the subject. In some embodiments, the reduction of body temperature in the subject comprises a reduction in the temperature of a hand of the subject. In some embodiments, the reduction of body temperature in the subject comprises a reduction in the temperature of a foot of the subject.

In some embodiments, the method comprises reducing susceptibility of a subject to cold-induced pain or discomfort.

In some embodiments, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 25° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 25° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 20° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 20° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 15° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 15° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 10° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 10° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 5° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 5° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than 0° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than 0° C. For example, the subject experiences a lesser degree of the pain or discomfort upon exposure to air having a temperature of less than −10° C. than as compared to a subject that is not administered the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and is exposed to air having a temperature of less than −10° C.

In some embodiments, vasoconstriction in the subject is reduced after administering the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) to the subject. In some embodiments, the method comprises measuring a reduction in vasoconstriction in the subject after administering the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) to the subject. In certain embodiments, the vasoconstriction comprises vasoconstriction of a body part, and the temperature of the vasoconstricted body part is lower than the subject's body temperature (e.g., the subject's body temperature at homeostasis).

In some embodiments, the method comprises reducing a sensation of burning pain, paresthesia, dysesthesia, hypoesthesia, or hyperesthesia (e.g., burning pain) in a subject having scleroderma, comprising administering a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor. A sensation of burning pain can be measured using one or more of the following: the Galer neuropathic pain scale, the ID pain Scale, NPQ, PainDETECT, LANS S, DN4 scales, and/or the Standardized Evaluation of Pain (StEP) tool. See, for example, Cruccu G, Truini A. Tools for assessing neuropathic pain. PLoS Med. 2009; 6(4):e1000045. doi:10.1371/journal.pmed.1000045, which is incorporated by reference herein in its entirety.

In some embodiments, the method comprises reducing the number and/or severity of digital ulcerations in a subject having secondary Raynaud's disease, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor.

In some embodiments, the method further comprises administering vitamin C and/or vitamin E to the subject.

In another aspect, disclosed herein is a method of treating endothelial dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel exhibits at least a 2-fold selectivity (e.g., at least a 4-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 80-fold, 100-fold, 130-fold, 150-fold, or 200-fold selectivity) for the N-type calcium channel over an L-type calcium channel. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel exhibits at least a 50-fold selectivity for the N-type calcium channel over an L-type calcium channel. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel exhibits a 50-fold to 100-fold selectivity for the N-type calcium channel over an L-type calcium channel.

In some embodiments, the dual N-type and L-type selective calcium blocker is selected from the group consisting of: cilnidipine, Z-160, CNV2197944, or pharmaceutically acceptable salts thereof. In some embodiments, the dual N-type and L-type selective calcium blocker is cilnidipine or a pharmaceutically acceptable salt thereof.

In some embodiments, the phosphodiesterase type 5 inhibitor is selected from sildenafil, tadalafil, or pharmaceutically acceptable salts thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is tadalafil or a pharmaceutically acceptable salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil or a pharmaceutically acceptable salt thereof.

In some embodiments, the amount of the dual N-type and L-type selective calcium blocker used in the method is less (e.g., at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, or at least 95% less) than the therapeutically effective amount of the dual N-type and L-type selective calcium blocker useful to treat scleroderma in a subject when administered alone.

In some embodiments, the amount of the phosphodiesterase type 5 inhibitor used in the method is less (e.g., at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, or at least 95% less) than the therapeutically effective amount of the phosphodiesterase type 5 inhibitor to treat scleroderma in a subject when administered alone.

In some embodiments, the subject experiences less side effects than a therapeutically effective amount of a non-N-selective calcium channel blocker useful to treat the scleroderma. In some embodiments, the side effects are selected from the group consisting of: constipation, nausea, headache, fatigue, rash, edema, pulmonary edema, drowsiness, dizziness, muscle weakness, muscle cramps, abnormal heartbeat, liver dysfunction, overgrowth of oral gums, flushing, low blood pressure, gastroesophageal reflux, bradycardia, tachycardia, QT interval prolongation, increased appetite, tenderness or bleeding of the gums, sexual dysfunction, abdominal pain, fainting, shortness of breath, altered taste, asthenia, muscle cramps, and itching.

In some embodiments of the methods disclosed herein, the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) are administered orally, parenterally, transdermally, intranasally, sublingually, neuraxially, or ocularly. In some embodiments, the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) are administered orally.

In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered separately, sequentially, or simultaneously. In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered separately. In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered sequentially. In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered simultaneously. In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered simultaneously as a fixed dosage form.

In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is less frequent than the frequency of administering either the dual N-type and L-type selective calcium blocker or the phosphodiesterase type 5 inhibitor alone useful to treat the scleroderma.

In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is separated by at least about 1 hour (e.g., at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 15 hours, at least about 20 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 72 hours, at least about 4 days, at least about 5 days, at least about 3 days, at least about 5 days, at least about 1 week). In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is separated by at least about 24 hours. In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is separated by at least about 48 hours. In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is separated by at least about 72 hours. In some embodiments, each administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor is separated by at least about 1 week.

In some embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)), the subject experiences gastrointestinal symptoms that are ameliorated by the consumption of food prior to administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the subject consumes food up to about 6 hours before administering the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). For example, the subject consumes food up to about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 1 minute, about 30 seconds, or about 5 seconds before administering the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). For example, the subject consumes food concurrently with administering the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)).

In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of adverse events than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the scleroderma. In some embodiments, the adverse events are one or more events selected from the group consisting of: tachycardia, headaches, flushing, increased heart rate, flushing, decreased renal blood flow, myalgia, pain (e.g., chest pain), heart palpitation, and/or pedal enema. In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of tachycardia, headaches, flushing, increased heart rate, flushing, decreased renal blood flow, myalgia, pain (e.g., chest pain), heart palpitation, and/or pedal enema than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the scleroderma. In some embodiments, the subject experiences less frequent, less severe, and/or shorter episodes of pain (e.g., chest pain) than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the scleroderma.

In some embodiments, the non-N-selective calcium channel blocker is a dihydropyridine. In some other embodiments, the non-N-selective calcium channel blocker is not a dihydropyridine. In some embodiments, the non-N-selective calcium channel blocker is selected from the group consisting of: nifedipine, nicardipine, amlodipine, Z-944, nimodipine, verapamil, diltiazem, felodipine, isradipine, nisoldipine, and nitrendipine.

It is understood that dual N-type and L-type calcium channel blocker selective for the N-type calcium channels may decrease the blood pressure of subjects that are hypertensive. As such, it may be beneficial to administer an agent that increases blood pressure in combination with the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; or the dual N-type and L-type selective calcium blocker (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments of the methods disclosed herein, the method further comprises administering to the subject a therapeutically effective amount of an agent that increases blood pressure. In certain embodiments, the agent that increases blood pressure is selected from the group consisting of: midodrine, cortisone, prednisone, trimipramine, venlafaxine, anabolic steroids, antidepressants, anti-obesity drugs, CETP inhibitors, herbal preparations, immunosuppressants, mineralocorticoids, NSAIDS/coxibs, serotonergics, stimulants, sulfonylureas, and sympathomimetic amines. In certain embodiments, the blood pressure of the subject before and after administration of the dual N-type and L-type selective calcium blocker, the phosphodiesterase type 5 inhibitor, and the agent that increases blood pressure is substantially the same.

In some embodiments, the treating comprises reducing pulmonary hypertension in the subject.

In some embodiments, the subject is also diagnosed with hypertension; and wherein after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; or the dual N-type and L-type selective calcium blocker (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) to the subject, the blood pressure (e.g., systolic blood pressure) of the subject is reduced. In some embodiments, the subject was not diagnosed with hypertension; and wherein after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject, the blood pressure (e.g., the systolic blood pressure) of the subject is not reduced. Without wishing to be bound by theory, it is believed that when the subject has hypertension, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel reduces the blood pressure of the subject; however, when the subject does not have hypertension (i.e., the subject is normotensive), the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel does not reduce the blood pressure of the subject.

In some embodiments, the systolic blood pressure of the subject is reduced by greater than about 1 mm Hg (e.g., greater than about 2 mm Hg, greater than about 5 mm Hg, greater than about 10 mm Hg, greater than about 15 mm Hg, greater than about 20 mm Hg, greater than about 30 mm Hg, or greater than about 40 mm Hg).

In some embodiments, the therapeutically effective amount of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor decreases the blood pressure of the subject to a lesser degree than a therapeutically effective amount of a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the secondary Raynaud's syndrome. In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor decreases the blood pressure of the subject at least 5% less than a therapeutically effective amount of a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor. For example, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor decreases the blood pressure of the subject at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, at least 75% less, at least 80% less, at least 85% less, at least 90% less, or at least 95% less, than a therapeutically effective amount of a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor.

In certain embodiments, the subject has scleroderma with interstitial lung disease. In some embodiments, the method further comprises administering an agent selected from the group consisting of: a calcineurin inhibitor, cyclophosphamide, nintedanib, methotrexate, mycophenolate, a glucocorticoid (e.g., prednisone, dexamethasone, and hydrocortisone), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), D-penicillamine, a diuretic, omeprazole, bosentan, epoprostenol, enalapril, Lisinopril, captopril, or any combination thereof. For example, the method further comprises administering nintedanib. In some embodiments, the method further comprises administering a calcineurin inhibitor, a non-steroidal anti-inflammatory drug, or both. In some embodiments, the calcineurin inhibitor is a cyclosporine. In some embodiments, the non-steroidal anti-inflammatory drug is aspirin.

In certain embodiments, the subject has lupus (e.g., systemic lupus erythematosus (SLE)). In some embodiments, the method further comprises administering an agent selected from the group consisting of: an antimalarial drug (e.g., hydroxychloroquine), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), belimumab, a corticosteroid (e.g., prednisone or prednisolone), an immunosuppressant (e.g., azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil), or any combination thereof.

In certain embodiments, the subject has rheumatoid arthritis. In some embodiments, the method further comprises administering an agent selected from the group consisting of: disease-modifying anti-rheumatic drugs (e.g., methotrexate or sulfasalazine), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), a corticosteroid (e.g., prednisone or prednisolone), a biologic (e.g., anakinra or tocilizumab), or any combination thereof.

In certain embodiments, the subject has Sjögren's syndrome. In some embodiments, the method further comprises administering an agent selected from the group consisting of: Plaquenil, an antimalarial drug (e.g., hydroxychloroquine), evoxac, cevimeline, infliximab, or any combination thereof.

In certain embodiments, the subject has idiopathic pulmonary fibrosis. In some embodiments, the method further comprises administering an agent selected from the group consisting of: nintedanib, pirfenidone, or any combination thereof.

In certain embodiments, the subject has atherosclerosis. In some of these embodiments, after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; or the dual N-type and L-type selective calcium blocker (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)), the atherosclerosis is treated. In some embodiments, treating the atherosclerosis comprises reducing the thickness and/or mass of a plaque in an artery of the subject.

In some embodiments, the method further comprises selecting a subject identified or diagnosed as having reduced bone density for the treatment. In some embodiments, the subject identified or diagnosed as having reduced bone density has osteoporosis. In some embodiments, the subject is female.

In some embodiments, the method further comprises selecting a subject identified or diagnosed as having reduced renal function for the treatment. In some embodiments, the renal function of the patient is not reduced after treatment.

In some embodiments, a reduction in the Raynaud's severity scale (RSS) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the reduction is a reduction in one measurement or the average of a plurality of measurements taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one measurement or the average of a plurality of measurements taken before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, when a plurality of measurements is taken before and after administration, they are taken over the same period of time (e.g., the same number of days). For example, a reduction of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). Information on the Raynaud's severity scale can be found at Wigley F M, Wise R A, Seibold J R et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994; 120:199-206, which is incorporated by reference herein in its entirety.

In some embodiments, an improvement (e.g., reduction) in the Raynaud's condition scale (RCS) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, an improvement (e.g., reduction) in the Raynaud's condition scale (RCS) is a reduction in one score or the average (e.g., daily average) of a plurality of scores measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to one score or the average (e.g., daily average) of a plurality of scores measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, when a plurality of scores is measured before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, the period of time is 2 weeks, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day (e.g., 7 day). In some embodiments, a daily average of a plurality of scores is the sum of the plurality of scores divided by the number of days during which the scores were obtained. In some embodiments, the reduction in the Raynaud's condition scale is at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 45%, 50%, 70%, 90%, 95%) after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, the reduction in the Raynaud's condition scale is at least about 25% after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, the reduction in the Raynaud's condition scale is at least about 27% after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, the reduction in the Raynaud's condition scale is at least about 45% after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. Information on the Raynaud's severity scale can be found in the Examples and at Black C M, Halkier-Sorensen L, Belch J J et al. Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 1998; 37:952-60, which is incorporated by reference herein in its entirety.

In some embodiments, a reduction in the average pain score (e.g., average weekly pain score) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). For example, a reduction of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%, about 14%, or about 53%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, a reduction in the average pain score is about 10% in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, a reduction in the pain score is a reduction in one score or the average of a plurality of scores measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to one score the average of a plurality of scores measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, when a plurality of scores are obtained before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, the time period is 2 weeks, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day (e.g., 7 day). In some embodiments, the average pain score is a pain score in the scleroderma health assessment questionnaire (SHAQ). Various scales used to measure pain include the Galer neuropathic pain scale, the Likert pain score, the ID pain Scale, NPQ, PainDETECT, LANS S, DN4 scales, and/or the Standardized Evaluation of Pain (StEP) tool. See, for example, the Examples or Cruccu G, Truini A. Tools for assessing neuropathic pain. PLoS Med. 2009; 6(4):e1000045. doi:10.1371/journal.pmed.1000045, which is incorporated by reference herein in its entirety.

In some embodiments, an increase in the temperature of a body part is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). For example, an increase of at least about 0.5% (e.g., at least about 1%, 2%, 3%, 4%, 5%, 8%, 10%, 12%, 15%, or 20%) in the temperature of the body part is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the increase in the temperature of the body part is an increase in one measurement or the average of a plurality of measurements taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one measurement or the average of a plurality of measurements taken before administration. In some embodiments, when a plurality of measurements is taken before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, the increase in temperature is measured by thermography. In some embodiments, the body part is a finger (e.g., an index finger, middle finger, or ring finger (e.g., an index finger)).

In some embodiments, an improvement in the SF-12 index of functional wellbeing is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the improvement is an improvement in one score or the average of a plurality of scores taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one score or the average of a plurality of scores taken before administration. In some embodiments, when a plurality of scores are taken before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, an improvement of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). Information on the SF-12 index of functional wellbeing can be found at https://www.physio-pedia.com/12-Item_Short_Form_Survey_(SF-12), which is incorporated by reference herein in its entirety.

In some embodiments, an improvement in the Scleroderma Health Assessment Questionnaire (SHAQ®) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, an improvement in the Scleroderma Health Assessment Questionnaire comprises an improvement in at least one (e.g., 1 to 8, 2 to 6, 2 to 4, 4 to 6, 6 to 8, 1, 2, 3, 4, 5, 6, 7, or 8) of 1) dressing and grooming, 2) arising, 3) eating, 4) walking, 5) hygiene, 6) reach, 7) grip, and 8) common daily activities in the subject. Information on the Scleroderma Health Assessment Questionnaire (SHAQ®) can be found in the Examples and at Steen V D, Medsger T A Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997 November; 40(11):1984-91 and Poole J L, Steen V D. The use of the Health Assessment Questionnaire (HAQ) to determine physical disability in systemic sclerosis. Arthritis Care Res. 1991 March; 4(1):27-31, each of which is incorporated by reference herein in its entirety.

In some embodiments, an improvement (i.e., an increase) in the Reactive Hyperemia Index (LnRHI) as measured by Endo PAT is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the improvement is an improvement in one score or the average of a plurality of scores taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one score or the average of a plurality of scores taken before administration. In some embodiments, when a plurality of scores are taken before and after administration, they are taken over the same period of time (e.g., the same number of days). For example, an increase of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, an improvement in the Reactive Hyperemia Index (LnRHI) is an improvement in the average of a plurality of values measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to the average of a plurality of values measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) taken over the same time period. In some embodiments, the time period is 2 weeks, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day (e.g., 7 days). In some embodiments, the subject exhibits a reactive hyperemia index of less than 0.51 before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and a reactive hyperemia index of at least 0.51 (e.g., 0.51 to 0.7; or at least 0.71) after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, the subject exhibits a reactive hyperemia index of 0.51 to 0.7 before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) and a reactive hyperemia index of at least 0.71 after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, an improvement in endothelial function as measured by Endo PAT is measured in the subject. In some embodiments, the improvement in endothelial function as measured by Endo PAT is an improvement in one measurement or an average of plurality of measurements taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one measurement or an average of plurality of measurements taken before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. For example, an improvement of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, nitric oxide levels in the endothelium are increased after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) as measured by Endo PAT in the subject. In some embodiments, the increase in nitric oxide levels in the endothelium as measured by Endo PAT is an increase in one measurement or an average of plurality of measurements taken after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor relative to one measurement or an average of plurality of measurements taken before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. For example, an increase of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor Information on the Reactive Hyperemia Index can be found at https://study.com/academy/lesson/reactive-hyperemia-definition-test.html, which is incorporated by reference herein in its entirety. Information on Endo PAT can be found at https://www.aimil.com/products/endopat#:˜:text=The%20EndoPAT%E2%84%A2%20is%20the%20only%20FDA%20approved%20diagnostic,in%20peripheral%20arterioles%20in%20response%20to%20oxidative%20stress., which is incorporated by reference herein in its entirety.

In some embodiments, an improvement (i.e., a decrease) in the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire is observed in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, a decrease in the UCLA SCTC GIT 2.0 questionnaire is a decrease in one score or the average of a plurality of total scores measured after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to one score or the average of a plurality of total scores measured before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). In some embodiments, when a plurality of scores is taken before and after administration, they are taken over the same period of time (e.g., the same number of days). In some embodiments, the time period is 2 weeks, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day (e.g., 7 day). In some embodiments, a decrease of at least about 2% (e.g., at least about 4%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 70%, 90%, 95%) is measured in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). More information on the UCLA SCTC GIT 2.0 questionnaire, including how the total score is obtained, can be found in the Examples section.

In some embodiments, an improvement in an answer to at least one question (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 questions) in the Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) is observed in the subject after administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) relative to before administration of the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor. In some embodiments, the improvement in the answer to a question is an improvement of at least one degree. An improvement of a degree is defined as an improvement from “very much/a lot” to “quite a bit”, “quite a bit” to “somewhat”, “somewhat” to “a little bit”, or “a little bit” to “not at all”. In some embodiments, the improvement in the answer to a question is an improvement of two degrees, three degrees, or four degrees. More information on the Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP), can be found in the Examples section and Pauling et. al. American College of Rheumatology Convergence 2021, Abstract Number 401 (https://acrabstracts.org/abstract/item-reduction-for-the-assessment-of-systemic-sclerosis-associated-raynauds-phenomenon-asrap-questionnaire-using-data-from-the-international-multicentre-asrap- validation-study/), which is incorporated by reference herein in its entirety.

Some embodiments provide a method of treating calcinosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

Some embodiments provide a method of treating calcinosis in a subject having scleroderma in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

In some embodiments, the calcinosis is identified or diagnosed in a hand (e.g., the right hand or the left hand) of the subject. In some embodiments, the calcinosis is identified or diagnosed in a finger (e.g., pollicus, phalange 2, phalange 3, phalange 4, or phalange 5) of the subject. In some embodiments, the calcinosis is identified or diagnosed in an arm (e.g., the right arm or the left arm) of the subject. In some embodiments, the calcinosis is identified or diagnosed in the neck of the subject. In some embodiments, the calcinosis is identified or diagnosed in the head (e.g., the brain) of the subject. In some embodiments, the calcinosis is identified or diagnosed in the torso (e.g., the chest, the back, or the abdomen) of the subject. In some embodiments, the calcinosis is identified or diagnosed in the buttocks of the subject. In some embodiments, the calcinosis is identified or diagnosed in a leg (e.g., the right leg or the left leg) of the subject. In some embodiments, the calcinosis is identified or diagnosed in a foot (e.g., the right foot or the left foot) of the subject. In some embodiments, the calcinosis is identified or diagnosed in or underneath the skin of the subject. For example, the calcinosis is calcinosis cutis. In some embodiments, the calcinosis is identified or diagnosed in the adipose tissue of the subject. In some embodiments, the calcinosis is identified or diagnosed in the muscle of the subject. In some embodiments, the calcinosis is identified or diagnosed in an organ of the subject.

In some embodiments, the subject has a calcium deposit. In some embodiments, treating the subject comprises reducing the rate of weight increase of the calcium deposit in the subject. In some embodiments, treating the subject comprises reducing the size, volume, and/or weight of the calcium deposit in the subject. In some embodiments, treating the subject comprises reducing the size (e.g., diameter) of the calcium deposit in the subject. In some embodiments, treating the subject comprises reducing the volume of the calcium deposit in the subject. In some embodiments, after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject, the volume of the calcium deposit is decreased by at least 1% (e.g., at least 2%, 4%, 6%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%) 1 month after start of the treatment or after the first administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel. In some embodiments, treating the subject comprises reducing the weight of the calcium deposit in the subject. In some embodiments, after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject, the weight of the calcium deposit is decreased by at least 1% (e.g., at least 2%, 4%, 6%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%) 1 month after start of the treatment or after the first administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

In some embodiments, the treating comprises alleviating one or more symptoms associated with calcinosis in the subject. In this context, alleviating one or more symptoms associated with calcinosis can, for example, comprise reducing the severity, duration, and/or frequency of the symptoms when compared to (1) the severity, duration, and/or frequency of the one or more symptoms in the subject before start of the treatment (e.g., before administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, and wherein the severity, duration, and/or frequency of the one or more symptoms before administration of the one or more therapeutic agents can, for example, be evaluated by a single measurement or assessment, or an average of a plurality of measurements or assessments taken, e.g., over the course of a 2 week period, a 7 day period, a 6 day period, a 5 day period, a 4 day period, a 3 day period, a 2 day period, or a 1 day period (e.g., a 7 day period)), wherein, for example, the reduction in severity, duration, and/or frequency of the symptoms is measured about 1 hour after treatment (e.g., after about 2 hours, 4 hours, 6 hours, 8 hours, 16 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 1.5 weeks, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, or 1 year of treatment); (2) the severity, duration, and/or frequency of the one or more symptoms experienced by a subject after the subject was administered a placebo; and/or (3) the severity, duration, and/or frequency of the one or more symptoms experienced by a subject after the subject was administered an alternative treatment such as a non-N selective calcium channel blocker. In some embodiments, the reduction in severity, duration, and/or frequency of the symptoms is greatest within 2 days (e.g., within 1.5 days, within 1 day, within 20 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 2 hours, or within 1 hour after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel. In some embodiments, the reduction in severity, duration, and/or frequency of the symptoms is greatest within 8 hours after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

In some embodiments, the calcinosis is dystrophic calcinosis. In some embodiments, the dystrophic calcinosis is identified or diagnosed in damaged and/or diseased tissue.

In some embodiments, the calcinosis is metastatic calcinosis. In some embodiments, the subject has elevated blood serum calcium and/or phosphate levels.

In some embodiments, the calcinosis is idiopathic calcinosis.

In some embodiments, the calcinosis is iatrogenic calcinosis.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel in the subject, a reduction in concentration of calcium (II) ions is measured in the tissue and/or a cell of the subject. In some embodiments, the tissue and/or cell is in a hand (e.g., the right hand or the left hand) of the subject. In some embodiments, the tissue and/or cell is in a finger (e.g., pollicus, phalange 2, phalange 3, phalange 4, or phalange 5) of the subject. In some embodiments, the tissue and/or cell is in an arm (e.g., the right arm or the left arm) of the subject. In some embodiments, the tissue and/or cell is in the neck of the subject. In some embodiments, the tissue and/or cell is in the head (e.g., the brain) of the subject. In some embodiments, the tissue and/or cell is in the torso (e.g., the chest, the back, or the abdomen) of the subject. In some embodiments, the tissue and/or cell is in the buttocks of the subject. In some embodiments, the tissue and/or cell is in a leg (e.g., the right leg or the left leg) of the subject. In some embodiments, the tissue and/or cell is in a foot (e.g., the right foot or the left foot) of the subject. In some embodiments, the tissue and/or cell is in or underneath the skin of the subject. In some embodiments, the tissue and/or cell is in the adipose tissue of the subject. In some embodiments, the tissue and/or cell is in the muscle of the subject. In some embodiments, the tissue and/or cell is in an organ of the subject.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel in the subject, intracellular calcium influx in tissue and/or macrophages is reduced. In some embodiments, the macrophages exhibit symptoms of calcinosis, are prone to exhibiting symptoms of calcinosis, or both. It is understood that the reduction in intracellular calcium levels can be attributed to inhibition of the TRPV-1 peripheral nociceptor ending.

Some embodiments provide is a method of reducing the frequency of one or more symptoms associated with calcinosis in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

Some embodiments provide is a method of reducing the severity of one or more symptoms associated with calcinosis in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

Some embodiments provide is a method of reducing the duration of one or more symptoms associated with calcinosis in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, symptoms associated with calcinosis include, but are not limited to, the presence of a calcium deposit in the subject, lesions, pruritis, ulcers, thickening of the skin, connective tissue disorder, kidney failure, tumorigenesis, cognitive impairment, or mood swings.

In another aspect, disclosed herein is a method of reducing the rate of weight increase of a calcium deposit in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, the rate of weight increase of the calcium deposit is reduced by at least 1% (e.g., at least 2%, 4%, 6%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%).

In another aspect, disclosed herein is a method of reducing the size, volume, and/or weight of a calcium deposit in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor.

In some embodiments, the calcium deposit is located in an extremity. In some embodiments, the calcium deposit is located in a hand (e.g., the right hand or the left hand) of the subject. In some embodiments, the calcium deposit is located in a finger (e.g., pollicus, phalange 2, phalange 3, phalange 4, or phalange 5) of the subject. In some embodiments, the calcium deposit is located in an arm (e.g., the right arm or the left arm) of the subject. In some embodiments, the calcium deposit is located in the neck of the subject. In some embodiments, the calcium deposit is located in the head (e.g., the brain) of the subject. In some embodiments, the calcium deposit is located in the torso (e.g., the chest, the back, or the abdomen) of the subject. In some embodiments, the calcium deposit is located in the buttocks of the subject. In some embodiments, the calcium deposit is located in a leg (e.g., the right leg or the left leg) of the subject. In some embodiments, the calcium deposit is located in a foot (e.g., the right foot or the left foot) of the subject. In some embodiments, the calcium deposit is located in or underneath the skin of the subject. In some embodiments, the calcium deposit is located in the adipose tissue of the subject. In some embodiments, the calcium deposit is located in the muscle of the subject. In some embodiments, the calcium deposit is located in an organ of the subject.

In some embodiments, the calcium deposit is located in an articulation of the subject. In some embodiments, the calcium deposit is located in a hip joint of the subject. In some embodiments, the calcium deposit is located in a shoulder joint of the subject. In some embodiments, the calcium deposit is located in an elbow joint of the subject. In some embodiments, the calcium deposit is located in a vertebral joint (e.g., a joint in the cervical spine, a joint in the thoracic spine, or a joint in the lumbar spine) of the subject. In some embodiments, the calcium deposit is located in a knee joint of the subject. In some embodiments, the calcium deposit is located in a wrist joint of the subject. In some embodiments, the calcium deposit is located in an ankle joint of the subject. In some embodiments, the calcium deposit is located in a sacroiliac joint of the subject.

In some embodiments, the calcium deposit is not located in an articulation of the subject. In some embodiments, the calcium deposit is not located in a hip joint of the subject. In some embodiments, the calcium deposit is not located in a shoulder joint of the subject. In some embodiments, the calcium deposit is not located in an elbow joint of the subject. In some embodiments, the calcium deposit is not located in a vertebral joint (e.g., a joint in the cervical spine, a joint in the thoracic spine, or a joint in the lumbar spine) of the subject. In some embodiments, the calcium deposit is not located in a knee joint of the subject. In some embodiments, the calcium deposit is not located in a wrist joint of the subject. In some embodiments, the calcium deposit is not located in an ankle joint of the subject.

In some embodiments the calcium deposit comprises calcium phosphate. In some embodiments, the calcium deposit comprises from about 1% to about 99% calcium phosphate. For example, from about 1% to about 25%, from about 25% to about 75%, from about 75% to about 99%, from about 2% to about 8%, from about 8% to about 16%, from about 16% to about 24%, from about 24% to about 32%, from about 32% to about 40%, from about 40% to about 48%, from about 48% to about 56%, from about 56% to about 64%, from about 64% to about 72%, from about 72% to about 80%, from about 80% to about 88%, or from about 88% to about 98% calcium phosphate. In some embodiments the calcium deposit comprises calcium hydroxyapatite. For example, from about 1% to about 25%, from about 25% to about 75%, from about 75% to about 99%, from about 2% to about 8%, from about 8% to about 16%, from about 16% to about 24%, from about 24% to about 32%, from about 32% to about 40%, from about 40% to about 48%, from about 48% to about 56%, from about 56% to about 64%, from about 64% to about 72%, from about 72% to about 80%, from about 80% to about 88%, or from about 88% to about 98% calcium hydroxyapatite.

In some embodiments, the subject is identified or diagnosed as having an autonomic system impairment. In some embodiments, the autonomic system impairment is a cardiac dysrhythmia. In some embodiments, the incidences of cardiac dysrhythmia in the subject are reduced after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel to the subject.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel autonomic function of the subject is improved; wherein the improvement of autonomic functioning in the subject is characterized by a lower reduction in systolic blood pressure in the upper arm (e.g., the portion of the arm between the elbow and shoulder, inclusive of the elbow and shoulder) of the subject when the subject is subjected to a tilt table test.

In some embodiments, the subject has (e.g., is identified or diagnosed as having) Raynaud's syndrome. In some embodiments, the Raynaud's syndrome is selected from the group consisting of: primary Raynaud's syndrome; secondary Raynaud's syndrome; Raynaud's syndrome of the nipple, nose, ear, penis, tongue, and/or any alar circulatory region. In some embodiments, the Raynaud's syndrome is primary Raynaud's syndrome. In some embodiments, the Raynaud's syndrome is secondary Raynaud's syndrome.

In some embodiments, after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel one or more symptoms of the Raynaud's syndrome are improved.

In some embodiments, the method comprises administering at least one additional therapeutic agent to the subject. The at least one additional therapeutic agent can be administered simultaneously, separately, sequentially, or in combination with the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)). Non-limiting examples of additional therapeutic agents include calcium channel blockers, sodium channel blockers (e.g., Nav 1.7 sodium channel blocker), agents that increase blood pressure, and therapeutic agents that relieve pain.

In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of: riociguat, amlodipine, nifedipine, nicardipine, conotoxins, cadmium, caroverine, gabapentin, levetiracetam, lamotrigine, NP078585, pregabalin, TROX-1, and ziconotide.

In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of: nifedipine, verapamil hydrochloride, diltiazem hydrochloride, cilnidipine, cimetidine, famotidine, nizatidine, ranitidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, and sucralfate.

In certain embodiments, the at least one additional therapeutic agent is selected from the group consisting of: oxycodone, tramadol, Dilaudid, OxyContin, Cymbalta, Fentanyl Transdermal System, acetaminophen/oxycodone, Roxicodone, Ultram, hydromorphone, Percocet, MS Contin, Butrans, morphine, methadone, buprenorphine, duloxetine, fentanyl, Duragesic, Endocet, Roxanol, Kadian, Roxicet, ConZip, Methadose, Oxyfast, Dazidox, Fentora, Irenka, Methadone Diskets, Oramorph SR, Roxicodone Intensol, Xtampza ER, Actiq, Belbuca, ETH-Oxydose, Infumorph, naloxone/pentazocine, Oxaydo, Oxydose, OxyIR, ziconotide, Abstral, Astramorph PF, Buprenex, Dolophine, Duramorph, Duramorph PF, Embeda, Lazanda, MorphaBond ER, morphine/naltrexone, Prialt, RMS, Roxanol-T, Sublimaze, Subsys, Talwin Nx, Magnacet, Nalocet, Narvox, Perloxx, Primlev, Xolox, and Prolate.

In some embodiments, the agent that increases blood pressure is selected from the group consisting of: midodrine, cortisone, prednisone, trimipramine, venlafaxine, anabolic steroids, antidepressants, anti-obesity drugs, CETP inhibitors, herbal preparations, immunosuppressants, mineralocorticoids, NSAIDS/coxibs, serotonergics, stimulants, sulfonylureas, and sympathomimetic amines.

In some embodiments, an antioxidant is not administered to the subject. In some embodiments, the anti-oxidant is selected from the group consisting of a hydralazine compound, a glutathione, vitamin C, cysteine, β-carotene, a ubiquinone, a ubiquinol-10, a tocopherol, coenzyme Q, or a mixture thereof.

In some embodiments, the occurrence of atrial fibrillation is decreased in the subject. It is understood that decreasing the occurrence of atrial fibrillation in the subject occurs by means of a decrease in autonomic dysfunction.

In another aspect, disclosed herein is a method of reducing atrial remodeling in a subject with atrial fibrillation and scleroderma, comprising administering a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or a phosphodiesterase type 5 inhibitor to the subject.

In another aspect, disclosed herein is a method of reducing atrial remodeling in a subject with atrial fibrillation and scleroderma, comprising administering a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor to the subject.

In some embodiments, the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered to the subject. In some embodiments, the dual N-type and L-type selective calcium blocker is administered to the subject. In some embodiments, the phosphodiesterase type 5 inhibitor is administered to the subject.

In some embodiments, the dual N-type and L-type selective calcium blocker is formulated to maintain the plasma level of the dual N-type and L-type selective calcium blocker in the subject at 10% or greater (e.g., 15% or greater, 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, 50% or greater, 55% or greater, 60% or greater, 65% or greater, 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, or 95% or greater) of the peak dual N-type and L-type selective calcium blocker plasma level for at least 6 hours (e.g., at least 8 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 36 hours, or at least 48 hours) after administration of the dual N-type and L-type selective calcium blocker. It is understood that the peak dual N-type and L-type selective calcium blocker plasma level is the highest plasma concentration of the dual N-type and L-type selective calcium blocker observed in the subject after administration of the dual N-type and L-type selective calcium blocker.

Some embodiments provide a method of treating secondary Raynaud's syndrome in a subject in need thereof, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining that the frequency of one or more symptoms associated with the secondary Raynaud's syndrome in the subject is reduced by at least 25%;
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating secondary Raynaud's syndrome in a subject in need thereof, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 30% in the Raynaud's difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating pain in a subject in need thereof having secondary Raynaud's syndrome, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 40% in the pain parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating a gastrointestinal disorder, gastrointestinal pain, or gastrointestinal dysfunction in a subject in need thereof having secondary Raynaud's syndrome, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 35% in the intestinal difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating a dyspnea in a subject in need thereof having secondary Raynaud's syndrome, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 25% in the breathing difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating finger ulcers in a subject in need thereof having secondary Raynaud's syndrome, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 15% in the burden of finger ulcers parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating secondary Raynaud's syndrome in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining that the frequency of one or more symptoms associated with the secondary Raynaud's syndrome in the subject is reduced by at least 25%;
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating secondary Raynaud's syndrome in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 30% in the Raynaud's difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating pain in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 40% in the pain parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating a gastrointestinal disorder, gastrointestinal pain, or gastrointestinal dysfunction in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 35% in the intestinal difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating a dyspnea in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 25% in the breathing difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating finger ulcers in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 15% in the burden of finger ulcers parameter of the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating secondary Raynaud's syndrome in a subject determined to have secondary Raynaud's syndrome and scleroderma, and determined to have a Raynaud's condition score (RCS) of 20 or greater, the method comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days;
- wherein the frequency of one or more symptoms associated with the secondary Raynaud's syndrome in the subject is reduced by at least 25%.

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 30% in the Raynaud's difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ).

Some embodiments provide a method of treating pain in a subject determined to have secondary Raynaud's syndrome and scleroderma, and determined to have a Raynaud's condition score (RCS) of 20 or greater, the method comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 40% in the pain parameter of the Scleroderma Health Assessment Questionnaire (SHAQ).

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 35% in the intestinal difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ).

Some embodiments provide a method of treating a dyspnea in a subject determined to have secondary Raynaud's syndrome and scleroderma, and determined to have a Raynaud's condition score (RCS) of 20 or greater, the method comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 25% in the breathing difficulty parameter of the Scleroderma Health Assessment Questionnaire (SHAQ).

Some embodiments provide a method of treating finger ulcers in a subject determined to have secondary Raynaud's syndrome and scleroderma, and determined to have a Raynaud's condition score (RCS) of 20 or greater, the method comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining a reduction of at least about 15% in the burden of finger ulcers parameter of the Scleroderma Health Assessment Questionnaire (SHAQ).

Some embodiments provide a method of treating scleroderma in a subject in need thereof, comprising:

- determining that the subject has secondary Raynaud's syndrome and scleroderma;
- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining an at least 50% decrease in the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating scleroderma in a subject determined to have secondary Raynaud's syndrome and scleroderma, comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days; and
- determining an at least 50% decrease in the Scleroderma Health Assessment Questionnaire (SHAQ);
- wherein the subject is identified as having a Raynaud's condition score (RCS) of 20 or greater.

Some embodiments provide a method of treating scleroderma in a subject determined to have secondary Raynaud's syndrome and scleroderma, and determined to have a Raynaud's condition score (RCS) of 20 or greater, the method comprising:

- orally administering about 10 mg or about 20 mg cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine and optionally about 5 mg of tadalafil or a pharmaceutically acceptable salt thereof on a free base basis of tadalafil to the subject once daily in the morning for at least five days;
- determining an at least 50% decrease in the Scleroderma Health Assessment Questionnaire (SHAQ).

In some embodiments, about 10 mg of cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine is administered to the subject.

In some embodiments, about 20 mg of cilnidipine or a pharmaceutically acceptable salt thereof on a free base basis of cilnidipine is administered to the subject.

In some embodiments, the tadalafil is administered to the subject. In some embodiments, the cilnidipine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof are administered as a fixed dosage form.

In some embodiments, the method comprises determining an at least 50% decrease (e.g., an at least 60% decrease) in the Scleroderma Health Assessment Questionnaire (SHAQ). In some embodiments, the method comprises determining an at least 50% decrease (e.g., an at least 60% decrease) in the overall disease severity scale in the Scleroderma Health Assessment Questionnaire (SHAQ).

In some embodiments, the method comprises determining that the frequency of one or more symptoms associated with the secondary Raynaud's syndrome in the subject is reduced by at least 40%.

Pharmaceutical Compositions and Formulations

In another aspect, disclosed herein is a pharmaceutical composition comprising a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.

In some embodiments, the composition comprises a phosphodiesterase type 5 (PDE-5) inhibitor.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

In some embodiments, the composition is in the form of a tablet or capsule.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel in the composition is about 5 mg to about 25 mg.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel in the composition is about 9 mg to about 21 mg.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel (e.g., cilnidipine) in the composition is about 10 mg.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel (e.g., cilnidipine) in the composition is about 20 mg.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel (e.g., cilnidipine) in the composition is about 30 mg.

In some embodiments, the amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel (e.g., cilnidipine) in the composition is about 33 mg.

In some embodiments, the amount of the phosphodiesterase type 5 inhibitor (e.g., tadalafil) in the composition is about 2 mg to about 8 mg.

In some embodiments, the amount of the phosphodiesterase type 5 inhibitor (e.g., tadalafil) in the composition is about 5 mg.

In some embodiments, the dual N-type and L-type selective calcium blocker is cilnidipine in an amount of about 33 mg and the phosphodiesterase type 5 inhibitor is tadalafil in an amount of about 5 mg. In some embodiments, the dual N-type and L-type selective calcium blocker is cilnidipine in an amount of about 30 mg and the phosphodiesterase type 5 inhibitor is tadalafil in an amount of about 5 mg. In some embodiments, the dual N-type and L-type selective calcium blocker is cilnidipine in an amount of about 20 mg and the phosphodiesterase type 5 inhibitor is tadalafil in an amount of about 5 mg. In some embodiments, the dual N-type and L-type selective calcium blocker is cilnidipine in an amount of about 10 mg and the phosphodiesterase type 5 inhibitor is tadalafil in an amount of about 5 mg.

In some embodiments, the pharmaceutical composition further comprises an agent that increases blood pressure.

In some embodiments, the pharmaceutical composition further comprises a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen).

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: a calcineurin inhibitor, cyclophosphamide, nintedanib, methotrexate, mycophenolate, a glucocorticoid (e.g., prednisone, dexamethasone, and hydrocortisone), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), D-penicillamine, a diuretic, omeprazole, bosentan, epoprostenol, enalapril, lisinopril, captopril, or any combination thereof. For example, the pharmaceutical composition further comprises administering nintedanib. In some embodiments, the pharmaceutical composition further comprises a calcineurin inhibitor, a non-steroidal anti-inflammatory drug, or both.

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: a calcineurin inhibitor, cyclophosphamide, nintedanib, methotrexate, mycophenolate, a glucocorticoid (e.g., prednisone, dexamethasone, and hydrocortisone), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), D-penicillamine, a diuretic, omeprazole, bosentan, epoprostenol, enalapril, Lisinopril, captopril, or any combination thereof. For example, the method further comprises administering nintedanib. In some embodiments, the pharmaceutical composition further comprises a calcineurin inhibitor, a non-steroidal anti-inflammatory drug, or both. In some embodiments, the calcineurin inhibitor is a cyclosporine. In some embodiments, the non-steroidal anti-inflammatory drug is aspirin.

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: an antimalarial drug (e.g., hydroxychloroquine), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), belimumab, a corticosteroid (e.g., prednisone or prednisolone), an immunosuppressant (e.g., azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil), or any combination thereof.

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: disease-modifying anti-rheumatic drugs (e.g., methotrexate or sulfasalazine), a non-steroidal anti-inflammatory drug (e.g., aspirin, ibuprofen, or naproxen), a corticosteroid (e.g., prednisone or prednisolone), a biologic (e.g., anakinra or tocilizumab), or any combination thereof.

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: plaquenil, an antimalarial drug (e.g., hydroxychloroquine), evoxac, cevimeline, infliximab, or any combination thereof.

In some embodiments, the pharmaceutical composition further comprises an agent selected from the group consisting of: nintedanib, pirfenidone, or any combination thereof.

In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, zicinotide, ralfinamide, CNV2197944, or pharmaceutically acceptable salts thereof. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, ralfinamide, CNV2197944, or pharmaceutically acceptable salts thereof. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, CNV2197944, or pharmaceutically acceptable salts thereof. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, or pharmaceutically acceptable salts thereof. In certain embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is a dihydropyridine N-type calcium channel blocker. In certain of these embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is cilnidipine or a pharmaceutically acceptable salt thereof. In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is CNV2197944.

In some embodiments, a combination of chemical entities (e.g., a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor) is administered as a pharmaceutical composition that includes the a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and a phosphodiesterase type 5 inhibitor, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^ndEdition (Pharmaceutical Press, London, U K. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, oral, parenteral, transdermal, intranasal, sublingual, neuraxial, or ocular (e.g., oral).

In some embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In some embodiments, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

In some embodiments, each administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor)) is separated by at least about 12 hours. For example, each administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or the phosphodiesterase type 5 inhibitor is separated by at least about 24 hours, at least about 30 hours, at least about 48 hours, at least about 60 hours, at least about 72 hours, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 9 days, at least about 12 days, or at least about 2 weeks. For example, each administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and/or the phosphodiesterase type 5 inhibitor is separated by about 24 hours.

In some embodiments, the period of administration of a compound described herein (e.g., the dual N-type and L-type selective calcium blocker and/or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor; the dual N-type and L-type selective calcium blocker; or the phosphodiesterase type 5 inhibitor (e.g., the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor))) is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

EXEMPLARY EMBODIMENTS

- Embodiment 1. A method of treating scleroderma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 2. The method of embodiment 1, wherein the scleroderma is limited scleroderma.
- Embodiment 3. The method of embodiment 1, wherein the scleroderma is diffuse scleroderma.
- Embodiment 4. The method of any one of embodiments 1-3, wherein the treating comprises reducing the frequency of one or more symptoms associated with scleroderma in the subject.
- Embodiment 5. The method of any one of embodiments 1-4, wherein the treating comprises reducing the severity of one or more symptoms associated with scleroderma in the subject.
- Embodiment 6. The method of any one of embodiments 1-5, wherein the treating comprises reducing the duration of one or more symptoms associated with scleroderma in the subject.
- Embodiment 7. A method of reducing the frequency, severity, or duration of one or more scleroderma symptoms in a subject, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 8. The method of any one of embodiments 4-7, wherein the symptoms are selected from the group consisting of: hardening and tightening of patches of skin, shiny skin, restricted movement due to hardness in skin, hair loss, white lumps under the skin due to calcium deposition, exaggerated responses to cold temperatures and emotional stress, numbness in finger and/or toe, pain in finger and/or toe, changes in color in finger and/or toe, digestive system, acid reflux, restricted movement of food through the digestive tract, malnutrition, fatigue, anxiety, and any combination thereof.
- Embodiment 9. The method of any one of embodiments 1-6, wherein the treating comprises reducing fibrosis in the subject.
- Embodiment 10. The method of embodiment 9, wherein reducing fibrosis comprises reducing formation of collagen and extracellular matrix proteins in the subject.
- Embodiment 11. The method of embodiment 10, wherein the collagen is formed by fibroblasts.
- Embodiment 12. The method of any one of embodiments 9-11, wherein the fibrosis is renal fibrosis or myocardial fibrosis.
- Embodiment 13. The method of any one of embodiments 1-6 or 9-12, wherein the treating comprises improving vascular function in the subject.
- Embodiment 14. The method of embodiment 13, wherein improving vascular function comprises decreasing intima media thickness (IMT), decreasing arterial stiffness, reducing urinary albumin excretion (UAE), reducing plaque in the arteries, or any combination thereof.
- Embodiment 15. The method of any one of embodiments 1-14, wherein the subject has digital ulcerations.
- Embodiment 16. The method of embodiment 15, wherein after administration of the dual N-type and L-type selective calcium blocker, the number and/or severity of the digital ulcerations is reduced.
- Embodiment 17. The method of any one of embodiments 1-6 or 9-16, wherein the treating comprises improving cardiac function in the subject.
- Embodiment 18. The method of embodiment 17, wherein improving cardiac function in the subject comprises reducing the frequency and/or severity of cardiac arrhythmias; reducing sympathomimetic increases in papillary muscle-developed tension (PMDT); reducing myocardial interstitial norepinephrine level; decreasing aortic pressure; increased aortic, vertebral, and coronary blood flow; reducing myocardial oxygen consumption; reducing blood pressure; or any combination thereof.
- Embodiment 19. The method of any one of embodiments 1-6 or 9-18, wherein the treating comprises improving renal function in the subject.
- Embodiment 20. The method of embodiment 19, wherein improving renal function comprises reducing intrarenal arterial stiffness, improving blood flow to the kidneys, increasing expression levels of podocyte proteins, or any combination thereof.
- Embodiment 21. The method of any one of embodiments 1-20, wherein starting before administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor, the subject was administered an alternative therapy useful to treat the scleroderma at regular intervals; and after administration of the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject, the dosage and/or frequency of the alternative therapy required to treat the subject is reduced.
- Embodiment 22. The method of embodiment 21, wherein the alternative therapy is a non-N-selective calcium channel blocker.
- Embodiment 23. A method of treating endothelial dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 24. The method of embodiment 23, wherein the subject has atherosclerosis, an increased adherence of monocytes and/or macrophages in a vessel wall, restenosis, or a combination thereof.
- Embodiment 25. The method of embodiment 24, wherein after administering the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, the atherosclerosis, increased adherence of monocytes and/or macrophages in a vessel wall, restenosis, or a combination thereof are treated or ameliorated.
- Embodiment 26. A method of treating diabetic neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 27. The method of embodiment 26, wherein the diabetic neuropathy is small fiber diabetic neuropathy.
- Embodiment 28. The method of any one of embodiments 26-27, wherein the diabetic neuropathy is peripheral neuropathy.
- Embodiment 29. The method of any one of embodiments 26-27, wherein the diabetic neuropathy is autonomic neuropathy.
- Embodiment 30. The method of any one of embodiments 26-27, wherein the diabetic neuropathy is proximal neuropathy.
- Embodiment 31. The method of any one of embodiments 26-27, wherein the diabetic neuropathy is focal neuropathy.
- Embodiment 32. The method of any one of embodiments 26-31, wherein after administration of the therapeutically effective amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and the second therapeutic agent, the severity, frequency, and/or duration of numbness, sensation of tingling in the feet or hands, sensation of pins and needles, prickling sensations, sensation of burning feet or hands, cold sensations, pinching sensations, stabbing sensations, heightened sensitivity to touch, indigestion, gastroparesis, nausea, vomiting, stomach pain, diarrhea, constipation, muscle weakness, lack of coordination, ulcers and/or infection in a foot, bone and joint pain, hip pain, hypoglycermia unawareness, reduced libido, vision impairment, eye pain, Bell's palsy, or any combination thereof are reduced in the subject.
- Embodiment 33. A method of treating dyspnea in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 34. The method of embodiment 33, wherein the dyspnea is acute dyspnea.
- Embodiment 35. The method of embodiment 33, wherein the dyspnea is chronic dyspnea.
- Embodiment 36. The method of any one of embodiments 33-35, wherein after administration of the therapeutically effective amount of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel and the second therapeutic agent, the severity, frequency, and/or duration of chest tightness, the urge to breathe deeply, labored breathing, tachypnea, stridor, or any combination thereof are reduced in the subject.
- Embodiment 37. A method of treating a gastrointestinal disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dual N-type and L-type calcium channel blocker selective for the N-type calcium channel.
- Embodiment 38. The method of embodiment 37, wherein the gastrointestinal disorder is gastroesophageal reflux disease (GERD).
- Embodiment 39. The method of any one of embodiments 23-38, wherein the subject has scleroderma.
- Embodiment 40. The method of embodiment 39, wherein the scleroderma is limited scleroderma.
- Embodiment 41. The method of embodiment 39, wherein the scleroderma is diffuse scleroderma.
- Embodiment 42. The method of any one of embodiments 1-41, wherein the subject has Raynaud's syndrome.
- Embodiment 43. The method of embodiment 42, wherein the Raynaud's syndrome is secondary Raynaud's syndrome.
- Embodiment 44. The method of any one of embodiments 42-43, wherein after administration of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel, one or more symptoms of the Raynaud's syndrome are improved.
- Embodiment 45. The method of any one of embodiments 1-44, further comprising administering a phosphodiesterase type 5 (PDE-5) inhibitor to the subject.
- Embodiment 46. The method of any one of embodiments 1-45, wherein vasoconstriction in the subject is reduced after administering the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor to the subject.
- Embodiment 47. The method of any one of embodiments 1-46, wherein the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is selected from the group consisting of: cilnidipine, Z-160, CNV2197944, or pharmaceutically acceptable salts thereof.
- Embodiment 48. The method of any one of embodiments 1-47, wherein the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is cilnidipine or a pharmaceutically acceptable salt thereof.
- Embodiment 49. The method of any one of embodiments 45-48, wherein the phosphodiesterase type 5 inhibitor is selected from sildenafil, tadalafil, or pharmaceutically acceptable salts thereof.
- Embodiment 50. The method of any one of embodiments 45-49, wherein the phosphodiesterase type 5 inhibitor is tadalafil or a pharmaceutically acceptable salt thereof.
- Embodiment 51. The method of any one of embodiments 45-50, wherein the amount of the phosphodiesterase type 5 inhibitor used in the method is less than the therapeutically effective amount of the phosphodiesterase type 5 inhibitor useful to treat scleroderma in a subject when administered in combination with a non-N selective calcium channel blocker.
- Embodiment 52. The method of any one of embodiments 1-51, wherein the dosage of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is about 5 mg to about 40 mg.
- Embodiment 53. The method of any one of embodiments 1-51, wherein the dosage of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is about 9 mg to about 21 mg.
- Embodiment 54. The method of any one of embodiments 1-51, wherein the dosage of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is about 10 mg.
- Embodiment 55. The method of any one of embodiments 1-51, wherein the dosage of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is about 20 mg.
- Embodiment 56. The method of any one of embodiments 1-51, wherein the dosage of the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is about 30 mg.
- Embodiment 57. The method of any one of embodiments 45-56, wherein the dosage of the phosphodiesterase type 5 inhibitor is about 2 mg to about 8 mg.
- Embodiment 58. The method of any one of embodiments 45-57, wherein the dosage of the phosphodiesterase type 5 inhibitor is about 5 mg.
- Embodiment 59. The method of any one of embodiments 1-58, wherein the dual N-type and L-type calcium channel blocker selective for the N-type calcium channel is administered orally.
- Embodiment 60. The method of any one of embodiments 45-59, wherein the phosphodiesterase type 5 inhibitor is administered orally.
- Embodiment 61. The method of any one of embodiments 45-60, wherein the dual N-type and L-type selective calcium blocker and the phosphodiesterase type 5 inhibitor are administered separately, sequentially, or simultaneously.
- Embodiment 62. The method of any one of embodiments 1-22 and 39-60, wherein the subject experiences less frequent, less severe, and/or shorter episodes of tachycardia, headaches, flushing, increased heart rate, flushing, decreased renal blood flow, myalgia, chest pain, heart palpitation, and/or pedal enema than when administered a therapeutically effective amount of a non-N-selective calcium channel blocker alone, a phosphodiesterase type 5 inhibitor alone, or a combination of a non-N-selective calcium channel blocker and a phosphodiesterase type 5 inhibitor useful to treat the scleroderma.
- Embodiment 63. The method of any one of embodiments 22, 51, and 61, wherein the non-N-selective calcium channel blocker is selected from the group consisting of: nifedipine, nicardipine, amlodipine, Z-944, nimodipine, verapamil, diltiazem, felodipine, isradipine, nisoldipine, and nitrendipine.
- Embodiment 64. The method of any one of embodiments 1-63, wherein a reduction in the Raynaud's condition scale is measured in the subject.
- Embodiment 65. The method of embodiment 64, wherein the reduction in the Raynaud's condition scale is at least about 25%.
- Embodiment 66. The method of any one of embodiments 1-65, wherein a reduction in the Raynaud's severity scale is measured in the subject.
- Embodiment 67. The method of any one of embodiments 1-66, wherein a reduction in the average weekly pain score is measured in the subject.
- Embodiment 68. The method of any one of embodiments 1-67, wherein an increase in the temperature of a body part as measured by thermography is observed in the subject.
- Embodiment 69. The method of embodiment 68, wherein the body part is an index finger.
- Embodiment 70. The method of any one of embodiments 1-69, wherein an improvement in the SF-12 index of functional wellbeing is measured in the subject.
- Embodiment 71. The method of any one of embodiments 1-70, wherein an improvement in Scleroderma Health Assessment Questionnaire (SHAQ®) is measured in the subject.
- Embodiment 72. The method of any one of embodiments 1-71, wherein a reduction in the Reactive Hyperemia Index as measured by Endo PAT is measured in the subject.
- Embodiment 73. The method of any one of embodiments 1-72, wherein an improvement in endothelial function as measured by Endo PAT is measured in the subject.
- Embodiment 74. The method of any one of embodiments 1-73, wherein nitric oxide levels in the endothelium are increased as measured by Endo PAT in the subject.
- Embodiment 75. The method of any one of embodiments 1-74, wherein an improvement in the finger ulcer visual analog scale (VAS) is measured or assessed in the subject.
- Embodiment 76. The method of any one of embodiments 1-75, wherein an improvement in the Standard Disability Index is measured or assessed in the subject.
- Embodiment 77. The method of any one of embodiments 1-76, wherein an improvement in the Alternative Disability Index is measured or assessed in the subject.
- Embodiment 78. The method of any one of embodiments 1-77, wherein an improvement in breathing is determined in the subject as measured by increased oxygen saturation in the blood of the subject.
- Embodiment 79. The method of any one of embodiments 1-78, wherein an improvement in breathing is determined in the subject as measured by the breathing visual analog scale (VAS).
- Embodiment 80. The method of any one of embodiments 1-79, wherein an improvement in the Standard Disability Index is measured or assessed in the subject.
- Embodiment 81. The method of any one of embodiments 1-80, wherein an improvement in scleroderma disease severity is measured or assessed in the subject.

EXAMPLES
Example 1. Clinical Trial Protocol

TABLE 1

Abbreviations.

Abbreviation
Term

ACR
American College of Rheumatology

AE
Adverse Event

ARB
Angiotensin II receptor blocker

ATC
Anatomical Therapeutic Class

AUC_0-inf
Area under the plasma concentration time

curve from time zero to infinity

BMI
Body Mass Index

BP
Blood pressure

Ca
Calcium

CCB
Calcium channel blocker

cGMP
Cyclic guanosine monophosphate

CKD
Chronic kidney disease

CL/F
Apparent total clearance of the drug from

plasma after oral administration

CRF
Case Report Form

CRP
C-reactive protein

CSR
Clinical Study Report

CTN
Clinical Trials Notification

CV
Coefficient of Variation

DDD
Distal-dorsal difference

DSMB
Data and Safety Monitoring Board

eCRF
Electronic case report form

EOS
End of study

ESR
Erythrocyte sedimentation rate

EULAR
European League Against Rheumatism

FIH
First in human

GCP
Good Clinical Practice

GEE
Generalized Estimating Equation

HREC
Human Research Ethics Committee

IB
Investigator's Brochure

ICF
Informed Consent Form

ICH
International Council for Harmonization

IP
Investigational product

ITT
Intent-to-treat

IVRS
Interactive voice response system

kel
Elimination rate constant

LS
Least Squares

MedDRA
Medical Dictionary for Regulatory Activities

NHMRC
National Health and Medical Research Council

NSAID
Nonsteroidal anti-inflammatory drug

PAH
Pulmonary arterial hypertension

PDE5
Phosphodiesterase type 5

PI
Principal Investigator

PK
Pharmacokinetic

PP
Per-Protocol

PT
Preferred term

RCS
Raynaud's Condition Score

RHI
Reactive Hyperemia Index

RP
Raynaud's Phenomenon

SAE
Serious Adverse Event

SAP
Statistical Analysis Plan

SBP
Systolic blood pressure

SD
Standard deviation

SE
Standard Error

SHAQ
Scleroderma Health Assessment Questionnaire

SMC
Safety Monitoring Committee

SoA
Schedule of Assessments

SOC
System organ class

SSc
Systemic Sclerosis

SSc-RP
Raynaud's Phenomenon secondary mostly

to systemic sclerosis

t½
Elimination half-life

TEAE
Treatment-emergent Adverse Event

TGA
Therapeutic Goods Administration

UCLA SCTC
University of California at Los Angeles

GIT 2.0
Scleroderma Clinical Trials Consortium

Gastrointestinal Tract 2.0

VAS
Visual analog scale

VMA
Vanylmandelic acids

Vz/F
Apparent volume of distribution during terminal

phase after non-intravenous administration

WHO
World Health Organization

WOCBP
Woman of childbearing potential

A randomized, placebo-controlled phase 2a study was performed and is in progress to assess the safety and efficacy of cilnidipine (10 mg and 20 mg) alone and in combination with 5 mg tadalafil, in participants with diagnosis of scleroderma and/or secondary Raynaud's disease.

Objectives:

Primary Efficacy:

To evaluate the effect of cilnidipine alone and in combination with

tadalafil on the frequency of weekly Raynaud's Phenomenon (RP)

attacks compared with placebo in participants with RP secondary

mostly to systemic sclerosis (SSc-RP).

Secondary Efficacy:

To evaluate the effect of cilnidipine alone and in combination with

tadalafil on the clinical features of SSc-RP and the severity and

burden of SSc-RP symptoms.

Safety:

To evaluate the safety of cilnidipine alone and in combination with

tadalafil compared to placebo in participants with SSc-RP.

Exploratory (Part A, Dose Selection)

To assess the endothelial function of participants with SSc-RP and

impact of treatment on sympathetic activity.

Methodology:

A randomized, placebo-controlled Phase 2a study to test the efficacy and safety of cilnidipine

alone and in combination with tadalafil in participants who have frequent attacks of SSc-RP.

The study consists of two parts.

Part A - Double-blind, Placebo-controlled, Parallel-group, Dose Selection to assess the

safety and efficacy of two doses of cilnidipine (10 mg and 20 mg), alone and in combination

with tadalafil. Participants were randomized to one of six pre-specified treatment arms. The

data from Part A of the study was and will be reviewed by an unblinded Data Safety and

Monitoring Board (DSMB) to select the cilnidipine dose and confirm the sample size

estimates for the randomized double-blind phase (Part B). The first review will occur after

approximately 50% of participants have completed.

Part B - Double-blind, Placebo-controlled, 4-way crossover to assess the safety and

efficacy of cilnidipine (at the dose selected in Part A) alone and in combination with 5 mg

tadalafil. Participants will be randomized to one of four pre-specified treatment sequences in

a 4-way crossover design. Each participant will undergo four Dosing Periods in which they

will receive a different treatment each Dosing Period followed by a 4 (±1) day washout

period.

During the study (Part A and Part B) participants received and/or will receive treatments in a

blinded fashion. Each Dosing Period lasted and/or will last for 12 days (±2 days) in which

participants took and/or will take daily doses of assigned treatment in the morning. For each

day of dosing, participants took and/or will take one capsule and one tablet to blind the active

therapy being received.

The schematic for dosing is presented for Part A (Table S1) and Part B (Table S2) below.

Table S1: Part A, Double-blind, Parallel-group, Dose Selection

Arm
N
Treatment

A
6
P

B
6
C10

C
6
C20

D
6
T05

E
6
C10 + T05

F
6
C20 + T05

Abbreviations: C = cilnidipine, P = placebo, T = tadalafil, N = number of participants, C10 = C 10 mg, C20 = C 20 mg; T05 = T 5 mg.

Table S2: Part B, Double-blind, Placebo-controlled, 4-way crossover

Sequence

Dosing
Dosing
Dosing
Dosing

Number
N
Period 1
Period 2
Period 3
Period 4

1
10
P
C
C + T05
T05

2
10
T05
C + T05
P
C

3
10
C + T05
T05
C
P

4
10
C
P
T05
C+ T05

Abbreviations: C = cilnidipine, P = placebo, T = tadalafil, N = number of participants, T05 = T 5 mg.

Dose of C, either 10 mg or 20 mg will be identified following completion of Part A.

Number of Participants (Planned):

Overall, 76 participants were and/or will be enrolled in this study: 36 in the were enrolled in

the parallel-group dose selection phase (Part A) and 40 will be enrolled in the 4-way

crossover phase (Part B). Dropouts will not be replaced.

Diagnosis and Main Criteria for Inclusion:

Participants at least 18 years of age diagnosed with severe secondary Raynaud's disease

(Raynaud's Condition Score [RCS] ≥40 and at least a 2-phase color change in fingers of

pallor, cyanosis, and/or reactive hypermedia in response to cold exposure or emotion) mostly

resulting from SSc and exhibiting regular and frequent RP attacks (averaging at least one

attack per day) during the Screening period.

Investigational Product, Dosage and Mode of Administration:

Cilnidipine

For Part A, Cilnidipine 10 mg and cilnidipine 20 mg for oral administration, were provided to

the site in cartons containing 16 tablets sealed in blister packs.

For Part B, the cilnidipine dose selected in Part A will be provided to the site in cartons

containing 16 tablets sealed in blister packs.

Tadalafil

Tadalafil 5 mg, for oral administration were over encapsulated (and back filled with inert

capsule filler consisting of only maize starch and pre-gelatinized maize starch, so that the

internal tablet cannot be detected) and provided in bottles containing 16 capsules to the site.

Medications were dispensed during the preceding in-clinic study visit for self-administration

by the participant once daily in the morning for a 12 (±2) day period. The duration of the

Dosing Period will be confirmed by the study staff when the in-clinic study visit is scheduled.

Duration of Treatment:

Part A, Double-blind, Parallel-group, Dose Selection: Participants enrolled participated for

up to 29 (±5) days:

Screening: up to 10 days (−3 days)

Treatment: 12 (±2) days

Follow-up: 7 days (+3 days)

Part B, Double-blind, Placebo-controlled, 4-way crossover: Participants enrolled will

participate for up to 77 days (±14 days):

Screening: up to 10 days (−3 days)

Treatment: 60 days (four Dosing Periods each lasting for 12 (±2) days, separated by a

4 (±1) day washout period)

Follow-up: 7 days (+3 days)

The total duration of the study is expected to be approximately 6 months.

Reference Therapy, Dosage, and Mode of Administration:

Placebo

Placebo tablets (matching cilnidipine) and placebo capsules (matching tadalafil), for oral

administration, were provided to the site.

Criteria for Evaluation:

Primary Efficacy Endpoint:

Percentage change from baseline in frequency of weekly RP attacks.

Secondary Efficacy Endpoints:

Change from baseline in frequency of weekly RP attacks

Change from Baseline in average duration of weekly RP attacks

Change from Baseline in average severity of weekly RP attacks

Change from Baseline in average daily RCS

Change from baseline in highest (most severe) pain score recorded during weekly RP

attacks

Change from baseline in average pain score recorded during weekly RP attacks

Change from baseline in net digital ulcer burden

Change from baseline in distal-dorsal difference (DDD) of the affected index finger sites

Change from baseline in participant quality of life measured using the Scleroderma

Health Assessment Questionnaire (SHAQ)

Change from baseline in Raynaud-visual analog scale (VAS)

Change from baseline in physician assessment of disease

Measurement of cilnidipine drug levels taken 2 to 6 hours following the last dose

The time to reach maximum degree of efficacy (in days) compared to baseline

The time to return to baseline symptom severity after termination of dosing

Impact of daily ambient temperature on symptomatic RP attacks

Use of rescue medications for breakthrough symptoms.

Exploratory Efficacy Endpoints (Part A):

Change from baseline in endothelial function as measured by reactive hyperemia index

(RHI) using Endo-PAT

Impact of treatment on sympathetic activity as measured by plasma vanylmandelic acids

(VMA)

Safety Endpoints:

Incidence of adverse events (AEs) and serious adverse events (SAEs), including clinically

significant vital signs from the time of randomization until 7 days following the last protocol

dose.

Serious adverse events will be monitored by a DSMB on an ongoing basis throughout the

study.

Adverse events were and will be coded using the Medical Dictionary for Regulatory

Activities (MedDRA) and summarized by System Organ Class (SOC), Preferred Term (PT),

and treatment group.

Statistical Methods:

Part A data will be analyzed in exploratory fashion to support cilnidipine dose selection and

treatment effect check for sample size confirmation for Part B. For Part B data, mixed effects

model will be used for analysis of the continuous efficacy endpoints in the crossover design.

For nominal data, Chi-square tests will be applied. Generalized Estimating Equations method

will be used, as appropriate, for adjusting for potential confounding factors. Safety endpoints

will be summarized by treatment group. No multiple comparison adjustment will be used to

control alpha for the multiple comparisons.

Statistical Analyses:

Data from Part A and Part B will be analyzed separately. The primary and secondary efficacy

analyses were and will be based on the Intent-To-Treat (ITT) population. Analyses based on

the PP population for Part B will be considered secondary and confirmatory. All safety

analyses will be performed on the safety population. Subgroup analyses will also be

performed.

Additional exploratory analyses may be performed and will be documented in the statistical

analysis plan. Any deviation from planned analyses described in this protocol will also be

documented in the statistical analysis plan.

Data will be summarized by treatment group for treatment effect comparison according to

crossover design; participants receiving each treatment will be pooled from all periods.

Baseline will be defined as Screening assessments for change from baseline analyses for all

periods.

Sample Size Calculation:

The sample size was calculated based on the confidence bound in literature report (Rirash

2017). Assuming a 2-sided.05 alpha for treatment (cilnidipine or combination therapy or

tadalafil) versus placebo and a common standard deviation (SD) of 0.5 for a decrease of 25%

attacks (moderate effect size of 0.5) and without controlling alpha for multiple efficacy

comparisons, a sample size of ten participants in each paired comparison group (cilnidipine or

combination therapy or tadalafil) is needed for 80% power in a four period crossover design,

assuming a 20% dropout rate.

Introduction

This protocol describes a study that has been and will be performed to evaluate the effect of cilnidipine alone and in combination with tadalafil on the frequency of weekly Raynaud's attacks in participants with SSc-RP.

Investigational Plan
Overall Study Design

A schematic of the study design is provided in FIG. 1.

This was and is a randomized, placebo-controlled Phase 2a study to assess the safety and efficacy of cilnidipine alone and in combination with tadalafil, in participants who have frequent attacks of secondary RP mostly resulting from SSc. Oversight for the study will be provided by a DSMB.

Participants will underwent and/or will undergo a Screening period beginning up to 10 days prior to randomization. The initial screening and capacity was and will be conducted via phone at the start of the Screening period with eligibility finalized prior to randomization on Day 0. Participants were and will be required to provide informed consent in a 2-step process at Screening (upload of the E-Diary will be considered implied consent for the Screening period) and at Randomization (Day 0) before undertaking any study-specific procedures or assessments. Only participants who met/meet all of the inclusion and none of the exclusion criteria were and will be randomized.

The study consists of two parts.

Part A—Double-blind, Placebo-controlled, Parallel-group, Dose selection, assessed the safety and efficacy of two doses of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil. A total of 27 participants were randomized to one of six pre-specified treatment arms. See Example 3 for data obtained in this phase of the study thus far, on 11 participants.

Please refer to FIG. 1 for treatment arms in Part A of the study. Dosing lasted last for 12 (±2) days in which participants self-administered daily doses of assigned treatment in the morning. Each participant took one capsule and one tablet to blind the active therapy being received. Study visits and assessments occurred as delineated in the SoA presented in FIG. 2.

The data from Part A of the study was reviewed by an unblinded DSMB prior to selecting the cilnidipine dose and confirming the sample size estimates for the randomized double-blind phase (Part B). The first review occurred after approximately 50% of participants have completed the study.

Part B—Double-blind, Placebo-controlled, 4-way Crossover will assess the safety and efficacy of cilnidipine (at the dose selected in Part A) alone and in combination with 5 mg tadalafil. A total of 40 participants (10 in each sequence) with a diagnosis of SSc-RP will be randomized into one of four pre-specified treatment sequences in a 4-way crossover design.

Please refer to FIG. 1 for treatment sequences in Part B of the study. Each participant will undergo four Dosing Periods in which they will receive a different treatment each Dosing Period followed by a 4 (±1) day washout period. Each Dosing Period will last for 12 (±2) days in which participants will self-administer daily doses of assigned treatment in the morning. At all Dosing Periods, each participant will take one capsule and one tablet to blind the active therapy being received. Study visits and assessments will occur as delineated in the SoA presented in FIG. 3A and/or 3B.

For both Part A and B of the study, participants were or are required to visit the clinic on last day of each Dosing Period (i.e., Day 10 to 14) to return/dispense study drug and conduct in person study assessments. Participants were or will be dispensed with 2 weeks' worth of study drug to be taken at home for the following Dosing Period; overage from the prior Dosing Period were or will also be collected.

Patients were or will be assessed for the occurrence of efficacy endpoints for each Dosing Period via the patient reported E-Diary and the in-clinic visit. Safety information was or will be collected from randomization until patient follow-up is complete (7 to 10) days after the last Dosing Period) and assessed for each Dosing Period.

Dose Selection, Sample Size Confirmation and Safety Oversight

Safety oversight was provided by a DSMB. The DSMB will conduct a review of the efficacy and safety data from Part A of the study. The first review occurred after data was available on the first 11 of the participants enrolled into the study. Subsequent reviews will occur as needed prior to commencement of Part B of the study to determine the optimal dose of cilnidipine to carry into Part 2 of the study and to assess the risk: benefit of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil.

Following review of the efficacy and safety data from Part A, the DSMB will make the following recommendations:

- 1. Select the dose of cilnidipine (10 mg or 20 mg) to be studied in Part B of the study
- 2. Confirm the sample size estimates for Part B of the study.

Serious adverse events have been and will be monitored by the DSMB on an ongoing basis throughout the study.

Safety Criteria for Stopping or Unblinding Treatment

Administration of study drug may be paused, and emergency unblinding of treatment conducted following consultation between the Investigator, the Medical Monitor, and the Sponsor representative under the following circumstances:

- Symptoms of possible allergic phenomena: rash, hives, urticaria, changes in breathing or wheezing.
- Systolic BP (SBP)<90 mmHg
  - Reduction in BP (relative to baseline values) considered to be significant in the opinion of the Investigator on an absolute basis or consistent with symptoms (dizziness, light-headedness) suggestive of being related to reduction in BP.
  - Two separate SBP measurements of <90 mmHg, taken at rest (where baseline SBP exceeded 110 mmHg), even in the absence of symptoms, shall be considered sufficient reason to unblind the study for that patient.
- Dizziness, when going from a recumbent to standing position and/or if accompanied by a reduction in BP.
  - Dizziness in the absence of a reduction in BP should be considered on an individual participant basis, as to its relative degree of severity, as to whether the participant continues in the study.
- Unexpected adverse event or reaction.

Study Termination

The study will be completed as planned unless:

- New information or other evaluation regarding the safety of the study medication indicates a change in the known risk/benefit profile for the compound, such that the risk/benefit is no longer acceptable for participants participating in the study. This may be determined by the Sponsor, the Investigator, the HREC or regulatory authorities.
- The study is terminated by the Sponsor for administrative reasons.

The Sponsor, Investigator, and the HREC reserve the right to terminate or suspend the study at any time; however, this should be discussed between the relevant parties beforehand and the reason for such decision recorded. Should this occur, all data available will also be recorded in the eCRFs. If the Sponsor, the HREC, or regulatory authority elects to terminate or suspend the study or the participation of the investigational site, a study-specific procedure for early termination or suspension will be provided by the Sponsor. The procedure will be followed by the investigational site during termination or study suspension.

The Investigator should notify the relevant HREC in writing of the study's completion or early discontinuation.

Participant Population

The study has been and will be conducted in participants at least 18 years of age diagnosed with severe secondary Raynaud's disease (RCS≥40 and at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hypermedia in response to cold exposure or emotion) mostly resulting from SSc (defined by consensus criteria 2013 American College of Rheumatology [ACR]) and exhibiting a frequency of attacks (at least one per day) during the Screening period.

Women of childbearing potential were or will be included and have been or are subject to contraceptive requirements during the study from Screening until study completion, including the follow-up period, and for at least 30 days after the last dose of study drug (see Section 0). Women of childbearing potential must demonstrate negative pregnancy testing at Screening. This is in line with regulatory Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (US FDA Guidance document, January 2010).

Number of Participants

Overall, 76 participants have or will be enrolled in this study: 36 in the parallel-group dose selection phase (Part A) and 40 will be in the 4-way crossover phase (Part B). Dropouts will not be replaced.

Participant Inclusion Criteria

To be eligible for this study, each participant has met or has to meet all of the following inclusion criteria:

- 1. Male or female participants, aged 18 to 80 years (inclusive at the time of informed consent).
- Severe secondary Raynaud's disease (defined as RCS at baseline of ≥40) based on ACR criteria mostly resulting from SSc.
- Regular and frequent Raynaud's attacks (averaging at least one attack per day) during the Screening week (in participants with at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hypermedia in response to cold exposure or emotion).
- Willingness to complete the daily diary entry's during the Screening period.
- Participants must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.
- Willingness to forego other routine therapies for Raynaud's during study participation. Ongoing treatment with CCBs for SSc-RP is permitted if it is not clinically feasible to stop therapy and the participant has been on a stable dose for the last 2 months. Rescue therapy (with acetaminophen, nonsteroidal anti-inflammatory drug [NSAIDs], other codeine analgesics, fluoxetine, angiotensin II receptor blockers (ARBs) such as losartan) or CCBs will be allowed to manage breakthrough symptoms of SSc-RP but must be documented).
- Participants who are on a stable dose (no change in the last 2 months) of a CCB for hypertension or sildenafil for pulmonary hypertension may continue these agents at this stable dose as long as they meet other inclusion criteria during Screening.
- Have agreed not to use (or initiate treatment with) other investigational therapies or unapproved therapies during the course of the study outside of protocol allowances for rescue medication (such medications include but are not limited to: nitroglycerin, topical creams, fenoldopam, nimodipine, amlodipine, fluoxetine, pregabalin, gabapentin, verapamil, sildenafil, tadalafil, vardenafil).
- Women of childbearing potential (WOCBP) who have agreed to use an effective method of contraception during the study and for 30 days after the last study dose. Acceptable methods of birth control in this study include oral contraceptive, barrier control, or implanted devices. A woman must agree not to donate eggs (ova; oocytes) for purposes of reproduction for at least 30 days after last dose of study drug.
- Post-menopausal females, aged over 45 years who have not had a period for at least 12 months, and are not using hormonal contraception, or females documented as permanently sterile (e.g., bilateral tubal ligation; hysterectomy, bilateral salpingectomy).
- Negative urine pregnancy test on Randomization day (WOCBP only).
- All sexually active men (due to potential risk of drug exposure through the ejaculate) who agree to a barrier method of birth control during the study and for 30 days after the last dose of the study drug. All men must agree not to donate sperm for at least 30 days after receiving last dose of study drug.
- Participants must have clinical laboratory values within normal range as specified by the testing laboratory at their most recent pre-screening sample, unless deemed not clinically significant by the Investigator or delegate. Lab sample may be within the last 2 months as long as there have been no significant clinical changes since the last labs and no new medications (e.g., Diuretics) have been introduced that are known to be associated with changes in clinical chemistry or hematology values (e.g., potassium with diuretics or cyclosporine associated with aplastic anemia).

Participant Exclusion Criteria

A participant who has met or meets any of the following exclusion criteria must be excluded from the study:

- 1. Primary Raynaud's disease.
- History of Raynaud's attacks of sufficient severity as to require in-patient hospitalization (within the last 6 months).
- The SBP of <95 mm Hg during Randomization visit (Day 0).
- Pulmonary hypertension requiring specific therapy for this condition.
- Participants with an allergy to dihydropyridine CCBs that results in clinical findings such as profound hypotension, hives, rash, urticaria, wheezing and changes in breathing (Common treatment limiting adverse events [AEs] that occur with CCBs nifedipine and amlodipine such as edema, headache, heart rate changes, tachycardia, fatigue, constipation, flushing, drowsiness, dizziness should not limit enrolment into this study).
- History of other chronic pain condition that could confound recording of pain scores during the study period.
- Any prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that in the opinion of the Investigator(s), would contraindicate administration of the study medication, or interfere with the study evaluations, or interfere with the participants ability to comply with the study protocol.
- Cognitive or language difficulties that would impair completion of the study assessments.
- Use of any investigational product (IP) or investigational medical device or participation in investigational drug studies within 30 days prior to enrolment in the study.
- Those receiving nitrates, alpha blockers, PDE inhibitors (outside of stable administration for PAH), prostacyclins or endothelin antagonists.
- History of orthostatic hypertension, dizziness or fainting spells, acute coronary or cerebrovascular event within 3 months of study enrollment.
- History of major thoracic, abdominal, or vascular surgery within 6 months of study enrollment; History of sympathectomy.
- Severe cardiomyopathy, severe valvular heart disease, chronic kidney disease (CKD) stage 3 or greater, evidence of malignancy, end stage lung disease.
- Pregnant or lactating women.
- Women of childbearing potential (WOCBP) unable to comply with contraceptive requirements during the study period.
- Males with partners who are WOCBP and are unable to comply with the contraceptive requirements during the study.
- History of drug or excess alcohol use that in the opinion of the Investigator(s) would affect the participant's ability to reliably participate in the study. NHMRC guidelines for regular alcohol consumption in healthy adults are no more than 10 standard drinks per week and no more than four standard drinks on any one day.
- Use of tobacco products of any type in the preceding one month and for the duration of the study.

Screen Failures

Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently randomized in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes screen failure details and eligibility criteria. Participants who withdraw from the study, for any reason, prior to randomization will be considered screen failures. Individuals who do not meet the criteria for participation in this study (screen failure) may be re-screened following a one month waiting period. Re-screened participants should be assigned a new participant number.

Participant Replacement

All participants who were or are randomized were or will be followed and included in the primary ITT analysis. Dropouts were not and will not be replaced.

Participant Withdrawal Criteria

Participants may withdraw their consent to participate in the study at any time. If a participant withdraws consent, the date and reason for consent withdrawal should be documented. Participants will be encouraged to remain in the clinic to complete all necessary assessments and until the Investigator deems that it is safe to be discharged. Participant data will be included in the analysis up to the date of the withdrawal of consent.

Apart from withdrawal of consent, reasons for early termination of individual participants can include:

- Protocol deviations or participant non-compliance (must be specified on the appropriate eCRF)
- Serious or severe AEs
- Administrative decision by the Investigator or the Sponsor
- Death
- Other (must be specified).

The primary reason for withdrawal will be identified and recorded on the appropriate eCRF, along with the date of withdrawal.

In accordance with applicable regulations, a participant has the right to withdraw from the study, at any time and for any reason, without prejudice to future medical care.

If a participant is withdrawn because of an AE, the Investigator must arrange for the participant to have appropriate follow-up care until the AE is resolved or has stabilized. Unresolved AEs will be followed until the last scheduled Follow-up/End of Study (EOS) visit or until the Investigator(s) determine that further follow-up is no longer indicated. In addition to AEs, other reasons for removal of participants from the study might include, but are not limited to, withdrawal of consent, administrative decision by the Investigator or the Sponsor, protocol deviation, or participant noncompliance.

If a participant asks or decides to withdraw from the study, all efforts will be made to complete and report the observations, especially those related to the listed primary and secondary objectives, as thoroughly as possible up to the date of withdrawal. Wherever possible, the tests and evaluations, including those listed for the EOS/follow-up visit, should be performed for all participants who discontinue prior to the completion of the study.

Treatments
Treatments Administered
Investigational Product
Cilnidipine

Cilnidipine is an orally administered dihydropyridine CCB that dilates blood vessels, increases blood flow, inhibits sympathetic nervous system activity, and improves endothelial structure and function. Please refer to IB for more information on composition of cilnidipine tablet (Profervia® Investigator's Brochure, 2020), which is incorporated by reference herein in its entirety.

Profervia® tablets are white film-coated tablets. Each tablet contains cilnidipine (10 or 20 mg) with microcrystalline cellulose, lactose, magnesium stearate, sodium starch glycollate, Opadry white, polyvinyl alcohol, titanium dioxide, macrogol, talc, and purified water.

Cilnidipine is commercially available and should be used only in accordance with this study protocol and IB.

Cilnidipine 10 mg and 20 mg oral tablets have been and will be provided to the site in cartons containing 16 tablets sealed in blister packs.

Tadalafil

Tadalafil for oral administration belong to a class of medications called PDE5 inhibitors. Tadalafil is commercially available and should be used only in accordance with this study protocol. Please refer to the pharmacy manual and product information sheet for more information on composition and storage information for tadalafil.

Tadalafil has been and will be over encapsulated (and back filled with inert capsule filler consisting only of maize starch and pre-gelatinized maize starch, so that the internal tablet cannot be detected) and provided in bottles containing 16 capsules to the site.

Reference Products

Placebo tablets (matching cilnidipine) and placebo capsules (matching tadalafil) for oral administration have been and will be provided for this study.

Dosage and Treatment Periods

At all Dosing Periods, each participant has taken or will take one capsule and one tablet to blind the active therapy being received. All medications for each Dosing Period (each Dosing Period will last for 12 days [±2 days]) have been or will be dispensed during the preceding in-clinic visit and then self-administered by the participant once daily, orally, in the morning.

If a participant accidentally misses a dose, they have been or should be advised to take the dose on the same day as soon as they realize. Only one tablet and capsule have been and should be taken each day. If more than one dose is lost, the participant should notify the study staff so that their in-clinic visit can be adjusted if needed.

Part A, Double-blind, Parallel-group, Dose Selection Study drug has been self-administered daily for 12 (±2) days. Each participant has or will receive only one treatment. Please refer to FIG. 2 for more details.

Part B, Double-blind, Placebo-controlled, 4-way Crossover Study drug will be self-administered daily in four Dosing Periods separated by a four-day (±1) washout period. Each participant will receive a different treatment during each Dosing Period, with a total of four treatments received. Please refer to FIG. 3A and/or 3B for more details.

Method of Assigning Participants to Treatment
Randomization

A randomization list has been or will be prepared using a statistical software package by a Biostatistician.

Each participant has been or will be provided with a unique screening number post-documentation of informed consent. Once deemed eligible, the participant has been or will be assigned a sequential randomization number prior to first dosing. Participants who withdraw from the study or who fail eligibility, for any reason, prior to randomization will be considered screen failures.

Concomitant Medications

All medications, including over the counter medications, vitamins, and herbal supplements, taken during the Screening period have been or will be reviewed by the Investigator to determine whether these medications render the participant as suitable for inclusion in the study.

Concomitant medications of interest have been or will be captured electronically from the start of the Screening period until study completion.

Treatment prior to enrollment with therapies for SSc-RP including but not limited to CCBs, nitroglycerin, topical creams fenoldopam, nimodipine, fluoxetine, pregabalin, gabapentin, sildenafil, tadalafil, vardenafil were or are permitted. In order to have been or be eligible, participants must be willing to forego these therapies for SSc-RP at the start of the Screening period and for the duration of the study. Participants who were or are on a stable dose (no change in dose in prior 2 months) of a CCB for hypertension or sildenafil for pulmonary hypertension may continue these agents at this stable dose as long as they meet other inclusion criteria during Screening. Similarly, participants who have been or are receiving CCBs to manage their symptoms of SSc-RP and are unwilling to stop treatment for the duration of the study would still be eligible if the participant's dose has been stable for the past 2 months. During the study participants were or will be able to decrease the dosage of their prior CCB for safety reasons only; no increase in dosage was or will be allowed during the study period.

The use of any other IP or investigational medical device within 30 days prior to Screening is prohibited.

Prior therapy or concomitant therapy (after study drug administration) with any medications, including both prescription and non-prescription drugs should be discussed with the Investigator and Sponsor's MM before study drug administration, except in the case of necessary treatment of AEs or where appropriate medical care necessitates that therapy should begin before the Investigator can consult with the Sponsor's MM.

Rescue Medicine

Medications required as rescue therapy can be taken to manage breakthrough symptoms of SSc-RP but must be recorded in the participant E-Diary. First-line therapy may include acetaminophen, NSAIDs, or other codeine-based analgesics. These rescue medications may be taken for the duration of symptoms of a Raynaud's attack. For participants in whom first-line rescue therapy is not effective, additional rescue medication therapy may be started per Investigator discretion and could include fluoxetine, ARBs such as losartan or CCBs. Rescue therapy should continue as long as clinically needed during an acute attack, but then patients should return to the pre-rescue study medication regimen. All participants receiving rescue therapy should continue in the study undergoing subsequent Dosing Periods through study completion. If a participant requires regular rescue medicine during dosing through at least four sequential Dosing Periods, then the participant may drop out of the study at the discretion of the participant and the Investigator.

Treatment Compliance

All doses have been or will be self-administered by participants remote from study sites (at home). For each Dosing Period, participants were or will be dispensed with two weeks' worth of study medication and will be asked to return the unused study medication on the last day of each Dosing Period at the time of in-clinic visit. The treatment compliance was or will be noted by the Investigator(s) during the in-clinic visit.

Blinding

This study is double-blind. To maintain the blind, all study medication has been and will be provided to the site in a blinded fashion. Cilnidipine tablets and matching placebo was and will be supplied in cartons containing 16 tablets sealed in blister packs, identical in appearance. Tadalafil was and will be provided in an over encapsulated form. The capsules, tadalafil, and placebo were and will be identical in appearance and weight and will be supplied in bottles containing 16 capsules.

Each study drug was and will be labeled with a unique ID number. The interactive voice response system (IVRS) was or will have access to the treatment arm assignment for each individual ID number.

In the Event of an Emergency: Unblinding a Code

It is recognized that, in the course of clinical practice, it may be necessary for the treating physician to have knowledge of the treatment assignment to ensure the safety of a study participant. This circumstance is extraordinary and will likely impact a minor fraction of the enrolled participants. Unblinding will be done via the IVRS. The treating physician is encouraged to contact the Sponsor MM in this circumstance. The Sponsor and DSMB will monitor all episodes of unblinding very carefully.

Study Schedule

The SoAs for Part A and Part B of the study are provided in FIG. 2 and FIG. 3A and/or 3B. Where possible, assessments have been and should be conducted in order of least invasive to most invasive.

This study consists of four periods:

- Screening period (begins with initial participant contact through participant completion of the screening E-Diary)
- Randomization period (from the time participant eligibility is confirmed and the participant randomized until immediately before the 1^stdose of study drug)
- Procedural period (from the first dose of study drug in the first Dosing Period until the last day of dosing)
- Follow-up period (from the end of the procedural period through 7 days).
  
  Part a—Double-Blind, Placebo-Controlled, Parallel-Group, Dose Selection

In Part A, the procedural period has required only one Dosing Period i.e. participants have or will receive only one treatment during the procedural period. Within the procedural period for Part A there have been and will be two sub-periods:

- Daily at home dosing (first ten to fourteen days of the Dosing Period)
- In-clinic visit (the last day of the Dosing Period that occurs on Day 12 [±2 days]).

Part B—Double-Blind, Placebo-Controlled, 4-Way Crossover

In Part B, the procedural period will require four Dosing Periods i.e. participants will receive four different treatments in a 4-way crossover design. Within the procedural period for Part B there will be three sub-periods associated with each Dosing Period/treatment received:

- Daily at home dosing (first ten to fourteen days of the Dosing Period)
- In-clinic visit (the last day of the Dosing Period that occurs on Day 12 [±2 days])
- Washout period (four days of no dosing that occurs between each Dosing Period).

Screening (Day −10 to Day −1)

Prior to enrolling in the study, and before performance of any procedures, potential participants have been or will be contacted via phone to discuss the details of the study and assess their eligibility and willingness to comply with all study procedures and duration. If the participant seemed or seems eligible and was or is interested in participating in the Screening period, then they were or will be asked to upload and start using an E-Diary to record the daily clinical features and symptoms of their SSc-RP for the next 7 to 10 days. Upload of the E-Diary was and will be considered implied consent for the Screening period, the data from which was and will be used to confirm eligibility and future baseline analyses assuming the participant is randomized.

During Screening, the E-Diary collected or will collect the following data to confirm eligibility and serve as the baseline measure for efficacy endpoints should the participant be randomized:

- Number of daily Raynaud's attacks
- Duration of each attack
- Symptoms of each attack, including numbness, pain, tingling, color changes
- Severity of each attack (all symptoms of the attack to be considered including tingling, numbness, pain, color changes)
- Location of participant during each attack (inside/outside)
- Pain score of each attack—using 11-point Likert scale, a validated pain scale which can be used to record intensity of pain
- Daily RCS— a validated outcome measure used to assess the level of difficulty experienced due to RP each day
- Rescue medications taken to manage breakthrough symptoms of SSc-RP including acetaminophen, NSAIDs, other codeine-based medicines, fluoxetine, ARBs such as losartan, CCBs
- Other concomitant medications of interest including allergy medications, stable medications for pre-existing hypertension or pulmonary hypertension, and prohibited medications for SSc-RP (including topical creams, fenoldopam, nimodipine, pregabalin, gabapentin, sildenafil, tadalafil, vardenafil).

Randomization Day (Day 0)

Participants were scheduled to visit the clinic for Randomization (Day 0) assessments between days 7 to 10 of the Screening period. Only participants who seemed eligible based on E-Diary compliance and frequency of RP attacks were requested to visit clinic for randomization. The participant was also be provided with an Informed Consent Form (ICF). Prior to being asked to sign the consent form, participants were or will be given time to review study information and ask any questions.

After the consent form is signed and the following assessments will be carried out:

- Medical history/demographics
- Previous/concomitant medications
- Vital signs
- Raynaud's functional assessment (by physician)
- Pregnancy test
- Review of daily participant E-dairy
- Scleroderma Health Assessment Questionnaire (SHAQ) which includes Raynaud's VAS to be completed by the participant with review by physician
- Digital ulcer assessment
- Thermography
- Endo-PAT (Part A only)
- Blood sample for PK
- Plasma VMA (Part A only)
- Inclusion/Exclusion
- Randomization
- AE/SAE reporting
- Dispensing study medication

Note: The data collected for assessments that were and are performed first time on Randomization (Day 0) visit (vital signs, digital ulcer assessment, and Endo-PAT) served and will serve as baseline measure for efficacy endpoints for those assessments.

Routine hospital tests including hematology, biochemistry, inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), antibody status (serum anti-topoisomerase [anti-Scl 70]) and nailfold capillaroscopy should be conducted as clinically indicated per standard of care but are not required per protocol. If conducted, results will be collected in the eCRF and used to describe the severity of disease in the baseline demographic and disease data.

Dosing Periods
Daily at Home Dosing (12 Days (+2 Days))

During the Dosing Period, participants were or will be required to self-administer the assigned study medication once daily in the morning at home. Participants were or will also be required to complete their E-Diary daily to capture the clinical features and symptoms of their SSc-RP, and report concomitant medications including rescue therapy (if any).

In-clinic Visit (Last Day of the Dosing Period)

Participants have been or will be required to visit the clinic following each Dosing Period—dosing Day 10 to Day 14. The day of the in-clinic visit is considered the last day of dosing in each Dosing Period.

After taking their last dose of study medication in the morning at home, the following assessments/procedures will take place during the in-clinic visit:

Following assessments/procedures have been and will take place on the day of the visit:

- Vital signs
- Blood sample for PK
- Blood sample for Plasma VMA (Part A)
- Daily participant E-dairy review for the most recent dosing sequence
- Scleroderma Health Assessment Questionnaire (SHAQ) which includes Raynaud's VAS to be completed by the participant with review by physician.

Physician has or will assess the below at the in-clinic visit, details of which will be recorded in the eCRF:

- Concomitant medications
- Rating severity of participant's Raynaud's disease
- Rating severity of participant's ulcers
- Rating overall health of participant for past week
- Physician's assessment of digital ulcers—how many ulcers, how many considered new, for each ulcer—location and diameter of the ulcer
- Thermography (for two most symptomatic areas in terms of Raynaud's)
- Endothelial dysfunction (Endo-PAT, Part A only)
- AE/SAE reporting
- Dispensing/returning study medication

Note: On the last clinic visit at the end of last Dosing Period (Dosing Period 1 for Part A and Dosing Period 4 for Part B), pregnancy test will be performed for WOCBP.

Washout Period

In Part B, each Dosing Period will be separated by a 4-day (±1 day) washout period. The washout period will commence the day after the in-clinic visit during which participants will not take any study medication. During the washout period, participants will be required to complete the daily participant E-Diary, reporting their symptoms of SSc-RP, and use of any concomitant medications. Once the 4-day washout is completed the participant will commence the daily at home dosing for the study medication dispensed at the pervious in-clinic visit. No washout period is required after the fourth and final in-clinic visit. After this visit participants will proceed directly to follow-up.

Follow-up

Participants have been or will be followed for 7 days following completion of the final Dosing Period.

Participants have or will be requested to complete the E-Diary for 7 days in Follow-up period. Participants have or will also be requested to report use of any concomitant medications and any AEs/SAEs during the Follow-up period.

This visit marks the end of participation in this study.

Early Termination (If Applicable)

Participants who withdraw early from the study will be encouraged to return to the clinic for an EOS assessment.

The following procedures will be conducted:

- Participants will be requested to complete the E-Diary for 7 days following termination
- Participants will be requested to report use of concomitant medications of interest for 7 days following termination
- Participants will be requested to report any AEs/SAEs for 7 days following termination.

This visit marks the end of participation for participants that withdraw early from the study.

Pharmacokinetic Assessments
Blood Sample Collection

One 4 mL blood sample has or will be obtained during each in-clinic visit within 2 to 6 hours of last dose of study drug in that Dosing Period as delineated in the SoA (FIG. 2 and FIG. 3A and/or FIG. 3B). The level of cilnidipine in blood has or will be measured following last dose of the Dosing Period. Sample handling details have been or will be provided in the PK manual. The actual collection time of each sample must be recorded in the source data documentation, on the collection tube and in the eCRF.

Efficacy Assessments
Efficacy Parameters

Study procedures should be completed as delineated in the SoAs (FIG. 2 and FIG. 3A and/or FIG. 3B).

E-Diary

The Sponsor-developed participant-informed E-Diary has been and will be used in this study to record data. Participants have been or will be required to keep and fill the E-Diary daily as delineated in the SoAs (FIG. 2 and FIG. 3A and/or FIG. 3B).

- The relevant metrics measured by this tool daily are:
- Study medication
- SSc-RP symptoms (Reporting an attack including duration of attack)
- Severity of the attack considering all symptoms of the attack e.g., tingling, numbness, pain, color changes (VAS 0-10 cm scale)
- Participant's location at the time of the attack (inside home/outside home)
- Selecting symptoms experienced during the attack (tingling, numbness, pain, color changes, other)
- Pain rating during the attack (11-point Likert scale)
- The RCS based on how much difficulty participants had with Raynaud's today, how many attacks the participant had, and how long they lasted. Participants will also be asked to consider how much pain, numbness, or other symptoms the Raynaud's caused in fingers (including painful sores), and how much the Raynaud's alone affected the use of hands today (VAS 0-10 cm scale).

The relevant metrics measured by this tool at the in-clinic visit (once in a Dosing Period) are:

- Digital ulcer severity (VAS 0-10 cm scale)—Applicable only if participant has digital ulcers.
- Scleroderma Health Assessment Questionnaire which includes Raynaud's VAS measuring participant quality of life over the past
  - Note: Digital ulcer severity (VAS 0-10 cm scale) and SHAQ scale can also be done on paper in-clinic, if necessary. Also, external temperature will be a feed into the E-Diary database based on participant's location.

Physician Assessments

The Physician has and will assess the below at the in-clinic visit, details of which will be recorded in the eCRF. In Part A, thermography and Endo-PAT will also be reported.

- Rating severity of participant's Raynaud's disease
- Rating severity of participant's ulcers
- Rating overall health of participant for past week
- Physician's assessment of digital ulcers—how many ulcers, how many considered new, for each ulcer: location and diameter of the ulcer
- Recording temperature of the affected index finger sites at two symptomatic areas at baseline and every in-clinic visit using the Fluor thermographic camera
- AE/SAE reporting.

Drug accountability, including dispensing and returning of the study medication will also be recorded at each visit.

Scleroderma Health Assessment Questionnaire (SHAQ)

The standard, validated, patient reported outcome measures tool for SSc patients, the SHAQ, will be collected at the time points specified in the study schedules (FIG. 2 and FIG. 2A and/or 3B). To assess the participant's quality of life. The SHAQ includes a Raynaud's VAS that will also be reported separately.

Thermography

Thermography assessments will be performed at the time points specified in the study schedules (FIG. 2 and FIG. 2A and/or 3B). Thermography will be conducted on the most severely impacted digits identified at Screening; the participant must be indoors for at least 30 minutes prior to the test to give the body time to equilibrate. Photos will be taken with the help of Fluor thermographic camera of these two areas at times specified in SoAs.

Plasma Vanylmandelic Acids (VMA)

Plasma VMA is a metabolite of norepinephrine. One sample was and will be collected during each in-clinic visit in Part A of the study to assess if a difference in sympathetic activity with cilnidipine can be detected.

Endothelial Dysfunction (Endo-PAT)

Assessments for endothelial dysfunction will be performed using Endo-PAT at timepoints specified in the Part A study schedule (FIG. 2). Endo-PAT assessment will not be performed in Part B of the study. The Endo-PAT is a diagnostic device used to assess endothelial vasodilator function in a rapid and non-invasive fashion.

The below points should be considered before assessment is started:

- 2. Prior to the study, the participant should fast for at least 4 hours, and should refrain from caffeine, vitamins or medications that might affect vascular tone for at least 8 hours. The participant must reconfirm their abstinence from tobacco and may use the restroom prior to the assessment.
- The Endo-PAT assessment should be conducted in a quiet, dimly lit, temperature-controlled (25° C. for at least 30 minutes) exam room to reduce fluctuations in vascular tone.
- Cell phones or paging devices should be silenced, and restrictive clothing that could interfere with blood flow to the arms should be removed. The participant should also remove watches, rings, or other jewelry on the hands or fingers.
- Participant's fingers should be inspected for any deformities or injuries that could affect the study. The probes should not be placed on a finger that is cut or injured. Fingernails should not extend more than 5 mm or ⅕ of an inch beyond the tip of the finger tissue.
- The index finger is recommended for the study; however, if this finger is unsuitable, a different digit (except the thumb) may be used, as long as the same finger is used on both hands.
- The participant should be supine and comfortable for 15 minutes so as to attain a cardiovascular steady state.

Safety Assessments
Safety Parameters

Study procedures should be completed as delineated in the SoA (FIG. 2 and FIG. 2A and/or 3B). Any unscheduled procedures required for urgent evaluation of safety concerns must take precedence over all routine scheduled procedures.

Demographic/Medical History

Medical history (including alcohol and smoking status), date of birth, age (calculated), weight, sex, ethnicity, and race were and will be recorded at Randomization (Day 0) visit.

Vital Signs

Vital signs (SBP, DBP, pulse rate, temperature) were measured and will be measured at the time points specified in the SoA (FIG. 2 and FIG. 2A and/or 3B) with participants resting for at least 5 minutes in a supine position. When the time of vital signs measurement coincides with a blood draw, the vital signs have been or will be taken before the scheduled blood draw where possible, ensuring the blood draw is within the window specified in the protocol.

Additional vital signs may be performed at other times if deemed necessary.

Laboratory Assessments

Routine hospital laboratory tests including hematology, biochemistry, inflammatory markers (CRP and ESR), and antibody status (Scl-70) should be conducted as clinically indicated per standard of care but are not required per protocol. If conducted, results will be collected in the eCRF and used to describe the severity of disease in the baseline demographic and disease data.

Additional clinical laboratory tests may be performed at other times if deemed necessary, based on the participant's clinical condition.

Pregnancy Testing

A urine pregnancy test will be performed at the Randomization (Day 0) visit and on the last clinic visit at the end of last Dosing Period for WOCBP only.

Adverse and Serious Adverse Events

In this study, AEs and SAEs will be reported for all participants from the time of randomization until the completion of the Follow-up/EOS visit. Adverse events that are ongoing at the EOS visit will be marked as Not Recovered/Not resolved on the AE eCRF page.

The Investigator will do full AE review during in-clinic visit. All spontaneously volunteered and enquired for, as well as observed AEs, will be recorded in the participant's medical records and the eCRF.

Complications of the Disease Under Study

Clinical features and symptoms of SSc-RP must be recorded as endpoints in the electronic data collection tools provided by the Sponsor, as well as in the source documents and should not be reported as AEs.

Definition of Adverse Events

An AE is any event, side effect, or other untoward medical occurrence that occurs in conjunction with the use of a medicinal product in humans, whether or not considered to have a causal relationship to this treatment. An AE can, therefore, be any unfavorable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

- Events meeting the definition of an AE include:
- Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition
- New conditions detected or diagnosed after study drug administration that occur during the reporting periods, even though it may have been present prior to the start of the study
- Signs, symptoms, or the clinical sequelae of a suspected interaction
- Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or concomitant medications (overdose per se will not be reported as an AE/SAE).
- Events that do not meet the definition of an AE include:
- Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure should be reported as an AE if it meets the criteria of an AE
- Situations where an untoward medical occurrence did not occur (e.g., social and/or convenience admission to a hospital)
- Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

If there is evidence of an AE through report or observation, the Investigator or designee will evaluate further and record the following information:

- Time of onset and resolution
- Severity
- Seriousness
- Causality/relation to study treatment
- Action taken regarding study drug
- Action taken regarding AE
- Outcome.

Severity of an Adverse Event

Severity of AEs will be graded by the Investigator as one of:

- Mild (Grade 1): A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living.
- Moderate (Grade 2): A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant.
- Severe (Grade 3): A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention.
- Life-threatening (Grade 4): A type of AE that places the participant at immediate risk of death.
- Death (Grade 5): Events that result in death.

Causal Relationship of an Adverse Event

The Investigator will assess the relationship between study drug and the occurrence of each AE. The Investigator's assessment of the relationship of each AE to study drug will be recorded in the source documents and the eCRF. Alternative causes, such as medical history, concomitant therapy, other risk factors, and the temporal relationship of the event to the study drug should be considered and investigated, if appropriate. The following definitions are general guidelines to help assign grade of attribution:

- Not related: The event is clearly related to other factors such as the participant's environment or clinical state, therapeutic interventions or concomitant drugs administered to the participant. This is especially so when an event occurs prior to the commencement of treatment with the study drug.
- Unlikely: The temporal association, participant history, and/or circumstances are such that the study drug is not likely to have had an association with the observed event. Other conditions, including concurrent illness, progression, or expression of the disease state, or reaction to a concomitant drug administered appear to explain the event.
- Possible: The event follows a reasonable temporal sequence from the time of study drug administration or follows a known response to the study drug but could have been produced by other factors such as the participant's clinical state, other therapeutic interventions, or concomitant drugs administered to the participant.
- Probable: The event follows a reasonable temporal sequence from the time of study drug administration and follows a known response to the study drug and cannot be reasonably explained by other factors such as the participant's clinical state, other therapeutic interventions, or concomitant drugs administered to the participant.
- Definite: The event follows a reasonable temporal sequence from the time of study drug administration or control abates upon discontinuation or cannot be explained by known characteristics of the participant's clinical state.
  
  Action Taken with Investigational Products

Should the Investigator need to alter the administration of the study drug from the procedure described in the protocol due to the wellbeing and safety of the participant then the action taken will be recorded on the AE eCRF page, as one of the following options:

- Dose Reduced
- Drug Interrupted
- Drug Withdrawn
- Not Applicable
- Other.

Outcome

- Outcome of an AE will be recorded on the AE eCRF as follows:
- Recovered/Resolved
- Recovering/Resolving
- Recovered/Resolved with Sequelae
- Not Recovered/Not Resolving
- Fatal
- Unknown.

Definition of Serious Adverse Event

An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the study drug (active or placebo), that fulfills one or more of the following:

- Results in death
- It is immediately life-threatening
- It requires in participant hospitalization or prolongation of existing hospitalization
- It results in persistent or significant disability or incapacity
- Results in a congenital abnormality or birth defect
- It is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above.

Important medical events that may not be one of the above may be considered an SAE by the Investigator when, based upon appropriate medical judgment, they are considered clinically significant and may jeopardize the participant, or may require medical or surgical intervention to prevent one of the outcomes listed above.

An AE is considered “life-threatening” if, in the opinion of either the Investigator or the Sponsor, its occurrence places the participant at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death.

Statistics

Statistical methods will be further outlined in the statistical analysis plan (SAP, see Example 2) and approved by the Sponsor. Procedures outlined in the SAP will supersede protocol specified statistical methods in the event of divergence.

Part A and Part B data will be analysed separately. Analysis of Part A data was and will be mainly exploratory to support cilnidipine dose selection and treatment effect check for sample size confirmation for Part B.

In general, descriptive statistics (e.g., arithmetic mean, SD, median, minimum and maximum) will be calculated for continuous safety data by treatment and protocol specified time point, while frequency summary (e.g., number of observed and percentage of each categories) will be applied for categorical safety data by treatment and protocol specified time point.

Sample Size

The sample size was calculated based on the CCB data in confidence bound in literature report (Rirash 2017). Assuming a 2-sided 0.05 alpha for treatment (cilnidipine or combination therapy or tadalafil) versus placebo and without controlling alpha for the multiple efficacy comparisons, a sample size of eight participants in each paired comparison group (cilnidipine or combination therapy or tadalafil) is needed for 80% power in a 4×4 crossover design to detect a 25% difference at common SD of 0.5 (a moderate effect size) in percent change from baseline of Raynaud's attack per week. Assuming a 20% dropout rate for final efficacy analysis, ten participants in each group is planned.

After reviewing the results from Part A: Run-in phase, the sample size for Part B may be adjusted.

Analysis Populations

Participant inclusion into each population has been or will be determined prior to the final analysis.

Intent-To-Treat (ITT) Population

All participants who are entered into the study and complete screening, sign an informed consent for the study and randomized have been or will be included in the ITT population.

Per Protocol Population

All participants who complete the study with all Dosing Periods (for Part B— at least 5 days of dosing within the last 7 days treatment for the first two periods, and 4 days of dosing within the last 7 days treatment for the second two periods) and meet all eligibility criteria, will be included in the PP Analysis Population.

Pharmacokinetic Population

All participants who receive any amount of active study drug and have sufficiently evaluable concentration time profile to allow determination of at least one PK parameter will be included in the PK population. An evaluable PK profile will be determined at the discretion of the pharmacokineticist following examination of participants with dosing or protocol deviations that could potentially affect the PK profile. The PK population will be used for the summaries of all PK data.

Safety Population

All randomized participants who received study drug have been or will be included in Safety population and will be classified according to the actual treatment received.

Statistical Methods
Participant Disposition

Participant disposition has been and will be analysed using counts and percentages. The number and percentage of screened participants, enrolled participants, treated participants, participants discontinued from the study and study treatment, as well as the primary reason for discontinuation has been and will be analysed and listed.

Demographics, Medical History, and Baseline Characteristics

Demography and baseline characteristics data has been and will be analysed using descriptive statistics. The following demographic variables will be summarized by dose level: race, gender, age, height and weight, concomitant diseases (Hypertension, peripheral vascular disease, diabetes, CKD and stage, osteoporosis, history and type of heart arrhythmia).

In addition, the following baseline characteristics of Raynauds Disease have been and will be analysed will be summarized: age of onset, seasonality (months disease is worst), usual number of attacks/day, usual peak severity, baseline RCS assessment, how attacks are usually treated, how long attacks last in general, experience with other treatments both pharmacological and non-pharmacological.

Medical history terms are coded using the MedDRA® Version 22.0 or higher. Medical history has been and will be analysed using descriptive statistics by MedDRA® SOC and PT.

Prior and Concomitant Medication

Prior and concomitant medications were or will be coded using the most current version of the WHO drug dictionary available at the start of the study. Prior and concomitant medications will be listed by participant and summarized by treatment using anatomical therapeutic chemical (ATC) and preferred name.

Treatment Compliance and Exposure

Treatment compliance and exposure has been and will be summarized and listed by treatment for all participants in the Safety population.

Analysis of Primary Endpoint

Percent change from baseline evaluation for frequency of weekly RP attacks is and will be the primary efficacy endpoint. Data collected in the last 7 days of each Dosing Period was and will be used for this analysis. Screening assessments were and will be used as baseline for the analysis of all periods. No multiple comparison adjustment will be used to control alpha for the multiple comparisons. Mixed effects model will be used for analysis of the primary endpoint according to the crossover design. Other efficacy endpoints of continuous variables will be analysed using similar methodology. For nominal data, Chi-square tests will be applied. Generalized Estimating Equations method will be used, as appropriate, for adjusting for potential confounding factors. In addition, the final analysis will assess whether in this study of severe Raynaud's disease participants, the minimally important difference, previously concluded of 14-15 points on the 100 point RCS scale (Khanna, 2010) has been achieved in the cilnidipine dose group. It also will record the percentage of participants achieving a PASS (34 point difference from baseline on a 0-100 VAS) (Khanna, 2010) in each treatment group.

Analysis of Secondary Endpoints

The secondary endpoints of change from baseline evaluation will be compared among treatment groups using mixed effects model. Kaplan-Meier method will be used to evaluate time to event endpoints. To evaluate the impact of daily ambient temperature on symptomatic Raynaud's attack, logistic regression will be used for temperature versus the occurrence of Raynaud's attack (Yes/No). The effect of temperature on the severity score of Raynaud's attacks and difference of using rescue medication between treatment groups will be evaluated by Chi-square test. The impact of therapy in sympathetic activity will be assessed by mixed model for repeated measures.

Safety Analyses

All safety assessments, including AEs, laboratory evaluations, vital signs, and other safety assessments will be analysed using the Safety population.

Adverse Event

Adverse events will be coded using the most current version of the MedDRA® Version 22.0 or higher. The analysis of AEs will be based on the concept of treatment emergent AEs. Treatment emergent AEs will be tabulated by treatment group and will include the number of participants for whom the event occurred, the severity, and relationship to study drug. Treatment emergent AEs (TEAEs) leading to discontinuation and SAEs with onset after the start of study drug will also be summarized.

All AEs and SAEs (including those with onset or worsening before the start of study drug) through the end of the study will be listed.

Laboratory Evaluations

Baseline laboratory evaluations will be listed and summarized by treatment.

Vital Signs

Vital signs (BP [systolic and diastolic], pulse rate, and oral temperature) will be listed and summarized by treatment and protocol specified collection time point. Observed and change from baseline will be summarized at each protocol specified collection time point.

Other Safety Assessments

The following assessments will be listed by participant:

- Pregnancy Test
- Raynaud's function assessment by physician.

Pharmacokinetics

Plasma concentrations and actual blood sampling times will be listed by treatment and protocol specified time point and summarized using descriptive statistics number of measurements, arithmetic mean, SD, and % CV, geometric mean, minimum, median, and maximum—at each scheduled time point. Individual and mean plasma concentration-time profiles will also be presented graphically for each treatment.

Pharmacokinetic parameters will be computed from the individual plasma concentrations using a non-compartmental approach.

Value for elimination rate constant (k_d), elimination half-life (t_1/2), Area under the plasma concentration-time curve from time zero to infinity (AUC_0-inf), apparent total clearance of the drug from plasma after oral administration (CL/F) or apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F) will not be reported. Additional analyses will be performed as deemed necessary upon review of the data.

REFERENCES

Khanna P P, Maranian P, Gregory J, Khanna D. The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomized controlled clinical trial. Ann Rheum Dis. 2010; 69(3):588-591. doi:10.1136/ard.2009.107706

Rirash F, Tingey P C, Harding S E, et al. Calcium channel blockers for primary and secondary Raynaud's phenomenon. The Cochrane database of systematic reviews, 2017; 12(12), CD000467.

Example 2. Statistical Analysis Plan
Introduction

The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical methods that have been and will be used to analyze data and report results collected as described in Example 1.

Study Objectives

This study is a placebo-controlled phase 2a study to test the efficacy and safety of cilnidipine alone and in combination with tadalafil in participants who have frequent attacks of secondary RP mostly resulting from SSc (e.g., SSc-RP). The study consists of two parts, Part A and Part B.

The primary purpose of Part A (a double-blind, placebo-controlled, parallel-group study testing 6 treatment combinations) was to generate efficacy and safety data that allows the DSMB to select the dose of cilnidipine (10 mg or 20 mg) to be studied in Part B and to confirm the sample size estimates for Part B of the study.

Part B will provide the primary evidence of efficacy and safety. Part B is a double-blind, placebo-controlled, 4-way crossover study, designed to assess the safety and efficacy of cilnidipine (at the dose selected in Part A) alone and in combination with 5 mg tadalafil. Participants will be randomized to one of four prespecified treatment sequences in a 4-way crossover design.

Primary Efficacy Objective

The primary efficacy objective of the study was and is to evaluate the effect of cilnidipine alone and in combination with tadalafil on the frequency of weekly Raynaud's Phenomenon (RP) attacks compared with placebo in participants with Raynaud's Phenomenon secondary mostly to systemic sclerosis (SSc-RP).

Secondary Efficacy Objective

The secondary efficacy objective of the study is to evaluate the effect of cilnidipine alone and in combination with tadalafil on the clinical, measured, and global features of SSc-RP and the severity and burden of these SSc-RP symptoms.

Safety Objective

The safety objective of the study was and is to evaluate the safety of cilnidipine alone and in combination with tadalafil compared to placebo in participants with SSc-RP.

Exploratory Objective (Part A, Dose Selection) To assess the endothelial function of participants with SSc-RP and impact of treatment on sympathetic activity and vascular functioning (Part A).

Study Endpoints
Primary Efficacy Endpoint

The primary efficacy endpoint of this study is:

- Percentage change from baseline in frequency of weekly RP attacks.

Secondary Efficacy Endpoints

Secondary efficacy endpoints of the study include:

- Change from baseline in frequency of weekly RP attacks
- Change from baseline in average duration of weekly RP attacks
- Change from baseline in average severity of weekly RP attacks
- Change from baseline in average daily Raynaud's Condition Score (RCS)
- Change from baseline in highest (most severe) pain score recorded during weekly RP attacks
- Change from baseline in average pain score recorded during weekly RP attacks
- Change from baseline in net digital ulcer burden
- Change from baseline in Distal-dorsal difference (DDD) of the affected index finger sites
- Change from baseline in participant quality of life measured using the Scleroderma Health Assessment Questionnaire (SHAQ)
- Change from baseline in participant gastrointestinal symptoms (of sclerosis) as assessed with the UCLA SCTC GIT 2.0 questionnaire
- Change from baseline in Raynaud—Visual analog scale (VAS)
- Change from baseline in physician assessment of disease
- Measurement of cilnidipine drug levels taken 2 to 6 hours following the last dose
- The time to reach maximum degree of efficacy (in days) compared to baseline
- The time to return to baseline symptom severity after termination of dosing
- Impact of daily ambient temperature on symptomatic RP attacks
- Use of rescue medications for breakthrough symptoms.

Safety Endpoints

The safety endpoint of the study is:

- Incidence of adverse events (AEs) and serious adverse events (SAEs), including clinically significant vital signs from the time of randomization until 7 days following the last protocol dose.

Exploratory Endpoint (Part A Dose Selection)

- Change from baseline in endothelial function as measured by Reactive Hyperemia Index (RHI) using Endothelial Dysfunction (Endo-PAT)

Summary of the Study Design
General Study Design and Plan

A schematic of the overall study design is provided in FIG. 1. Participants have or will undergo a screening period beginning up to 10 days prior to randomization. The initial screening and capacity was or will be conducted via phone at the start of the Screening period with eligibility finalized prior to randomization on Day 0. Participants were or will be required to provide informed consent in a 2-step process at Screening (by agreeing to complete the screening Diary) and at Randomization (Day 0) before undertaking any study-specific procedures or assessments. Only participants who met or will meet all of the inclusion and none of the exclusion criteria were or will be randomized.

Part a—Double-Blind, Placebo-Controlled, Parallel-Group, Dose Selection

Assess the safety and efficacy of two doses of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil. A total of 36 participants were or will be randomized to one of six pre-specified parallel treatment arms.

Please refer to FIG. 1 for treatment arms in Part A of the study. Dosing lasted or will last for 12 (±2) days in which participants self-administered or will self-administer daily doses of assigned treatment in the morning. Each participant took or will take one capsule and one tablet to blind the active therapy being received.

The data from Part A of the study will be reviewed by a data and safety monitoring board (DSMB) including unblinded analysis results, to support selecting the cilnidipine dose and confirming the sample size estimates for the randomized, double-blind, crossover design, phase (Part B).

The first review by the DSMB will occur after 16 participants completed the study in Part A.

Part B—Double-Blind, Placebo-Controlled, 4-Way Crossover

Assess the safety and efficacy of cilnidipine (at the dose selected in Part A) alone and in combination with 5 mg tadalafil. A total of 40 participants (10 in each sequence) with a diagnosis of SSc-RP will be randomized into one of four pre-specified treatment sequences in a 4-way crossover design. Part B is designed to provide the primary evidence for efficacy analyses.

FIG. 1 depicts the treatment sequences in Part B of the study. Each participant will undergo four dosing periods in which they will receive a different treatment each dosing period followed by a 4 (±1) day washout period. Each dosing period will last for 12 (±2) days in which participants will self-administer daily doses of assigned treatment in the morning. At all dosing periods, each participant will take one capsule and one tablet to blind the active therapy being received.

For both Part A and B of the study, participants were or are required to visit the clinic on last day of each dosing period (i.e., Day 10 to 14) to return/dispense study drug and conduct in person study assessments. Participants were or will be dispensed with 2 weeks' worth of study drug to be taken at home for the following dosing period; overage from the prior dosing period will also be collected.

Patients were and will be assessed for the occurrence of efficacy endpoints for each dosing period via the patient reported diary and the in-clinic visit. Safety information was and will be collected for each dosing period from randomization until patient follow-up is complete (7 to 10) days after the last dosing.

Patients completing Part A may also be enrolled in Part B, as long as they are eligible per the inclusion criteria of Example 1 is met.

Randomization and Blinding

Each participant was or will be provided with a unique screening number post-documentation of informed consent. Once deemed eligible, the participant was or will be assigned a sequential randomization number prior to first dosing in each Part A and Part B as described below. Participants who withdraw from the study or who fail to meet inclusion criteria, for any reason, prior to randomization will be considered screen failures.

Part A

A total of 27 participants were randomized in a 1:1:1:1:1:1 ratio to receive one of six pre-specified, parallel treatment arms cilnidipine 10 mg, cilnidipine 20 mg, tadalafil 5 mg, cilnidipine 10 mg+tadalafil 5 mg, cilnidipine 20 mg+tadalafil 5 mg, or placebo.

Part B

A total of 40 participants (10 in each sequence) will be randomized to 1 of 4 treatment sequences of 4 crossover periods, according to a 4×4 Williams square, as outlined in Table 1.

TABLE 1

Part B 4-way crossover

Dosing
Dosing
Dosing
Dosing

Sequence #
Period 1
Period 2
Period 3
Period 4

1
P
C
C + T05
T05

2
T05
C + T05
P
C

3
C + T05
T05
C
P

4
C
P
T05
C + T05

Abbreviations: C = cilnidipine, P = placebo, T = tadalafil, N = number of participants, T05 = T 5 mg.

Dose of C, either 10 mg or 20 mg will be identified following completion of Part A.

Once a randomization number was or is assigned, it cannot be reassigned to any other participant. All participants who are randomized will be followed and included in the primary ITT analysis. Dropouts will not be replaced.

All randomization codes were or will be generated by the designated unblinded independent statistician prior to the start of the study. Sealed code break envelopes will be provided prior to start of the study.

Sample Size and Statistical Power Considerations

The sample size was calculated based on the CCB data in confidence bound in literature report (Rirash 2017 referenced in Example 1). Assuming a 2-sided 0.05 alpha for treatment (cilnidipine or combination therapy or tadalafil) versus placebo and without controlling alpha for the multiple efficacy comparisons, a sample size of eight participants in each paired comparison group (cilnidipine or combination therapy or tadalafil) is needed for 80% power in a 4×4 crossover design to detect a 25% difference at common SD of 0.5 (a moderate effect size) in percent change from baseline of Raynaud's attack per week. Assuming a 20% dropout rate for final efficacy analysis, ten participants in each group is planned for Part B.

After reviewing the results from Part A: Dose selection phase, the power assumptions will be reviewed and sample size for Part B may be adjusted.

Statistical Considerations
General Considerations

The statistical analysis will be conducted following the principles specified in the International Council for Harmonization (ICH) Topic E9 Statistical Principles for Clinical Trials. For more information, see https://www.ema.europa.eu/en/ich-e9-statistical-principles-clinical-trials, which is incorporated by reference herein in its entirety.

Unless otherwise noted, continuous variables will be summarized by number of subjects (n), mean, standard deviation (SD), first quartile (Q1), median, third quartile (Q3), minimum and maximum values. In addition, change from baseline values will be calculated at each time point and summarized descriptively. Categorical variables will be summarized by frequency count and the percentage of subjects in each category. Summaries will be generated for each treatment, where appropriate. Individual subject data will be presented in subject data listings.

The default significant level will be 5%; confidence intervals (CIs) will be 95% and all tests will be two-sided, unless otherwise specified in the description of the analyses. Min and max values will be rounded to the precision of the original value. Means, and medians will be rounded to one decimal place greater than the precision of the original value. SDs, SEs, and 95% CIs will be rounded to two decimal places greater than the precision of the original value. Percentages for summarizing categorical data will be rounded to one decimal place. P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999.”

Definitions of Analysis Populations

Participant inclusion into each analysis population will be determined prior to the final analysis.

Intent-To-Treat (ITT) Population

All participants who enter or entered into the study and complete screening, sign or signed an informed consent for the study and randomized will be included in the ITT population. Treatment classification will be based on the randomized treatment for analysis.

Per Protocol Population

All participants who complete the study with all Dosing Periods (for Part B— at least 5 days of dosing within the last 7 days treatment for the first two periods, and 4 days of doing within the last 7 days treatment for the second two periods), meet all eligibility criteria, and without any major/important protocol deviations, will be included in the per-protocol (PP) population. PP analysis population will be evaluated and finalized before database lock.

Pharmacokinetic Population

All participants who receive any amount of active study drug and have sufficiently evaluable concentration time profile to allow determination of at least one pharmacokinetic (PK) parameter were or will be included in the PK population. An evaluable PK profile was or will be determined at the discretion of the pharmacokinetic specialist following examination of participants with dosing or protocol deviations that could potentially affect the PK profile. The PK population was or will be used for the summaries of all PK data.

Safety Population

All randomized participants who received study drug were or will be included in Safety population and have been or will be classified according to the actual treatment received.

Data from Part A and Part B will be analyzed separately. The pooled analyses of Part A and Part B may be conducted as exploratory for participants with common treatment. The intent-to-treat (ITT) population will be used to summarize participant disposition. The primary and secondary efficacy analyses will be based on the ITT population. Analyses based on the PP population for Part B will be considered secondary and confirmatory. All safety analyses will be performed on the safety population.

Definitions and Conventions for Data Handling
Baseline Definition

In general, the non-missing measurements collected during the last 7 days prior to the date of randomization served and will serve as the data for calculation of baseline measurements for efficacy variables. The data collected for assessments that were or are performed first time on randomization (Day 0) visit (vital signs, digital ulcer assessment, and Endo-PAT) will serve as baseline measure for efficacy endpoints for those assessments. If there is no value on or prior to the date of randomization, then the baseline value will not be imputed, and will be set to missing.

Study Day

Study day has been and will be calculated from the reference start date and was and will be used to show start/stop day of assessments and events.

Reference start date (Day 1) was or is defined as the date of first dose of study drug.

- Study day=(date of event−reference start date+1) if the event date is on or later than reference start date
- Study day=(date of event−reference start date) if the event date is earlier than reference start date

In the situation where the event date is partial or missing, Study day, and any corresponding durations will appear partial or missing in the listings.

Analysis Visit Windows

For all analyses for this study, the scheduled visit and/or time point from the case report form (CRF) (i.e., CRF visit) was or will be used as the analysis visit and/or time point.

Measurements collected from unscheduled visits will not be included in the by visit summary tables but will be included in the listings.

Missing Data Handling Rules

Missing data as well as data from participants who drop out early was or will not be imputed.

Examination of Subgroups

The following subgroup analysis will be performed for the primary efficacy analysis. Subgroup results need to be interpreted with caution if there are insufficient number of subjects in a subgroup.

Part A/Part B:

- Baseline RP attack frequency: >=13-<=20 attacks per week, >20-<=30 attacks per week, >30 attacks per week
- Average baseline RCS score: Baseline RCS<35, >=35-<=75, >75
- Time of RP attacks since daily study medication: <8 hours, >=8-<=16 hours, >16-<=24 hours

Part B (Additional Analyses):

- Age group (<45, >=45 and <=64, >=65)
- Gender
- Baseline Weight: <60 kg, >=60-<=100 kg, >100 kg
- Baseline scleroderma diagnosis: Y/N
- Smoking status: active, former, non-smoker
- Duration of dosing: <10 days, >=10-<12 days, >=12-<=14 days
- Stable use of concomitant CCBs: Y/N
- Rescue medicines required: Y/N
- Behavioral modifications required: Y/N

Primary, Secondary and Other Variables
Primary Efficacy Variable

Percent change from baseline evaluation for frequency of weekly RP attacks were or will be used as the primary efficacy variable. The sponsor-developed participant-informed diary will be used to record data. Frequency of weekly RP attacks is defined as the total number of RP attacks divided by the number of days with available diary data within the last 7 days of each dosing period then multiplied by 7. Total number of RP attacks during the last 7 days of screening period divided by the number of days with available data then multiplied by 7 will be used as baseline for the analysis of all periods. The variable will be calculated as follows:

$Percentage change = {(weekly RP attacks for the last 7 days of each dosing period - Baseline weekly RP attacks) / Baseline weekly RP attacks} * 100 % .$

Secondary Efficacy Variables

Change from Baseline in Frequency of Weekly RP Attacks

The absolute change in frequency of weekly RP attacks from baseline to the end of each Dosing Period was and will be a secondary outcome variable and calculated as follows:

Absolute change=weekly RP attacks for the last 7 days of each dosing period−Baseline weekly RP attacks

Change from Baseline in Average Duration of Weekly RP Attacks

The absolute change in average duration of weekly RP attacks from baseline to the end of each dosing period was and will be a secondary outcome variable. The sponsor-developed participant-informed diary was and will be used to record data. Average duration of weekly RP attacks is defined as the total duration of RP attacks divided by total number of RP attacks within the last 7 days of each dosing period. Total duration of RP attacks during the last 7 days of screening period divided by the total number of RP attacks will be used as baseline for the analysis of all periods. The variable will be calculated similar to frequency data as before.

Change from Baseline in Average Severity of Weekly RP Attacks

The absolute change in average severity of weekly RP attacks (VAS 0-10 cm scale) from baseline to the end of each Dosing Period was and will be a secondary outcome variable. The sponsor-developed participant-informed diary will be used to record data. Average severity of weekly RP attacks is defined as the total severity scores of RP attacks divided by total number of RP attacks within the last 7 days of each dosing period. Total severity scores of RP attacks during the last 7 days of screening period divided by the total number of RP attacks will be used as baseline for the analysis of all periods. The variable will be calculated similar to frequency data as before.

Change from Baseline in Average Daily RCS

The RCS is based on how much difficulty participants had with Raynaud's today, how many attacks the participant had, and how long they lasted. In addition participants were and will be asked to consider how much pain, numbness, or other symptoms the Raynaud's caused in fingers (including painful sores), and how much the Raynaud's along affected the use of hand today (VAS 0-10 cm scale).

The absolute change in average daily RCS from baseline to the end of each dosing period was and will be a secondary outcome variable. The sponsor-developed participant-informed diary has been and will be used to record data. The average daily RCS is defined as the total RCS divided by the number of days with available diary data of each dosing period. Total RCS during screening period divided by the number of days with available data will be used as baseline for the analysis of all periods. If there are multiple daily RCS scores, the latest daily RCS will be used. The variable will be calculated similar to frequency data as before.

Change from Baseline in Highest (Most Severe) Pain Score Recorded During Weekly RP Attacks

The absolute change in highest pain score (11-point Likert scale) of weekly RP attacks from baseline to the end of each dosing period will be a secondary outcome variable. The sponsor-developed participant-informed diary will be used to record data. The highest pain score collected during the last 7 days of each dosing period will be used for this analysis. The highest pain score among the last 7 days of screening assessments will be used as baseline for the analysis of all periods. The variable will be calculated similar to frequency data as before.

Change from Baseline in Average Pain Score Recorded During Weekly RP Attacks

The absolute change in average pain score (11-point Likert scale) of weekly RP attacks from baseline to the end of each Dosing Period will be a secondary outcome variable. The sponsor-developed participant-informed diary will be used to record data. The average pain score of weekly RP attacks is defined as the total pain scores divided by total number of RP attacks within the last 7 days of each dosing period. Average of the last 7 days of screening assessments will be used as baseline for the analysis of all periods. The variable will be calculated similar to frequency data as before.

Change from Baseline in Net Digital Ulcer Burden

If participant has digital ulcers, the absolute change in digital ulcer severity (VAS 0-10 cm scale) from baseline to the end of each dosing period will be a secondary outcome variable. The digital ulcer will be assessed by physician at screening and the in-clinic visit. Screening assessments will be used as baseline for the analysis of all periods. The variable will be calculated similar to frequency data as before.

Change from Baseline in Distal Dorsal Difference (DDD) of the Affected Index Finger Sites

Thermography assessments will be performed by physician at the in-clinic visit. Thermography will be conducted on the ring, middle and index digits of both hands; the participant must be indoors for at least 30 minutes prior to the test to give the body time to equilibrate. Photos will be taken with the help of Fluor thermographic camera of these two areas at the in-clinic visit.

The absolute change in DDD measured by thermography from baseline to the end of each dosing period will be a secondary outcome variable. Each participant will have 4 DDD scores at each visit: PIP nailbed Left, DIP-PIP Left, PIP nailbed Right and DIP-PIP Right. The variable will be calculated similar to frequency data as before and the analysis will be summarized by hand and location.

Change from Baseline in Participant Quality of Life Measured Using the SHAQ

The standard, validated, patient reported outcome measures tool for SSc patients, the Scleroderma Health Assessment Questionnaire (SHAQ), will be used to assess the participant qualify of life. Details are attached in the Appendix. The participant quality of life will be scored, and a disability index calculated for each questionnaire completed by the patient at Screening and each in-clinic visit. The absolute change in participant quality of life from baseline to the end of each dosing period will be calculated similar to frequency data as before.

Change from Baseline in Participant Gastrointestinal Symptoms (of Sclerosis) as Assessed with the UCLA SCTC GIT 2.0 Questionnaire

The standard, validated, patient reported outcome measures tool for SSc patients, the University of California at Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0), will be used to assess the participant gastrointestinal symptoms (of sclerosis). Details are attached in the Appendix. The participant gastrointestinal symptoms will be assessed at Screening and each in-clinic visit. Participant responses to the questionnaire will be scored and used to calculate a total score indicating the impact of gastrointestinal symptoms on quality of life. The constipation score is not included in the calculation of the total score and will be reported separately. The absolute change in participant gastrointestinal symptoms from baseline to the end of each dosing period will be calculated similar to frequency data as before.

Change from Baseline in Raynaud—Visual Analog Scale (VAS)

The SHAQ includes a Raynaud's VAS, which will be reported at screening and each in-clinic visit. The absolute change in Raynaud-VAS, assessed by the participants response to the SHAQ question ‘In the past 7 days, how much have your Raynaud's interfered with your daily activities?’ at baseline and the end of each dosing period will be calculated similar to frequency data as before.

Change from Baseline in Physician Assessment of Disease

The Physician will rate severity of participant's Raynaud's disease at Screening and in-clinic visit. The absolute change in physician assessment of disease from baseline to the end of each dosing period will be calculated similar to frequency data as before.

Measurement of Cilnidipine Drug Levels Taken 2 to 6 Hours Following the Last Dose

One 4 mL blood sample will be obtained during each in-clinic visit within 2 to 6 hours of the last dose of study drug in that dosing period. The level of cilnidipine in blood will be measured following last dose of the dosing period. The actual sampling times will be used in the PK parameter calculations.

Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of concentration and resulting PK parameters, with amount or concentration in the unit, will be presented as they are received from the analytical laboratory. If values below LLOQ is noted, half of the LLOQ will be imputed for summary analysis, but below LLOQ will be left as is in listings.

The Time to Reach Maximum Degree of Efficacy (in Days) Compared to Baseline

The maximum degree of efficacy is defined as the least daily frequency of PR attacks. If there are more than one day with the same least frequency of PR attacks, the time to the first maximum degree of efficacy will be used for this analysis.

The Time to Return to Baseline Symptom Severity after Termination of Dosing

During each washout period and follow-up period, the time to return to the worst baseline severity of weekly PR attacks will be calculated as the first time of return to the worst baseline severity—the previous in-clinic visit date. A participant with no improvement after baseline or never returns to baseline symptom severity will be regarded as censored.

Safety Variables
Extent of Exposure

Extent of exposure in days for each Dosing Period was and will be derived from the following formula:

$Extent of exposure (days) = (date of first dose of each Dosing Period) - (date of last dose of each Dosing Period) + 1$

All doses were and will be self-administered by participants remote from study sites (at home). For each dosing period, participants were or will be dispensed with two weeks' worth of study medication and will be asked to return the unused study medication on the last day of each Dosing Period at the time of in-clinic visit. The treatment compliance was and will be noted by the Investigator(s) during the in-clinic visit.

Adverse Events

AEs will be coded by System Organ Class (SOC) and Preferred Term (PT) using the MedDRA® Version 22.0 or higher. The verbatim term will be included in the AE listings.

Treatment-emergent AEs (TEAEs) are defined as AEs that occur or worsen after the dose of study drug. If the timing of the start of an AE could not be determined unambiguously from the start or end dates provided, it will be assumed to be a TEAE. An AE is considered related if the relationship to either of the study drug has been indicated as possibly or probably or definite related by the investigator. An AE leading to study withdrawal is defined as an AE that cause a subject early terminated from the study. AEs will be identified as emerging in the following parts:

- TEAEs for Part A will be those that started during Part A (i.e., from the first dose in Part A to end of follow up of Part A)
- TEAEs for Part B will be those that started during Part B (i.e., from the first dose in Part B to end of follow-up of Part B).

The TEAEs by treatment will be presented according to the last treatment received prior to the AE start date for crossover periods in Part B.

All AEs will be listed by participant but only TEAEs will be summarized.

Clinical Laboratory Variables

Routine hospital laboratory tests including hematology, biochemistry, inflammatory markers (CRP and ESR), and antibody status (Scl-70) will be conducted as clinically indicated per standard of care but are not required per protocol.

Vital Signs

Vital signs including Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), pulse rate, and temperature were and will be measured at Screening and each in-clinic visit.

Changes in vital signs variables between baseline and each subsequent scheduled assessment will be calculated. Absolute values will be compared to the relevant reference ranges and classified as LNH (low (below range), normal (within range or on limits) or high (above range)). All values (absolute and change) falling outside the reference ranges (see Table 2) will be flagged.

TABLE 2

Vital signs reference ranges

Standard
Lower
Upper

Parameter
Units
Limit
Limit

Diastolic Blood Pressure (DBP)
mmHg
60
120

Systolic Blood Pressure (SBP)
mmHg
100
160

Pulse Rate
Beats/min
40
120

Body Temperature
Celsius
36.5
38

Weight
kg
40
200

Body mass index (BMI) will be calculated from the height and weight as follows: BMI (kg/m²) = weight (kg)/(height (m))²

Other Safety Variables

A urine pregnancy test will be performed at the randomization (Day 0) visit and on the last clinic visit at the end of last dosing period for Woman of childbearing potential (WOCBP) only.

Raynaud's function assessment will be conducted by Physician at Randomization (Day 0) visit and each in-clinic visit.

Exploratory Variables
Endothelial Function

Assessments for endothelial dysfunction will be performed using Endo-PAT at randomization (Day 0) visit and each in-clinic visit for Part A only; Endo-PAT assessment will not be performed in Part B of the study. The Endo-PAT is a diagnostic device used to assess endothelial vasodilator function in a rapid and non-invasive fashion. Endothelial function will be measured using the reactive hyperemia index (LnRHI): (normal LnRHI is ≥0.7; Grey zone 0.51-0.7; Abnormal ≤0.51). The absolute change from baseline will be calculated similar to frequency data as before.

Analysis Methods
Subject Information
Disposition of Subjects

All screened participants will be included in the summaries of participant disposition. Separate summaries will be provided for Part A and Part B. The summaries will include the number of screened participants, the number of randomized participants, the number and percentage of treated participants, participants discontinued from the study and study treatment, and the primary reason for discontinuation.

The number and percentage of participants in each of the ITT population, PP population, PK population, and Safety population will also be summarized.

Listings of participant disposition will be provided by participant.

Protocol Deviations

Prior to database lock, all Protocol Deviations (PDs) will be identified and documented based on a blinded review of potential PDs. The potential PDs will be reviewed by study team and classified as major or minor. All PDs will be listed by participant.

Major PDs will be summarized by classification and treatment sequence.

Demographics and Baseline Characteristics

Demography and baseline characteristics data will be summarized using descriptive statistics. The following demographic variables will be summarized by treatment sequence: race, gender, age (summarized both as a continuous variable and as a categorical variable, with categories <45 years, >=45 to <=64 years, and >=65 years), height and weight, concomitant diseases (hypertension, peripheral vascular disease, diabetes, CKD and stage, osteoporosis, history and type of heart arrhythmia). Separate summaries will be provided for Part A and Part B.

In addition, the following baseline characteristics of Raynaud's Disease will be summarized: age of onset, seasonality (months disease is worst), usual number of attacks/day, usual peak severity, baseline RCS assessment, how attacks are usually treated, how long attacks last in general, experience with other treatments both pharmacological and non-pharmacological.

Pregnancy test results will be listed but not summarized.

A listing of demographic and baseline characteristics will be provided by participant.

Medical History

Medical history terms will be coded using the MedDRA® Version 22.0 or higher. Medical history will be summarized by MedDRA® SOC and PT. Medical history will be listed by participant.

Prior and Concomitant Therapy

Medications will be coded using the most current version of the WHO drug dictionary available at the start of the study.

Those medications taken prior to first dose of randomized study drug will be denoted “Prior.” Those medications started at the same time or after the first dose of randomized study drug will be denoted “Concomitant.”

Medications will be presented according to whether they are “Prior” or “Concomitant,” as defined above. Note that a medication could be both prior and concomitant. If medication dates are incomplete and it is not clear whether the medication was concomitant, it will be assumed to be concomitant.

Prior and concomitant medications will be listed by participant and summarized by treatment using anatomical therapeutic chemical (ATC) and preferred name.

Treatment Compliance and Exposure

Descriptive summary statistics will be provided for treatment exposure and compliance for each treatment sequence and all participants.

Mean, standard deviation, median, minimum, and maximum of amount of unused study medication returned will be provided. The cell frequencies and percentage of participants in each category (<50%, >=50% and <=75%, >75%) will be provided.

Efficacy Analyses
Primary Efficacy Analysis
Primary Analysis

Percent change from baseline evaluation for frequency of weekly RP attacks was and will be the primary efficacy endpoint. Frequency of weekly RP attacks is defined as the total number of RP attacks divided by the number of days with available diary data within the last 7 days of each dosing period then multiplied by 7. Total number of RP attacks during the last 7 days of screening period divided by the number of days with available data then multiplied by 7 will be used as baseline for the analysis of all periods.

The absolute value, change and percent change from baseline for frequency of weekly RP attacks was or will be summarized via descriptive statistics by treatment.

Analysis will be performed in ITT population using a mixed model. The dependent variable is percent change from baseline in frequency of weekly RP attacks, and the independent variables include treatment, sequence, period, as fixed effects, and participant as a random effect. Kenward and Roger's method will be used to calculate the denominator degrees of freedom for the fixed effects (DDFM=KR). The lease square mean (95% CI) of percent change from baseline for each treatment and the least square difference between each treatment and placebo will be obtained from the LSMEANS statement.

Separate analyses were provided will be provided for Part A and Part B. The pooled analyses of Part A and Part B may be conducted as exploratory for participants with common treatment.

Confirmatory Analysis

For the primary endpoint, a confirmatory analysis will be conducted in the same manner as the primary analysis in PP population.

Subgroup Analysis

The following subgroups will be examined for the primary endpoint in the same manner as the primary analysis:

Part A/Part B:

- Baseline RP attack frequency: >=13-<=20 attacks per week, >20-<=30 attacks per week, >30 attacks per week
- Average baseline RCS score: Baseline RCS<35, >=35-<=75, >75
- Time of RP attacks since daily study medication: <8 hours, >=8-<=16 hours, >16
- <=24 hours

Part B (Additional Analyses):

- Age group (<45, >=45 and <=64, >=65)
- Gender
- Baseline Weight: <60 kg, >=60-<=100 kg, >100 kg
- Baseline scleroderma diagnosis: Y/N
- Smoking status: active, former, non-smoker
- Duration of dosing: <10 days, >=10-<12 days, >=12-<=14 days
- Stable use of concomitant CCBs: Y/N
- Rescue medicines required: Y/N
- Behavioral modifications required: Y/N

Secondary Efficacy Analyses

Change from Baseline Evaluation

The secondary endpoints of change from baseline evaluation including: frequency of weekly RP attacks, average duration of weekly RP attacks, average severity of weekly RP attacks, average daily RCS, highest pain score recorded during weekly RP attacks, average pain score recorded during weekly RP attacks, digital ulcer severity, Distal-dorsal difference (DDD) measured by thermography, quality of life measured by SHAQ, gastrointestinal symptoms assessed by UCLA SCTC GIT 2.0, Raynaud-VAS and physician assessment of disease, will be analyzed by treatment groups using mixed effect model in the same manner as the primary analysis.

Time to Reach Maximum Degree of Efficacy

The mean time to reach maximum degree of efficacy will be summarized by treatment.

Time to reach maximum degree of efficacy (in days) will be evaluated using the Kaplan-Meier Survival Analysis approach. Descriptive summary, including time to event percent-tiles (25%, 50%, and 75%) and 95% confidence intervals and Kaplan-Meier mean (SE) will be estimated.

Time to Return to Baseline Symptom Severity after termination of dosing

The mean time to return to the worst baseline symptom severity will be summarized by treatment.

Time to return to the worst baseline symptom severity (in days) will be evaluated using the Kaplan-Meier Survival Analysis approach. If a participant doesn't return to baseline symptom severity during washout period or follow-up period, it will be regarded as censor for that Dosing Period. Descriptive summary, including number of participants (%) censored, time to event percent-tiles (25%, 50%, and 75%) and 95% confidence intervals and Kaplan-Meier mean (SE) will be estimated.

Impact of Daily Ambient Temperature on Symptomatic RP Attacks

To examine the impact of daily ambient temperature on RP attacks, a Generalized Estimating Equation (GEE) with adjustment for the ambient temperature, treatment effect, period effect, and interaction between treatment and period will be conducted to investigate whether daily ambient temperature predicts the dichotomous dependent variable RP attacks (Yes/No). The outcome will be presented as odds ratio and 95% CI.

Mixed model will be adopted to test the effect of daily ambient temperature on the severity score of RP attacks.

Use of Rescue Medications for Breakthrough Symptoms.

The difference of using rescue medication between treatment groups will be evaluated by Chi-square test.

Exploratory Efficacy Analyses

Change from baseline in endothelial function as measured by LnRHI using Endo-PAT for Part A only will be analyzed by treatment groups using mixed effect model in the same manner as the primary analysis.

Safety Analysis

All safety analyses will be performed on the Safety population. Safety data presented by treatment sequence will be summarized on an ‘as treated’ basis. Safety variables include treatment-emergent adverse events (TEAEs), laboratory evaluations, vital signs, and other safety assessments. Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.

Adverse Events

Adverse events will be coded using the most current version of the MedDRA® Version 22.0 or higher. Only those AEs that are treatment emergent will be included in summary tables. All AEs, treatment emergent or otherwise, will be presented in participant data listings. Separate summaries will be provided for Part A and Part B. as well as the pooled data. The pooled analyses of Part A and Part B may be conducted as exploratory for participants with common treatment.

An overview AE table, including number and percentage of participants with TEAEs, TEAEs by severity (mild, moderate, severe), TEAEs related to study drug, AEs leading to study withdrawal, AEs leading to study drug discontinuation, SAEs, SAEs related to study drug, and death will be provided.

In addition, number and percentage of subjects will be provided for the following summary tables:

- TEAE by PT
- TEAE by SOC and PT
- TEAE by SOC, PT, and relationship (related, not related)
- TEAE by SOC, PT, and maximum severity (mild, moderate, and severe)

A participant having the same AE (as determined by the coded MedDRA preferred term) more than once will be counted only once in the number and percentage of participants calculation for that AE. Similarly, if a participant had more than one AE in a SOC, the participant will be counted only once in the number of subjects with an AE for that SOC. If a participant has multiple AEs with the same preferred term, the maximum severity (severe>moderate>mild) recorded for the events will be presented in the AEs by severity table; if severity is missing, these TEAEs will not be included in the severity table. Similarly, if a participant has multiple AEs with the same preferred term, the worst relationship (related worse than not related) for the event will be presented in the AEs by relationship table; if relationship is missing for an AT it is assumed to be related.

Laboratory Evaluations

Baseline laboratory evaluations will be summarized by treatment sequence and listed by participant.

Vital Signs

Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse rate, oral temperature, weight (if collected) and changes from baseline will be presented by visit and treatment sequence.

All vital signs will be listed by participant.

Other Safety Analyses

Urine pregnancy test and Raynaud's function assessment will be listed by participant.

Pharmacokinetics

Interim Analysis and Data Safety Monitoring Board
Interim Analysis

No formal interim efficacy analyses are planned for this study.

Data Safety Monitoring Board (DSMB)

Safety oversight was and will be provided by a DSMB, the details of which will be set out in a DSMB Charter. The DSMB plans on conducting a review of the efficacy and safety data from Part A of the study, when data is available on the first 16 to 25 patients that have completed the study. However an early review occurred after an initial 11 participants completed the study.

Following review of the efficacy and safety data from Part A, the DSMB will make the following recommendations:

- 1. Select the dose of cilnidipine (10 mg or 20 mg) to be studied in Part B of the study
- 2. Confirm the sample size estimates for Part B of the study.

Serious adverse events will be monitored by the DSMB on an ongoing basis throughout the study.

Summary of Major Changes in the Planned Analyses Appendices
Scleroderma Health Assessment Questionnaire

The SHAQ is used to calculate a Disability Index to assess the participant qualify of life. The eight categories assessed by the Disability Index are 1) dressing and grooming, 2) arising, 3) eating, 4) walking, 5) hygiene, 6) reach, 7) grip, and 8) common daily activities. For each of these categories, patients report the amount of difficulty they have in performing two or three specific activities.

Ratings such as SOME, MUCH, or USUAL are deliberately not defined for the patients; patients are instructed to respond idiomatically, using their own frame of reference. For example, if a patient asks what “SOME” means, an appropriate response would be “Whatever you think ‘SOME’ means to you”.

Scoring Conventions for the Disability Index

There are four possible responses for the Disability Index questions:

- Without any difficulty=0
- With some difficulty=1
- With much difficulty=2
- Unable to do=3
  - The highest score reported by the patient for any component question of the eight categories determines the score for that category.
  - If a component question is left blank or the response is too ambiguous to assign a score, then the score for that category is determined by the remaining completed question(s).
  - If all component questions are blank or if more than one answer is given, then follow up with the respondent is required.
  - If the respondent's mark is between the response columns, then move it to the closest one. If it's directly between the two, move it to the higher one.

Each of the disability items on the SHAQ has a companion aids/devices variable that is used to record what type(s) of assistance, if any, the participant uses for his/her usual activities. These variables (see below) are coded as follows:

- 0=No assistance is needed.
- 1=A special device is used by the patient in his/her usual activities.
- 2=The patient usually needs help from another person.
- 3=The patient usually needs BOTH a special device AND help from another person.

Computed Variables:

The scoring variables and scoring rules permit the computation of two disability indices, the Standard Disability Index and the Alternative Disability Index. For either of these, a disability index cannot be computed if the patient does not have scores for at least six (6) categories.

1) The Standard Disability Index. “What is the Disability Level of this Person?”

This question results in a new set of category scores that are computed by adjusting the score for each category, if necessary, based on the patient's use of an aid or device or assistance for that category. If either devices and/or help from another person are checked for a category, the score is set to “2”, unless the score is already “3” (i.e., scores of “0” or “1” are increased to “2”). For example, if the highest score for the dressing category is “1”, and the patient says they use a device for dressing, the computed category score would be “2”. The sum of the computed categories scores is then calculated and divided by the number of categories answered. This gives a score in the 0 to 3 range.

2) The Alternative Disability Index. “What is the Disability Level of this Patient when Using Aids and Devices to Compensate for Disability?”

The aid and device variables are not used to calculate the alternative disability index; it is calculated by adding the scores for each of the categories and dividing by the number of categories answered. This gives a score in the 0 to 3 range.

The UCLA SCTC GIT 2.0 Questionnaire

The UCLA SCTC GIT 2.0 Questionnaire contains 34 questions in 7 sections to ask about gastrointestinal symptoms and evaluate the Impact of life over the past 7 days. The 7 sections will obtain 7 scores: Reflux score (R), Distension/Bloating score (D/B), Faecal Soilage score (S), Diarrhoea score (D), Social functioning score (SF), Emotional wellbeing score (EWB) and Constipation score (C).

$Total score = (R + D / B + S + D + SF + EWB) / 6.$

Constipation score is not included in the calculation of total score.

Partial Dates for Adverse Events and Prior/Concomitant Medication

Dates missing the day or both the day and month of the year will adhere to the following conventions in order to classify treatment-emergent AEs and to classify prior/concomitant medications:

Adverse Events

- The missing day of onset of an AE will be set to:
  - First day of the month that the event occurred, if the onset YYYY-MM is after the YYYY-MM of first study treatment
  - The day of the first study treatment, if the onset YYYY-MM is the same as YYYY-MM of the first study treatment
  - The date of informed consent, if the onset YYYY-MM is before the YYYY-MM of the first treatment.
- The missing day of resolution of an AE will be set to:
  - The last day of the month of the occurrence. If the patient died in the same month, then set the imputed date as the death date.
- If the onset date of an AE is missing both the day and month, the onset date will be set to:
  - January 1 of the year of onset, if the onset year is after the year of the first study treatment
  - The date of the first treatment, if the onset year is the same as the year of the first study treatment
  - The date of informed consent, if the onset year is before the year of the first treatment
- If the resolution date of an AE or end date of an IP is missing both the day and month, the date will be set to:
  - December 31 of the year of occurrence. If the patient died in the same year, then set the imputed date as the death date.

Prior/Concomitant Medication

The missing day of start date of a therapy will be set to the first day of the month that the event occurred.

- The missing day of end date of a therapy will be set to the last day of the month of the occurrence.
- If the start date of a therapy is missing both the day and month, the onset date will be set to January 1 of the year of onset.
- If the end date of a therapy is missing both the day and month, the date will be set to December 31 of the year of occurrence.
- If the start date of a therapy is null and the end date is not a complete date then the start date will be set to the earlier of the imputed partial end date and the date of the first study visit.
- If the start date of a therapy is null and the end date is a complete date
  - and the end date is after the date of the first study visit then the start date will be set to the date of the first study visit.
  - otherwise the start date will be set to the end date of the therapy.
- If the end date of a therapy is null and the start date is not a complete date then the end date will be set to the study end date.
- If the end date of a therapy is null and the start date is a complete date
  - and the start date is prior to the study end date then the end date will be set to the study end date.
  - otherwise, the end date will be set to the start date of the therapy.

Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) Questionnaire

The Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) questionnaire is a patient-reported outcome (PRO) instrument devised to assess the severity and impact of systemic sclerosis-associated Raynaud's Syndrome. See Pauling et. al. American College of Rheumatology Convergence 2021, Abstract Number 401 (https://acrabstracts.org/abstract/item-reduction-for-the-assessment-of-systemic-sclerosis-associated-raynauds-phenomenon-asrap-questionnaire-using-data-from-the-international-multicentre-asrap-validation-study/), which is incorporated by reference herein in its entirety.

Example 3. Phase 2A Clinical Trial Data Collected

The following data was actually obtained in accordance with the protocol and plan delineated in Examples 1 and 2. The accompanying data involved 11 patients out of the planned 76 patient study. The study was done in patients with scleroderma (systemic sclerosis) who had relatively frequent Raynaud symptoms as they needed to average at least one attack per day during a screening period of up to two weeks. In this first phase of this double-blind placebo-controlled, prospective randomized study, patients were treated in parallel and after meeting study criteria were randomized to receive either placebo, cilnidipine 10 mg daily, cilnidipine 20 mg daily, tadalafil 5 mg daily, cilnidipine 10 mg plus 5 mg of tadalafil, or cilnidipine 20 mg plus 5 mg of tadalafil.

Tables A-1 to A-8 include data that relates to the frequency of symptomatic Raynaud's attacks.

TABLE A-1

Weekly Symptomatic RP Attacks Change and Percent Change

from Baseline. ITT Population - Part A.

Frequency of weekly symptomatic RP attacks is defined as the total number of

symptomatic RP attacks divided by the number of days with available diary data within

the last 7 days of the dosing period (excluding the last dosing day) then multiplied by 7.

Baseline is calculated as total number of symptomatic RP attacks during the last 7 days of

screening period (excluding the first dosing day) divided by the number of days with

available data then multiplied by 7. Only symptomatic RP attacks, defined as RP attacks

with patient reported finger color changes associated with at least one symptom (pain,

numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean (SD)
21.00
12.50
8.00
8.00
14.25
17.83

(7.778)
(5.657)
(1.414)
(5.303)
(8.721)

Median
21.00
12.50
8.00
8.00
14.25
17.83

Q1, Q3
21.00, 21.00
7.00, 18.00
4.00, 12.00
7.00, 9.00
10.50, 18.00
11.67, 24.00

Min, Max
21.0, 21.0
7.0, 18.0
4.0, 12.0
7.0, 9.0
10.5, 18.0
11.7, 24.0

Weekly Symptomatic RP Attacks

n
1
2
2
2
2
2

Mean (SD)
14.00
8.00
12.50
4.50
11.50
8.83

(4.243)
(7.778)
(0.707)
(2.121)
(5.893)

Median
14.00
8.00
12.50
4.50
11.50
8.83

Q1, Q3
14.00, 14.00
5.00, 11.00
7.00, 18.00
4.00, 5.00
10.00, 13.00
4.67, 13.00

Min, Max
14.0, 14.0
5.0, 11.0
7.0, 18.0
4.0, 5.0
10.0, 13.0
4.7, 13.0

Change from Baseline

n
1
2
2
2
2
2

Mean (SD)
−7.00
−4.50
4.50
−3.50
−2.75
−9.00

(3.536)
(2.121)
(0.707)
(3.182)
(2.828)

Median
−7.00
−4.50
4.50
−3.50
−2.75
−9.00

Q1, Q3
−7.00, −7.00
−7.00, −2.00
3.00, 6.00
−4.00, −3.00
−5.00, −0.50
−11.00, −7.00

Min, Max
−7.0, −7.0
−7.0, −2.0
3.0, 6.0
−4.0, −3.0
−5.0, −0.5
−11.0, −7.0

Percent Change from Baseline

n
1
2
2
2
2
2

Mean (SD)
−33.33
−33.73
62.50
−43.65
−16.27
−52.92

(7.296)
(17.678)
(1.122)
(16.275)
(10.017)

Median
−33.33
−33.73
62.50
−43.65
−16.27
−52.92

Q1, Q3
−33.33, −33.33
−38.89, −28.57
50.00, 75.00
−44.44, −42.86
−27.78, −4.76
−60.00, −45.83

Min, Max
−33.3, −33.3
−38.9, −28.6
50.0, 75.0
−44.4, −42.9
−27.8, −4.8
−60.0, −45.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean (SD)
15.33
11.13
12.33
13.38
12.92

(7.371)
(4.802)
(7.572)
(5.528)
(6.426)

Median
18.00
9.75
9.00
14.25
11.67

Q1, Q3
7.00, 21.00
8.00, 14.25
7.00, 21.00
8.75, 18.00
7.00, 18.00

Min, Max
7.0, 21.0
7.0, 18.0
7.0, 21.0
7.0, 18.0
4.0, 24.0

Weekly Symptomatic RP Attacks

n
3
4
3
4
11

Mean (SD)
10.00
8.00
7.67
9.75
9.52

(4.583)
(4.243)
(5.508)
(3.403)
(4.689)

Median
11.00
7.50
5.00
10.50
10.00

Q1, Q3
5.00, 14.00
4.50, 11.50
4.00, 14.00
7.50, 12.00
5.00, 13.00

Min, Max
5.0, 14.0
4.0, 13.0
4.0, 14.0
5.0, 13.0
4.0, 18.0

Change from Baseline

n
3
4
3
4
11

Mean (SD)
−5.33
−3.13
−4.67
−3.63
−3.41

(2.887)
(1.931)
(2.082)
(2.926)
(4.893)

Median
−7.00
−3.50
−4.00
−3.50
−4.00

Q1, Q3
−7.00, −2.00
−4.50, −1.75
−7.00, −3.00
−6.00, −1.25
−7.00, −0.50

Min, Max
−7.0, −2.0
−5.0, −0.5
−7.0, −3.0
−7.0, −0.5
−11.0, 6.0

Percent Change from Baseline

n
3
4
3
4
11

Mean (SD)
−33.60
−29.96
−40.21
−25.00
−18.32

(5.164)
(18.401)
(6.009)
(14.410)
(42.640)

Median
−33.33
−35.32
−42.86
−28.17
−33.33

Q1, Q3
−38.89, −28.57
−43.65, −16.27
−44.44, −33.33
−33.73, −16.27
−44.44, −4.76

Min, Max
−38.9, −28.6
−44.4, −4.8
−44.4, −33.3
−38.9, −4.8
−60.0, 75.0

TABLE A-2

Weekly Symptomatic RP Attacks Change and Percent Change

from Baseline (Excluding Outliers). ITT Population - Part A.

Frequency of weekly symptomatic RP attacks is defined as the total number of

symptomatic RP attacks divided by the number of days with available diary data within

the last 7 days of the dosing period (excluding the last dosing day) then multiplied by 7.

Baseline is calculated as total number of symptomatic RP attacks during the last 7 days of

screening period (excluding the first dosing day) divided by the number of days with

available data then multiplied by 7. Only symptomatic RP attacks, defined as RP attacks

with patient reported finger color changes associated with at least one symptom (pain,

numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean (SD)
21.00
12.50
12.00
8.00
14.25
17.83

(7.778)

(1.414)
(5.303)
(8.721)

Median
21.00
12.50
12.00
8.00
14.25
17.83

Q1, Q3
21.00, 21.00
7.00, 18.00
12.00, 12.00
7.00, 9.00
10.50, 18.00
11.67, 24.00

Min, Max
21.0, 21.0
7.0, 18.0
12.0, 12.0
7.0, 9.0
10.5, 18.0
11.7, 24.0

Weekly Symptomatic RP Attacks

n
1
2
1
2
2
2

Mean (SD)
14.00
8.00
18.00
4.50
11.50
8.83

(4.243)

(0.707)
(2.121)
(5.893)

Median
14.00
8.00
18.00
4.50
11.50
8.83

Q1, Q3
14.00, 14.00
5.00, 11.00
18.00, 18.00
4.00, 5.00
10.00, 13.00
4.67, 13.00

Min, Max
14.0, 14.0
5.0, 11.0
18.0, 18.0
4.0, 5.0
10.0, 13.0
4.7, 13.0

Change from Baseline

n
1
2
1
2
2
2

Mean (SD)
−7.00
−4.50
6.00
−3.50
−2.75
−9.00

(3.536)

(0.707)
(3.182)
(2.828)

Median
−7.00
−4.50
6.00
−3.50
−2.75
−9.00

Q1, Q3
−7.00, −7.00
−7.00, −2.00
6.00, 6.00
−4.00, −3.00
−5.00, −0.50
−11.00, −7.00

Min, Max
−7.0, −7.0
−7.0, −2.0
6.0, 6.0
−4.0, −3.0
−5.0, −0.5
−11.0, −7.0

Percent Change from Baseline

n
1
2
1
2
2
2

Mean (SD)
−33.33
−33.73
50.00
−43.65
−16.27
−52.92

(7.296)

(1.122)
(16.275)
(10.017)

Median
−33.33
−33.73
50.00
−43.65
−16.27
−52.92

Q1, Q3
−33.33, −33.33
−38.89, −28.57
50.00, 50.00
−44.44, −42.86
−27.78, −4.76
−60.00, −45.83

Min, Max
−33.3, −33.3
−38.9, −28.6
50.0, 50.0
−44.4, −42.9
−27.8, −4.8
−60.0, −45.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean (SD)
15.33
11.13
12.33
13.38
13.82

(7.371)
(4.802)
(7.572)
(5.528)
(6.013)

Median
18.00
9.75
9.00
14.25
11.83

Q1, Q3
7.00, 21.00
8.00, 14.25
7.00, 21.00
8.75, 18.00
9.00, 18.00

Min, Max
7.0, 21.0
7.0, 18.0
7.0, 21.0
7.0, 18.0
7.0, 24.0

Weekly Symptomatic RP Attacks

n
3
4
3
4
10

Mean (SD)
10.00
8.00
7.67
9.75
9.77

(4.583)
(4.243)
(5.508)
(3.403)
(4.864)

Median
11.00
7.50
5.00
10.50
10.50

Q1, Q3
5.00, 14.00
4.50, 11.50
4.00, 14.00
7.50, 12.00
5.00, 13.00

Min, Max
5.0, 14.0
4.0, 13.0
4.0, 14.0
5.0, 13.0
4.0, 18.0

Change from Baseline

n
3
4
3
4
10

Mean (SD)
−5.33
−3.13
−4.67
−3.63
−4.05

(2.887)
(1.931)
(2.082)
(2.926)
(4.645)

Median
−7.00
−3.50
−4.00
−3.50
−4.50

Q1, Q3
−7.00, −2.00
−4.50, −1.75
−7.00, −3.00
−6.00, −1.25
−7.00, −2.00

Min, Max
−7.0, −2.0
−5.0, −0.5
−7.0, −3.0
−7.0, −0.5
−11.0, 6.0

Percent Change from Baseline

n
3
4
3
4
10

Mean (SD)
−33.60
−29.96
−40.21
−25.00
−27.65

(5.164)
(18.401)
(6.009)
(14.410)
(30.918)

Median
−33.33
−35.32
−42.86
−28.17
−36.11

Q1, Q3
−38.89, −28.57
−43.65, −16.27
−44.44, −33.33
−33.73, −16.27
−44.44, −27.78

Min, Max
−38.9, −28.6
−44.4, −4.8
−44.4, −33.3
−38.9, −4.8
−60.0, 50.0

TABLE A-3

Weekly Symptomatic RP Attacks Change and Percent Change from Baseline

by Baseline RCS. ITT Population - Part A.

Frequency of weekly symptomatic RP attacks is defined as the total number of

symptomatic RP attacks divided by the number of days with available diary data within

the last 7 days of the dosing period (excluding the last dosing day) then multiplied by 7.

Baseline is calculated as total number of symptomatic RP attacks during the last 7 days of

screening period (excluding the first dosing day) divided by the number of days with

available data then multiplied by 7. Only symptomatic RP attacks, defined as RP attacks

with patient reported finger color changes associated with at least one symptom (pain,

numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean (SD)
21.00
12.50

9.00
18.00
17.83

(7.778)

(8.721)

Median
21.00
12.50

9.00
18.00
17.83

Q1, Q3
21.00, 21.00
7.00, 18.00

9.00, 9.00
18.00, 18.00
11.67, 24.00

Min, Max
21.0, 21.0
7.0, 18.0

9.0, 9.0
18.0, 18.0
11.7, 24.0

Weekly Symptomatic RP Attacks

n
1
2

1
1
2

Mean (SD)
14.00
8.00

5.00
13.00
8.83

(4.243)

(5.893)

Median
14.00
8.00

5.00
13.00
8.83

Q1, Q3
14.00, 14.00
5.00, 11.00

5.00, 5.00
13.00, 13.00
4.67, 13.00

Min, Max
14.0, 14.0
5.0, 11.0

5.0, 5.0
13.0, 13.0
4.7, 13.0

Change from Baseline

n
1
2

1
1
2

Mean (SD)
−7.00
−4.50

−4.00
−5.00
−9.00

(3.536)

(2.828)

Median
−7.00
−4.50

−4.00
−5.00
−9.00

Q1, Q3
−7.00, −7.00
−7.00, −2.00

−4.00, −4.00
−5.00, −5.00
−11.00, −7.00

Min, Max
−7.0, −7.0
−7.0, −2.0

−4.0, −4.0
−5.0, −5.0
−11.0, −7.0

Percent Change from Baseline

n
1
2

1
1
2

Mean (SD)
−33.33
−33.73

−44.44
−27.78
−52.92

(7.296)

(10.017)

Median
−33.33
−33.73

−44.44
−27.78
−52.92

Q1, Q3
−33.33, −33.33
−38.89, −28.57

−44.44, −44.44
−27.78, −27.78
−60.00, −45.83

Min, Max
−33.3, −33.3
−38.9, −28.6

−44.4, −44.4
−27.8, −27.8
−60.0, −45.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean (SD)
15.33
13.50
15.00
14.33
15.52

(7.371)
(6.364)
(8.485)
(6.351)
(6.380)

Median
18.00
13.50
15.00
18.00
18.00

Q1, Q3
7.00, 21.00
9.00, 18.00
9.00, 21.00
7.00, 18.00
9.00, 21.00

Min, Max
7.0, 21.0
9.0, 18.0
9.0, 21.0
7.0, 18.0
7.0, 24.0

Weekly Symptomatic RP Attacks

n
3
2
2
3
7

Mean (SD)
10.00
9.00
9.50
9.67
9.38

(4.583)
(5.657)
(6.364)
(4.163)
(4.297)

Median
11.00
9.00
9.50
11.00
11.00

Q1, Q3
5.00, 14.00
5.00, 13.00
5.00, 14.00
5.00, 13.00
5.00, 13.00

Min, Max
5.0, 14.0
5.0, 13.0
5.0, 14.0
5.0, 13.0
4.7, 14.0

Change from Baseline

n
3
2
2
3
7

Mean (SD)
−5.33
−4.50
−5.50
−4.67
−6.14

(2.887)
(0.707)
(2.121)
(2.517)
(2.854)

Median
−7.00
−4.50
−5.50
−5.00
−7.00

Q1, Q3
−7.00, −2.00
−5.00, −4.00
−7.00, −4.00
−7.00, −2.00
−7.00, −4.00

Min, Max
−7.0, −2.0
−5.0, −4.0
−7.0, −4.0
−7.0, −2.0
−11.0, −2.0

Percent Change from Baseline

n
3
2
2
3
7

Mean (SD)
−33.60
−36.11
−38.89
−31.75
−39.84

(5.164)
(11.785)
(7.857)
(6.199)
(11.396)

Median
−33.33
−36.11
−38.89
−28.57
−38.89

Q1, Q3
−38.89, −28.57
−44.44, −27.78
−44.44, −33.33
−38.89, −27.78
−45.83, −28.57

Min, Max
−38.9, −28.6
−44.4, −27.8
−44.4, −33.3
−38.9, −27.8
−60.0, −27.8

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

2
1
1

Mean (SD)

8.00
7.00
10.50

(5.657)

Median

8.00
7.00
10.50

Q1, Q3

4.00, 12.00
7.00, 7.00
10.50, 10.50

Min, Max

4.0, 12.0
7.0, 7.0
10.5, 10.5

Weekly Symptomatic RP Attacks

n

2
1
1

Mean (SD)

12.50
4.00
10.00

(7.778)

Median

12.50
4.00
10.00

Q1, Q3

7.00, 18.00
4.00, 4.00
10.00, 10.00

Min, Max

7.0, 18.0
4.0, 4.0
10.0, 10.0

Change from Baseline

n

2
1
1

Mean (SD)

4.50
−3.00
−0.50

(2.121)

Median

4.50
−3.00
−0.50

Q1, Q3

3.00, 6.00
−3.00, −3.00
−0.50, −0.50

Min, Max

3.0, 6.0
−3.0, −3.0
−0.5, −0.5

Percent Change from Baseline

n

2
1
1

Mean (SD)

62.50
−42.86
−4.76

(17.678)

Median

62.50
−42.86
−4.76

Q1, Q3

50.00, 75.00
−42.86, −42.86
−4.76, −4.76

Min, Max

50.0, 75.0
−42.9, −42.9
−4.8, −4.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean (SD)

8.75
7.00
10.50
8.38

(2.475)

(3.591)

Median

8.75
7.00
10.50
8.75

Q1, Q3

7.00, 10.50
7.00, 7.00
10.50, 10.50
5.50, 11.25

Min, Max

7.0, 10.5
7.0, 7.0
10.5, 10.5
4.0, 12.0

Weekly Symptomatic RP Attacks

n

2
1
1
4

Mean (SD)

7.00
4.00
10.00
9.75

(4.243)

(6.021)

Median

7.00
4.00
10.00
8.50

Q1, Q3

4.00, 10.00
4.00, 4.00
10.00, 10.00
5.50, 14.00

Min, Max

4.0, 10.0
4.0, 4.0
10.0, 10.0
4.0, 18.0

Change from Baseline

n

2
1
1
4

Mean (SD)

−1.75
−3.00
−0.50
1.38

(1.768)

(3.945)

Median

−1.75
−3.00
−0.50
1.25

Q1, Q3

−3.00, −0.50
−3.00, −3.00
−0.50, −0.50
−1.75, 4.50

Min, Max

−3.0, −0.5
−3.0, −3.0
−0.5, −0.5
−3.0, 6.0

Percent Change from Baseline

n

2
1
1
4

Mean (SD)

−23.81
−42.86
−4.76
19.35

(26.937)

(53.190)

Median

−23.81
−42.86
−4.76
22.62

Q1, Q3

−42.86, −4.76
−42.86, −42.86
− 4.76, −4.76
−23.81, 62.50

Min, Max

−42.9, −4.8
−42.9, −42.9
−4.8, −4.8
−42.9, 75.0

TABLE A-4

Weekly Symptomatic RP Attacks Change and Percent Change from Baseline

(Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Frequency of weekly symptomatic RP attacks is defined as the total number of

symptomatic RP attacks divided by the number of days with available diary data within

the last 7 days of the dosing period (excluding the last dosing day) then multiplied by 7.

Baseline is calculated as total number of symptomatic RP attacks during the last 7 days of

screening period (excluding the first dosing day) divided by the number of days with

available data then multiplied by 7. Only symptomatic RP attacks, defined as RP attacks

with patient reported finger color changes associated with at least one symptom (pain,

numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean (SD)
21.00
12.50

9.00
18.00
17.83

(7.778)

(8.721)

Median
21.00
12.50

9.00
18.00
17.83

Q1, Q3
21.00, 21.00
7.00, 18.00

9.00, 9.00
18.00, 18.00
11.67, 24.00

Min, Max
21.0, 21.0
7.0, 18.0

9.0, 9.0
18.0, 18.0
11.7, 24.0

Weekly Symptomatic RP Attacks

n
1
2

1
1
2

Mean (SD)
14.00
8.00

5.00
13.00
8.83

(4.243)

(5.893)

Median
14.00
8.00

5.00
13.00
8.83

Q1, Q3
14.00, 14.00
5.00, 11.00

5.00, 5.00
13.00, 13.00
4.67, 13.00

Min, Max
14.0, 14.0
5.0, 11.0

5.0, 5.0
13.0, 13.0
4.7, 13.0

Change from Baseline

n
1
2

1
1
2

Mean (SD)
−7.00
−4.50

−4.00
−5.00
−9.00

(3.536)

(2.828)

Median
−7.00
−4.50

−4.00
−5.00
−9.00

Q1, Q3
−7.00, −7.00
−7.00, −2.00

−4.00, −4.00
−5.00, −5.00
−11.00, −7.00

Min, Max
−7.0, −7.0
−7.0, −2.0

−4.0, −4.0
−5.0, −5.0
−11.0, −7.0

Percent Change from Baseline

n
1
2

1
1
2

Mean (SD)
−33.33
−33.73

−44.44
−27.78
−52.92

(7.296)

(10.017)

Median
−33.33
−33.73

−44.44
−27.78
−52.92

Q1, Q3
−33.33, −33.33
−38.89, −28.57

−44.44, −44.44
−27.78, −27.78
−60.00, −45.83

Min, Max
−33.3, −33.3
−38.9, −28.6

−44.4, −44.4
−27.8, −27.8
−60.0, −45.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean (SD)
15.33
13.50
15.00
14.33
15.52

(7.371)
(6.364)
(8.485)
(6.351)
(6.380)

Median
18.00
13.50
15.00
18.00
18.00

Q1, Q3
7.00, 21.00
9.00, 18.00
9.00, 21.00
7.00, 18.00
9.00, 21.00

Min, Max
7.0, 21.0
9.0, 18.0
9.0, 21.0
7.0, 18.0
7.0, 24.0

Weekly Symptomatic RP Attacks

n
3
2
2
3
7

Mean (SD)
10.00
9.00
9.50
9.67
9.38

(4.583)
(5.657)
(6.364)
(4.163)
(4.297)

Median
11.00
9.00
9.50
11.00
11.00

Q1, Q3
5.00, 14.00
5.00, 13.00
5.00, 14.00
5.00, 13.00
5.00, 13.00

Min, Max
5.0, 14.0
5.0, 13.0
5.0, 14.0
5.0, 13.0
4.7, 14.0

Change from Baseline

n
3
2
2
3
7

Mean (SD)
−5.33
−4.50
−5.50
−4.67
−6.14

(2.887)
(0.707)
(2.121)
(2.517)
(2.854)

Median
−7.00
−4.50
−5.50
−5.00
−7.00

Q1, Q3
−7.00, −2.00
−5.00, −4.00
−7.00, −4.00
−7.00, −2.00
−7.00, −4.00

Min, Max
−7.0, −2.0
−5.0, −4.0
−7.0, −4.0
−7.0, −2.0
−11.0, −2.0

Percent Change from Baseline

n
3
2
2
3
7

Mean (SD)
−33.60
−36.11
−38.89
−31.75
−39.84

(5.164)
(11.785)
(7.857)
(6.199)
(11.396)

Median
−33.33
−36.11
−38.89
−28.57
−38.89

Q1, Q3
−38.89, −28.57
−44.44, −27.78
−44.44, −33.33
−38.89, −27.78
−45.83, −28.57

Min, Max
−38.9, −28.6
−44.4, −27.8
−44.4, −33.3
−38.9, −27.8
−60.0, −27.8

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

1
1
1

Mean (SD)

12.00
7.00
10.50

Median

12.00
7.00
10.50

Q1, Q3

12.00, 12.00
7.00, 7.00
10.50, 10.50

Min, Max

12.0, 12.0
7.0, 7.0
10.5, 10.5

Weekly Symptomatic RP Attacks

n

1
1
1

Mean (SD)

18.00
4.00
10.00

Median

18.00
4.00
10.00

Q1, Q3

18.00, 18.00
4.00, 4.00
10.00, 10.00

Min, Max

18.0, 18.0
4.0, 4.0
10.0, 10.0

Change from Baseline

n

1
1
1

Mean (SD)

6.00
−3.00
−0.50

Median

6.00
−3.00
−0.50

Q1, Q3

6.00, 6.00
−3.00, −3.00
−0.50, −0.50

Min, Max

6.0, 6.0
−3.0, −3.0
−0.5, −0.5

Percent Change from Baseline

n

1
1
1

Mean (SD)

50.00
−42.86
−4.76

Median

50.00
−42.86
−4.76

Q1, Q3

50.00, 50.00
−42.86, −42.86
−4.76, −4.76

Min, Max

50.0, 50.0
−42.9, −42.9
−4.8, −4.8

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean (SD)

8.75
7.00
10.50
9.83

(2.475)

(2.566)

Median

8.75
7.00
10.50
10.50

Q1, Q3

7.00, 10.50
7.00, 7.00
10.50, 10.50
7.00, 12.00

Min, Max

7.0, 10.5
7.0, 7.0
10.5, 10.5
7.0, 12.0

Weekly Symptomatic RP Attacks

n

2
1
1
3

Mean (SD)

7.00
4.00
10.00
10.67

(4.243)

(7.024)

Median

7.00
4.00
10.00
10.00

Q1, Q3

4.00, 10.00
4.00, 4.00
10.00, 10.00
4.00, 18.00

Min, Max

4.0, 10.0
4.0, 4.0
10.0, 10.0
4.0, 18.0

Change from Baseline

n

2
1
1
3

Mean (SD)

−1.75
−3.00
−0.50
0.83

(1.768)

(4.646)

Median

−1.75
−3.00
−0.50
−0.50

Q1, Q3

−3.00, −0.50
−3.00, −3.00
−0.50, −0.50
−3.00, 6.00

Min, Max

−3.0, −0.5
−3.0, −3.0
−0.5, −0.5
−3.0, 6.0

Percent Change from Baseline

n

2
1
1
3

Mean (SD)

−23.81
−42.86
−4.76
0.79

(26.937)

(46.677)

Median

−23.81
−42.86
−4.76
−4.76

Q1, Q3

−42.86, −4.76
−42.86, −42.86
− 4.76, −4.76
−42.86, 50.00

Min, Max

−42.9, −4.8
−42.9, −42.9
−4.8, −4.8
−42.9, 50.0

TABLE A-5

Weekly RP Attacks (All Attacks) Change and Percent Change from Baseline.

ITT Population - Part A.

Frequency of weekly RP attacks is defined as the total number of RP attacks divided by

the number of days with available diary data within the last 7 days of the dosing period

(excluding the last dosing day) then multiplied by 7. Baseline is calculated as total

number of RP attacks during the last 7 days of screening period (excluding the first

dosing day) divided by the number of days with available data then multiplied by 7.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
32.00
14.67
10.00
10.00
15.92
17.83

(SD)

(7.542)
(4.243)
(1.414)
(4.360)
(8.721)

Median
32.00
14.67
10.00
10.00
15.92
17.83

Q1, Q3
32.00, 32.00
9.33, 20.00
7.00, 13.00
9.00, 11.00
12.83, 19.00
11.67, 24.00

Min, Max
32.0, 32.0
9.3, 20.0
7.0, 13.0
9.0, 11.0
12.8, 19.0
11.7, 24.0

Weekly RP Attacks

n
1
2
2
2
2
2

Mean
23.00
8.00
13.00
5.50
13.00
9.83

(SD)

(4.243)
(8.485)
(0.707)
(2.828)
(7.307)

Median
23.00
8.00
13.00
5.50
13.00
9.83

Q1, Q3
23.00, 23.00
5.00, 11.00
7.00, 19.00
5.00, 6.00
11.00, 15.00
4.67, 15.00

Min, Max
23.0, 23.0
5.0, 11.0
7.0, 19.0
5.0, 6.0
11.0, 15.0
4.7, 15.0

Change from Baseline

n
1
2
2
2
2
2

Mean
−9.00
−6.67
3.00
−4.50
−2.92
−8.00

(SD)

(3.300)
(4.243)
(0.707)
(1.532)
(1.414)

Median
−9.00
−6.67
3.00
−4.50
−2.92
−8.00

Q1, Q3
−9.00, −9.00
−9.00, −4.33
0.00, 6.00
−5.00, −4.00
−4.00, −1.83
−9.00, −7.00

Min, Max
−9.0, −9.0
−9.0, −4.3
0.0, 6.0
−5.0, −4.0
−4.0, −1.8
−9.0, −7.0

Percent Change from Baseline

n
1
2
2
2
2
2

Mean
−28.13
−45.71
23.08
−44.95
−17.67
−48.75

(SD)

(1.010)
(32.636)
(0.714)
(4.785)
(15.910)

Median
−28.13
−45.71
23.08
−44.95
−17.67
−48.75

Q1, Q3
−28.13, −28.13
−46.43, −45.00
0.00, 46.15
−45.45, −44.44
−21.05, −14.29
−60.00, −37.50

Min, Max
−28.1, −28.1
−46.4, −45.0
0.0, 46.2
−45.5, −44.4
−21.1, −14.3
−60.0, −37.5

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean
20.44
12.96
17.33
15.29
15.35

(SD)
(11.340)
(4.321)
(12.741)
(5.082)
(7.600)

Median
20.00
11.92
11.00
15.92
12.83

Q1, Q3
9.33, 32.00
10.00, 15.92
9.00, 32.00
11.08, 19.50
9.33, 20.00

Min, Max
9.3, 32.0
9.0, 19.0
9.0, 32.0
9.3, 20.0
7.0, 32.0

Weekly RP Attacks

n
3
4
3
4
11

Mean
13.00
9.25
11.33
10.50
11.06

(SD)
(9.165)
(4.646)
(10.116)
(4.123)
(6.270)

Median
11.00
8.50
6.00
11.00
11.00

Q1, Q3
5.00, 23.00
5.50, 13.00
5.00, 23.00
8.00, 13.00
5.00, 15.00

Min, Max
5.0, 23.0
5.0, 15.0
5.0, 23.0
5.0, 15.0
4.7, 23.0

Change from Baseline

n
3
4
3
4
11

Mean
−7.44
−3.71
−6.00
−4.79
−4.29

(SD)
(2.694)
(1.336)
(2.646)
(3.017)
(4.527)

Median
−9.00
−4.00
−5.00
−4.17
−4.33

Q1, Q3
−9.00, −4.33
−4.50, −2.92
−9.00, −4.00
−6.67, −2.92
−9.00, −1.83

Min, Max
−9.0, −4.3
−5.0, −1.8
−9.0, −4.0
−9.0, −1.8
−9.0, 6.0

Percent Change from Baseline

n
3
4
3
4
11

Mean
−39.85
−31.31
−39.34
−31.69
−26.92

(SD)
(10.180)
(15.996)
(9.727)
(16.436)
(29.706)

Median
−45.00
−32.75
−44.44
−33.03
−37.50

Q1, Q3
−46.43, −28.13
−44.95, −17.67
−45.45, −28.13
−45.71, −17.67
−45.45, −14.29

Min, Max
−46.4, −28.1
−45.5, −14.3
−45.5, −28.1
−46.4, −14.3
−60.0, 46.2

TABLE A-6

Weekly RP Attacks (All Attacks) Change and Percent Change from Baseline

(Excluding Outliers). ITT Population - Part A.

Frequency of weekly RP attacks is defined as the total number of RP attacks

divided by the number of days with available diary data within the last 7 days

of the dosing period (excluding the last dosing day) then multiplied by 7.

Baseline is calculated as total number of RP attacks during the last 7 days of

screening period (excluding the first dosing day) divided by the number of

days with available data then multiplied by 7.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
32.00
14.67
13.00
10.00
15.92
17.83

(SD)

(7.542)

(1.414)
(4.360)
(8.721)

Median
32.00
14.67
13.00
10.00
15.92
17.83

Q1, Q3
32.00, 32.00
9.33, 20.00
13.00, 13.00
9.00, 11.00
12.83, 19.00
11.67, 24.00

Min, Max
32.0, 32.0
9.3, 20.0
13.0, 13.0
9.0, 11.0
12.8, 19.0
11.7, 24.0

Weekly RP Attacks

n
1
2
1
2
2
2

Mean
23.00
8.00
19.00
5.50
13.00
9.83

(SD)

(4.243)

(0.707)
(2.828)
(7.307)

Median
23.00
8.00
19.00
5.50
13.00
9.83

Q1, Q3
23.00, 23.00
5.00, 11.00
19.00, 19.00
5.00, 6.00
11.00, 15.00
4.67, 15.00

Min, Max
23.0, 23.0
5.0, 11.0
19.0, 19.0
5.0, 6.0
11.0, 15.0
4.7, 15.0

Change from Baseline

n
1
2
1
2
2
2

Mean
−9.00
−6.67
6.00
−4.50
−2.92
−8.00

(SD)

(3.300)

(0.707)
(1.532)
(1.414)

Median
−9.00
−6.67
6.00
−4.50
−2.92
−8.00

Q1, Q3
−9.00, −9.00
−9.00, −4.33
6.00, 6.00
−5.00, −4.00
−4.00, −1.83
−9.00, −7.00

Min, Max
−9.0, −9.0
−9.0, −4.3
6.0, 6.0
−5.0, −4.0
−4.0, −1.8
−9.0, −7.0

Percent Change from Baseline

n
1
2
1
2
2
2

Mean
−28.13
−45.71
46.15
−44.95
−17.67
−48.75

(SD)

(1.010)

(0.714)
(4.785)
(15.910)

Median
−28.13
−45.71
46.15
−44.95
−17.67
−48.75

Q1, Q3
−28.13, −28.13
−46.43, −45.00
46.15, 46.15
−45.45, −44.44
−21.05, −14.29
−60.00, −37.50

Min, Max
−28.1, −28.1
−46.4, −45.0
46.2, 46.2
−45.5, −44.4
−21.1, −14.3
−60.0, −37.5

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
20.44
12.96
17.33
15.29
16.18

(SD)
(11.340)
(4.321)
(12.741)
(5.082)
(7.460)

Median
20.00
11.92
11.00
15.92
12.92

Q1, Q3
9.33, 32.00
10.00, 15.92
9.00, 32.00
11.08, 19.50
11.00, 20.00

Min, Max
9.3, 32.0
9.0, 19.0
9.0, 32.0
9.3, 20.0
9.0, 32.0

Weekly RP Attacks

n
3
4
3
4
10

Mean
13.00
9.25
11.33
10.50
11.47

(SD)
(9.165)
(4.646)
(10.116)
(4.123)
(6.454)

Median
11.00
8.50
6.00
11.00
11.00

Q1, Q3
5.00, 23.00
5.50, 13.00
5.00, 23.00
8.00, 13.00
5.00, 15.00

Min, Max
5.0, 23.0
5.0, 15.0
5.0, 23.0
5.0, 15.0
4.7, 23.0

Change from Baseline

n
3
4
3
4
10

Mean
−7.44
−3.71
−6.00
−4.79
−4.72

(SD)
(2.694)
(1.336)
(2.646)
(3.017)
(4.530)

Median
−9.00
−4.00
−5.00
−4.17
−4.67

Q1, Q3
−9.00, −4.33
−4.50, −2.92
−9.00, −4.00
−6.67, −2.92
−9.00, −4.00

Min, Max
−9.0, −4.3
−5.0, −1.8
−9.0, −4.0
−9.0, −1.8
−9.0, 6.0

Percent Change from Baseline

n
3
4
3
4
10

Mean
−39.85
−31.31
−39.34
−31.69
−29.61

(SD)
(10.180)
(15.996)
(9.727)
(16.436)
(29.865)

Median
−45.00
−32.75
−44.44
−33.03
−40.97

Q1, Q3
−46.43, −28.13
−44.95, −17.67
−45.45, −28.13
−45.71, −17.67
−45.45, −21.05

Min, Max
−46.4, −28.1
−45.5, −14.3
−45.5, −28.1
−46.4, −14.3
−60.0, 46.2

TABLE A-7

Weekly RP Attacks (All Attacks) Change and Percent Change from

Baseline by Baseline RCS. ITT Population - Part A.

Frequency of weekly RP attacks is defined as the total number of RP

attacks divided by the number of days with available diary data within

the last 7 days of the dosing period (excluding the last dosing day) then

multiplied by 7. Baseline is calculated as total number of RP attacks

during the last 7 days of screening period (excluding the first dosing day)

divided by the number of days with available data then multiplied by 7.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
32.00
14.67

9.00
19.00
17.83

(SD)

(7.542)

(8.721)

Median
32.00
14.67

9.00
19.00
17.83

Q1, Q3
32.00, 32.00
9.33, 20.00

9.00, 9.00
19.00, 19.00
11.67, 24.00

Min, Max
32.0, 32.0
9.3, 20.0

9.0, 9.0
19.0, 19.0
11.7, 24.0

Weekly RP Attacks

n
1
2

1
1
2

Mean
23.00
8.00

5.00
15.00
9.83

(SD)

(4.243)

(7.307)

Median
23.00
8.00

5.00
15.00
9.83

Q1, Q3
23.00, 23.00
5.00, 11.00

5.00, 5.00
15.00, 15.00
4.67, 15.00

Min, Max
23.0, 23.0
5.0, 11.0

5.0, 5.0
15.0, 15.0
4.7, 15.0

Change from Baseline

n
1
2

1
1
2

Mean
−9.00
−6.67

−4.00
−4.00
−8.00

(SD)

(3.300)

(1.414)

Median
−9.00
−6.67

−4.00
−4.00
−8.00

Q1, Q3
−9.00, −9.00
−9.00, −4.33

−4.00, −4.00
−4.00, −4.00
−9.00, −7.00

Min, Max
−9.0, −9.0
−9.0, −4.3

−4.0, −4.0
−4.0, −4.0
−9.0, −7.0

Percent Change from Baseline

n
1
2

1
1
2

Mean
−28.13
−45.71

−44.44
−21.05
−48.75

(SD)

(1.010)

(15.910)

Median
−28.13
−45.71

−44.44
−21.05
−48.75

Q1, Q3
−28.13, −28.13
−46.43, −45.00

−44.44, −44.44
−21.05, −21.05
−60.00, −37.50

Min, Max
−28.1, −28.1
−46.4, −45.0

−44.4, −44.4
−21.1, −21.1
−60.0, −37.5

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
20.44
14.00
20.50
16.11
17.86

(SD)
(11.340)
(7.071)
(16.263)
(5.891)
(8.496)

Median
20.00
14.00
20.50
19.00
19.00

Q1, Q3
9.33, 32.00
9.00, 19.00
9.00, 32.00
9.33, 20.00
9.33, 24.00

Min, Max
9.3, 32.0
9.0, 19.0
9.0, 32.0
9.3, 20.0
9.0, 32.0

Weekly RP Attacks

n
3
2
2
3
7

Mean
13.00
10.00
14.00
10.33
11.24

(SD)
(9.165)
(7.071)
(12.728)
(5.033)
(6.925)

Median
11.00
10.00
14.00
11.00
11.00

Q1, Q3
5.00, 23.00
5.00, 15.00
5.00, 23.00
5.00, 15.00
5.00, 15.00

Min, Max
5.0, 23.0
5.0, 15.0
5.0, 23.0
5.0, 15.0
4.7, 23.0

Change from Baseline

n
3
2
2
3
7

Mean
−7.44
−4.00
−6.50
−5.78
−6.62

(SD)
(2.694)
(0.000)
(3.536)
(2.795)
(2.453)

Median
−9.00
−4.00
−6.50
−4.33
−7.00

Q1, Q3
−9.00, −4.33
−4.00, −4.00
−9.00, −4.00
−9.00, −4.00
−9.00, −4.00

Min, Max
−9.0, −4.3
−4.0, −4.0
−9.0, −4.0
−9.0, −4.0
−9.0, −4.0

Percent Change from Baseline

n
3
2
2
3
7

Mean
−39.85
−32.75
−36.28
−37.49
−40.36

(SD)
(10.180)
(16.541)
(11.540)
(14.256)
(12.854)

Median
−45.00
−32.75
−36.28
−45.00
−44.44

Q1, Q3
−46.43, −28.13
−44.44, −21.05
−44.44, −28.13
−46.43, −21.05
−46.43, −28.13

Min, Max
−46.4, −28.1
−44.4, −21.1
−44.4, −28.1
−46.4, −21.1
−60.0, −21.1

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

2
1
1

Mean

10.00
11.00
12.83

(SD)

(4.243)

Median

10.00
11.00
12.83

Q1, Q3

7.00, 13.00
11.00, 11.00
12.83, 12.83

Min, Max

7.0, 13.0
11.0, 11.0
12.8, 12.8

Weekly RP Attacks

n

2
1
1

Mean

13.00
6.00
11.00

(SD)

(8.485)

Median

13.00
6.00
11.00

Q1, Q3

7.00, 19.00
6.00, 6.00
11.00, 11.00

Min, Max

7.0, 19.0
6.0, 6.0
11.0, 11.0

Change from Baseline

n

2
1
1

Mean

3.00
−5.00
−1.83

(SD)

(4.243)

Median

3.00
−5.00
−1.83

Q1, Q3

0.00, 6.00
−5.00, −5.00
−1.83, −1.83

Min, Max

0.0, 6.0
−5.0, −5.0
−1.8, −1.8

Percent Change from Baseline

n

2
1
1

Mean

23.08
−45.45
−14.29

(SD)

(32.636)

Median

23.08
−45.45
−14.29

Q1, Q3

0.00, 46.15
−45.45, −45.45
−14.29, −14.29

Min, Max

0.0, 46.2
−45.5, −45.5
−14.3, −14.3

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean

11.92
11.00
12.83
10.96

(SD)

(1.296)

(2.790)

Median

11.92
11.00
12.83
11.92

Q1, Q3

11.00, 12.83
11.00, 11.00
12.83, 12.83
9.00, 12.92

Min, Max

11.0, 12.8
11.0, 11.0
12.8, 12.8
7.0, 13.0

Weekly RP Attacks

n

2
1
1
4

Mean

8.50
6.00
11.00
10.75

(SD)

(3.536)

(5.909)

Median

8.50
6.00
11.00
9.00

Q1, Q3

6.00, 11.00
6.00, 6.00
11.00, 11.00
6.50, 15.00

Min, Max

6.0, 11.0
6.0, 6.0
11.0, 11.0
6.0, 19.0

Change from Baseline

n

2
1
1
4

Mean

−3.42
−5.00
−1.83
−0.21

(SD)

(2.239)

(4.626)

Median

−3.42
−5.00
−1.83
−0.92

Q1, Q3

−5.00, −1.83
−5.00, −5.00
−1.83, −1.83
−3.42, 3.00

Min, Max

−5.0, −1.8
−5.0, −5.0
−1.8, −1.8
−5.0, 6.0

Percent Change from Baseline

n

2
1
1
4

Mean

−29.87
−45.45
−14.29
−3.40

(SD)

(22.040)

(38.097)

Median

−29.87
−45.45
−14.29
−7.14

Q1, Q3

−45.45, −14.29
−45.45, −45.45
−14.29, −14.29
−29.87, 23.08

Min, Max

−45.5, −14.3
−45.5, −45.5
−14.3, −14.3
−45.5, 46.2

TABLE A-8

Weekly RP Attacks (All Attacks) Change and Percent Change from Baseline

(Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Frequency of weekly RP attacks is defined as the total number of RP attacks divided by

the number of days with available diary data within the last 7 days of the dosing period

(excluding the last dosing day) then multiplied by 7. Baseline is calculated as total

number of RP attacks during the last 7 days of screening period (excluding the first

dosing day) divided by the number of days with available data then multiplied by 7.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
32.00
14.67

9.00
19.00
17.83

(SD)

(7.542)

(8.721)

Median
32.00
14.67

9.00
19.00
17.83

Q1, Q3
32.00, 32.00
9.33, 20.00

9.00, 9.00
19.00, 19.00
11.67, 24.00

Min, Max
32.0, 32.0
9.3, 20.0

9.0, 9.0
19.0, 19.0
11.7, 24.0

Weekly RP Attacks

n
1
2

1
1
2

Mean
23.00
8.00

5.00
15.00
9.83

(SD)

(4.243)

(7.307)

Median
23.00
8.00

5.00
15.00
9.83

Q1, Q3
23.00, 23.00
5.00, 11.00

5.00, 5.00
15.00, 15.00
4.67, 15.00

Min, Max
23.0, 23.0
5.0, 11.0

5.0, 5.0
15.0, 15.0
4.7, 15.0

Change from Baseline

n
1
2

1
1
2

Mean
−9.00
−6.67

−4.00
−4.00
−8.00

(SD)

(3.300)

(1.414)

Median
−9.00
−6.67

−4.00
−4.00
−8.00

Q1, Q3
−9.00, −9.00
−9.00, −4.33

−4.00, −4.00
−4.00, −4.00
−9.00, −7.00

Min, Max
−9.0, −9.0
−9.0, −4.3

−4.0, −4.0
−4.0, −4.0
−9.0, −7.0

Percent Change from Baseline

n
1
2

1
1
2

Mean
−28.13
−45.71

−44.44
−21.05
−48.75

(SD)

(1.010)

(15.910)

Median
−28.13
−45.71

−44.44
−21.05
−48.75

Q1, Q3
−28.13, −28.13
−46.43, −45.00

−44.44, −44.44
−21.05, −21.05
−60.00, −37.50

Min, Max
−28.1, −28.1
−46.4, −45.0

−44.4, −44.4
−21.1, −21.1
−60.0, −37.5

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
20.44
14.00
20.50
16.11
17.86

(SD)
(11.340)
(7.071)
(16.263)
(5.891)
(8.496)

Median
20.00
14.00
20.50
19.00
19.00

Q1, Q3
9.33, 32.00
9.00, 19.00
9.00, 32.00
9.33, 20.00
9.33, 24.00

Min, Max
9.3, 32.0
9.0, 19.0
9.0, 32.0
9.3, 20.0
9.0, 32.0

Weekly RP Attacks

n
3
2
2
3
7

Mean
13.00
10.00
14.00
10.33
11.24

(SD)
(9.165)
(7.071)
(12.728)
(5.033)
(6.925)

Median
11.00
10.00
14.00
11.00
11.00

Q1, Q3
5.00, 23.00
5.00, 15.00
5.00, 23.00
5.00, 15.00
5.00, 15.00

Min, Max
5.0, 23.0
5.0, 15.0
5.0, 23.0
5.0, 15.0
4.7, 23.0

Change from Baseline

n
3
2
2
3
7

Mean
−7.44
−4.00
−6.50
−5.78
−6.62

(SD)
(2.694)
(0.000)
(3.536)
(2.795)
(2.453)

Median
−9.00
−4.00
−6.50
−4.33
−7.00

Q1, Q3
−9.00, −4.33
−4.00, −4.00
−9.00, −4.00
−9.00, −4.00
−9.00, −4.00

Min, Max
−9.0, −4.3
−4.0, −4.0
−9.0, −4.0
−9.0, −4.0
−9.0, −4.0

Percent Change from Baseline

n
3
2
2
3
7

Mean
−39.85
−32.75
−36.28
−37.49
−40.36

(SD)
(10.180)
(16.541)
(11.540)
(14.256)
(12.854)

Median
−45.00
−32.75
−36.28
−45.00
−44.44

Q1, Q3
−46.43, −28.13
−44.44, −21.05
−44.44, −28.13
−46.43, −21.05
−46.43, −28.13

Min, Max
−46.4, −28.1
−44.4, −21.1
−44.4, −28.1
−46.4, −21.1
−60.0, −21.1

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

1
1
1

Mean

13.00
11.00
12.83

(SD)

Median

13.00
11.00
12.83

Q1, Q3

13.00, 13.00
11.00, 11.00
12.83, 12.83

Min, Max

13.0, 13.0
11.0, 11.0
12.8, 12.8

Weekly RP Attacks

n

1
1
1

Mean

19.00
6.00
11.00

(SD)

Median

19.00
6.00
11.00

Q1, Q3

19.00, 19.00
6.00, 6.00
11.00, 11.00

Min, Max

19.0, 19.0
6.0, 6.0
11.0, 11.0

Change from Baseline

n

1
1
1

Mean

6.00
−5.00
−1.83

(SD)

Median

6.00
−5.00
−1.83

Q1, Q3

6.00, 6.00
−5.00, −5.00
−1.83, −1.83

Min, Max

6.0, 6.0
−5.0, −5.0
−1.8, −1.8

Percent Change from Baseline

n

1
1
1

Mean

46.15
−45.45
−14.29

(SD)

Median

46.15
−45.45
−14.29

Q1, Q3

46.15, 46.15
−45.45, −45.45
−14.29, −14.29

Min, Max

46.2, 46.2
−45.5, −45.5
−14.3, −14.3

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean

11.92
11.00
12.83
12.28

(SD)

(1.296)

(1.110)

Median

11.92
11.00
12.83
12.83

Q1, Q3

11.00, 12.83
11.00, 11.00
12.83, 12.83
11.00, 13.00

Min, Max

11.0, 12.8
11.0, 11.0
12.8, 12.8
11.0, 13.0

Weekly RP Attacks

n

2
1
1
3

Mean

8.50
6.00
11.00
12.00

(SD)

(3.536)

(6.557)

Median

8.50
6.00
11.00
11.00

Q1, Q3

6.00, 11.00
6.00, 6.00
11.00, 11.00
6.00, 19.00

Min, Max

6.0, 11.0
6.0, 6.0
11.0, 11.0
6.0, 19.0

Change from Baseline

n

2
1
1
3

Mean

−3.42
−5.00
−1.83
−0.28

(SD)

(2.239)

(5.663)

Median

−3.42
−5.00
−1.83
−1.83

Q1, Q3

−5.00, −1.83
−5.00, −5.00
−1.83, −1.83
−5.00, 6.00

Min, Max

−5.0, −1.8
−5.0, −5.0
−1.8, −1.8
−5.0, 6.0

Percent Change from Baseline

n

2
1
1
3

Mean

−29.87
−45.45
−14.29
−4.53

(SD)

(22.040)

(46.577)

Median

−29.87
−45.45
−14.29
−14.29

Q1, Q3

−45.45, −14.29
−45.45, −45.45
−14.29, −14.29
−45.45, 46.15

Min, Max

−45.5, −14.3
−45.5, −45.5
−14.3, −14.3
−45.5, 46.2

TABLE B-1

Average Duration of Weekly Symptomatic RP Attacks Change and Percent

Change from Baseline. ITT Population - Part A.

Average duration (minutes) of weekly symptomatic RP attacks is defined as the

total duration of symptomatic RP attacks divided by total number of symptomatic

RP attacks within the last 7 days of the dosing period (excluding the last dosing

day). Baseline is calculated as total duration of symptomatic RP attacks during the

last 7 days of screening period (excluding the first dosing day) divided by the total

number of symptomatic RP attacks. Only symptomatic RP attacks, defined as RP

attacks with patient reported finger color changes associated with at least one

symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
48.38
19.86
271.54
38.17
51.11
56.42

(SD)

(9.232)
(369.051)
(28.845)
(54.997)
(66.350)

Median
48.38
19.86
271.54
38.17
51.11
56.42

Q1, Q3
48.38, 48.38
13.33, 26.39
10.58, 532.50
17.78, 58.57
12.22, 90.00
9.50, 103.33

Min, Max
48.4, 48.4
13.3, 26.4
10.6, 532.5
17.8, 58.6
12.2, 90.0
9.5, 103.3

Average Duration

n
1
2
2
2
2
1

Mean
31.64
16.73
412.29
28.38
39.23
98.08

(SD)

(19.413)
(574.575)
(14.672)
(33.615)

Median
31.64
16.73
412.29
28.38
39.23
98.08

Q1, Q3
31.64, 31.64
3.00, 30.45
6.00, 818.57
18.00, 38.75
15.46, 63.00
98.08, 98.08

Min, Max
31.6, 31.6
3.0, 30.5
6.0, 818.6
18.0, 38.8
15.5, 63.0
98.1, 98.1

Change from Baseline

n
1
2
2
2
2
1

Mean
−16.74
−3.13
140.74
−9.80
−11.88
−5.26

(SD)

(10.182)
(205.524)
(14.173)
(21.382)

Median
−16.74
−3.13
140.74
−9.80
−11.88
−5.26

Q1, Q3
−16.74, −16.74
−10.33, 4.07
−4.58, 286.07
−19.82, 0.22
−27.00, 3.24
−5.26, −5.26

Min, Max
−16.7, −16.7
−10.3, 4.1
−4.6, 286.1
−19.8, 0.2
−27.0, 3.2
−5.3, −5.3

Percent Change from Baseline

n
1
2
2
2
2
1

Mean
−34.60
−31.05
5.21
−16.30
−1.75
−5.09

(SD)

(65.695)
(68.610)
(24.813)
(39.954)

Median
−34.60
−31.05
5.21
−16.30
−1.75
−5.09

Q1, Q3
−34.60, −34.60
−77.50, 15.41
−43.31, 53.72
−33.84, 1.25
−30.00, 26.50
−5.09, −5.09

Min, Max
−34.6, −34.6
−77.5, 15.4
−43.3, 53.7
−33.8, 1.3
−30.0, 26.5
−5.1, −5.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
(N = 11)

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
Participants

Baseline

n
3
4
3
4
11

Mean
29.37
44.64
41.58
35.49
83.87

(SD)
(17.713)
(36.625)
(21.231)
(36.907)
(152.403)

Median
26.39
38.17
48.38
19.86
26.39

Q1, Q3
13.33, 48.38
15.00, 74.29
17.78, 58.57
12.78, 58.19
12.22, 90.00

Min, Max
13.3, 48.4
12.2, 90.0
17.8, 58.6
12.2, 90.0
9.5, 532.5

Average Duration

n
3
4
3
4
10

Mean
21.70
33.80
29.46
27.98
112.30

(SD)
(16.205)
(22.084)
(10.545)
(25.905)
(249.796)

Median
30.45
28.38
31.64
22.96
31.05

Q1, Q3
3.00, 31.64
16.73, 50.88
18.00, 38.75
9.23, 46.73
15.46, 63.00

Min, Max
3.0, 31.6
15.5, 63.0
18.0, 38.8
3.0, 63.0
3.0, 818.6

Change from Baseline

n
3
4
3
4
10

Mean
−7.67
−10.84
−12.11
−7.51
20.99

(SD)
(10.655)
(14.859)
(10.793)
(14.576)
(93.700)

Median
−10.33
−9.80
−16.74
−3.55
−4.92

Q1, Q3
−16.74, 4.07
−23.41, 1.73
−19.82, 0.22
−18.67, 3.65
−16.74, 3.24

Min, Max
−16.7, 4.1
−27.0, 3.2
−19.8, 0.2
−27.0, 4.1
−27.0, 286.1

Percent Change from Baseline

n
3
4
3
4
10

Mean
−32.23
−9.02
−22.40
−16.40
−12.74

(SD)
(46.499)
(28.423)
(20.481)
(47.506)
(38.518)

Median
−34.60
−14.38
−33.84
−7.30
−17.54

Q1, Q3
−77.50, 15.41
−31.92, 13.88
−34.60, 1.25
−53.75, 20.96
−34.60, 15.41

Min, Max
−77.5, 15.4
−33.8, 26.5
−34.6, 1.3
−77.5, 26.5
−77.5, 53.7

TABLE B-2

Average Duration of Weekly Symptomatic RP Attacks Change and Percent

Change from Baseline (Excluding Outliers). ITT Population - Part A.

Average duration (minutes) of weekly symptomatic RP attacks is defined

as the total duration of symptomatic RP attacks divided by total number

of symptomatic RP attacks within the last 7 days of the dosing period

(excluding the last dosing day). Baseline is calculated as total duration

of symptomatic RP attacks during the last 7 days of screening period

(excluding the first dosing day) divided by the total number of

symptomatic RP attacks. Only symptomatic RP attacks, defined as RP

attacks with patient reported finger color changes associated with at least

one symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
48.38
19.86
10.58
38.17
51.11
56.42

(SD)

(9.232)

(28.845)
(54.997)
(66.350)

Median
48.38
19.86
10.58
38.17
51.11
56.42

Q1, Q3
48.38, 48.38
13.33, 26.39
10.58, 10.58
17.78, 58.57
12.22, 90.00
9.50, 103.33

Min, Max
48.4, 48.4
13.3, 26.4
10.6, 10.6
17.8, 58.6
12.2, 90.0
9.5, 103.3

Average Duration

n
1
2
1
2
2
1

Mean
31.64
16.73
6.00
28.38
39.23
98.08

(SD)

(19.413)

(14.672)
(33.615)

Median
31.64
16.73
6.00
28.38
39.23
98.08

Q1, Q3
31.64, 31.64
3.00, 30.45
6.00, 6.00
18.00, 38.75
15.46, 63.00
98.08, 98.08

Min, Max
31.6, 31.6
3.0, 30.5
6.0, 6.0
18.0, 38.8
15.5, 63.0
98.1, 98.1

Change from Baseline

n
1
2
1
2
2
1

Mean
−16.74
−3.13
−4.58
−9.80
−11.88
−5.26

(SD)

(10.182)

(14.173)
(21.382)

Median
−16.74
−3.13
−4.58
−9.80
−11.88
−5.26

Q1, Q3
−16.74, −16.74
−10.33, 4.07
−4.58, −4.58
−19.82, 0.22
−27.00, 3.24
−5.26, −5.26

Min, Max
−16.7, −16.7
−10.3, 4.1
−4.6, −4.6
−19.8, 0.2
−27.0, 3.2
−5.3, −5.3

Percent Change from Baseline

n
1
2
1
2
2
1

Mean
−34.60
−31.05
−43.31
−16.30
−1.75
−5.09

(SD)

(65.695)

(24.813)
(39.954)

Median
−34.60
−31.05
−43.31
−16.30
−1.75
−5.09

Q1, Q3
−34.60, −34.60
−77.50, 15.41
−43.31, −43.31
−33.84, 1.25
−30.00, 26.50
−5.09, −5.09

Min, Max
−34.6, −34.6
−77.5, 15.4
−43.3, −43.3
−33.8, 1.3
−30.0, 26.5
−5.1, −5.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg+

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
29.37
44.64
41.58
35.49
39.01

(SD)
(17.713)
(36.625)
(21.231)
(36.907)
(34.759)

Median
26.39
38.17
48.38
19.86
22.08

Q1, Q3
13.33, 48.38
15.00, 74.29
17.78, 58.57
12.78, 58.19
12.22, 58.57

Min, Max
13.3, 48.4
12.2, 90.0
17.8, 58.6
12.2, 90.0
9.5, 103.3

Average Duration

n
3
4
3
4
9

Mean
21.70
33.80
29.46
27.98
33.82

(SD)
(16.205)
(22.084)
(10.545)
(25.905)
(30.274)

Median
30.45
28.38
31.64
22.96
30.45

Q1, Q3
3.00, 31.64
16.73, 50.88
18.00, 38.75
9.23, 46.73
15.46, 38.75

Min, Max
3.0, 31.6
15.5, 63.0
18.0, 38.8
3.0, 63.0
3.0, 98.1

Change from Baseline

n
3
4
3
4
9

Mean
−7.67
−10.84
−12.11
−7.51
−8.47

(SD)
(10.655)
(14.859)
(10.793)
(14.576)
(10.836)

Median
−10.33
−9.80
−16.74
−3.55
−5.26

Q1, Q3
−16.74, 4.07
−23.41, 1.73
−19.82, 0.22
−18.67, 3.65
−16.74, 0.22

Min, Max
−16.7, 4.1
−27.0, 3.2
−19.8, 0.2
−27.0, 4.1
−27.0, 4.1

Percent Change from Baseline

n
3
4
3
4
9

Mean
−32.23
−9.02
−22.40
−16.40
−20.13

(SD)
(46.499)
(28.423)
(20.481)
(47.506)
(32.489)

Median
−34.60
−14.38
−33.84
−7.30
−30.00

Q1, Q3
−77.50, 15.41
−31.92, 13.88
−34.60, 1.25
−53.75, 20.96
−34.60, 1.25

Min, Max
−77.5, 15.4
−33.8, 26.5
−34.6, 1.3
−77.5, 26.5
−77.5, 26.5

TABLE B-3

Average Duration of Weekly Symptomatic RP Attacks Change and

Percent Change from Baseline by Baseline RCS. ITT Population - Part A.

Average duration (minutes) of weekly symptomatic RP attacks is defined as the total duration

of symptomatic RP attacks divided by total number of symptomatic RP attacks within the last 7

days of the dosing period (excluding the last dosing day). Baseline is calculated as total

duration of symptomatic RP attacks during the last 7 days of screening period (excluding the

first dosing day) divided by the total number of symptomatic RP attacks. Only symptomatic RP

attacks, defined as RP attacks with patient reported finger color changes associated with at

least one symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
48.38
19.86

17.78
12.22
56.42

(SD)

(9.232)

(66.350)

Median
48.38
19.86

17.78
12.22
56.42

Q1, Q3
48.38, 48.38
13.33, 26.39

17.78, 17.78
12.22, 12.22
9.50, 103.33

Min, Max
48.4, 48.4
13.3, 26.4

17.8, 17.8
12.2, 12.2
9.5, 103.3

Average

Duration

n
1
2

1
1
1

Mean
31.64
16.73

18.00
15.46
98.08

(SD)

(19.413)

Median
31.64
16.73

18.00
15.46
98.08

Q1, Q3
31.64, 31.64
3.00, 30.45

18.00, 18.00
15.46, 15.46
98.08, 98.08

Min, Max
31.6, 31.6
3.0, 30.5

18.0, 18.0
15.5, 15.5
98.1, 98.1

Change from

Baseline

n
1
2

1
1
1

Mean
−16.74
−3.13

0.22
3.24
−5.26

(SD)

(10.182)

Median
−16.74
−3.13

0.22
3.24
−5.26

Q1, Q3
−16.74, −16.74
−10.33, 4.07

0.22, 0.22
3.24, 3.24
−5.26, −5.26

Min, Max
−16.7, −16.7
−10.3, 4.1

0.2, 0.2
3.2, 3.2
−5.3, −5.3

Percent Change

from Baseline

n
1
2

1
1
1

Mean
−34.60
−31.05

1.25
26.50
−5.09

(SD)

(65.695)

Median
−34.60
−31.05

1.25
26.50
−5.09

Q1, Q3
−34.60, −34.60
−77.50, 15.41

1.25, 1.25
26.50, 26.50
−5.09, −5.09

Min, Max
−34.6, −34.6
−77.5, 15.4

1.3, 1.3
26.5, 26.5
−5.1, −5.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
29.37
15.00
33.08
17.31
32.99

(SD)
(17.713)
(3.928)
(21.640)
(7.878)
(33.738)

Median
26.39
15.00
33.08
13.33
17.78

Q1, Q3
13.33, 48.38
12.22, 17.78
17.78, 48.38
12.22, 26.39
12.22, 48.38

Min, Max
13.3, 48.4
12.2, 17.8
17.8, 48.4
12.2, 26.4
9.5, 103.3

Average

Duration

n
3
2
2
3
6

Mean
21.70
16.73
24.82
16.31
32.77

(SD)
(16.205)
(1.795)
(9.647)
(13.747)
(33.692)

Median
30.45
16.73
24.82
15.46
24.23

Q1, Q3
3.00, 31.64
15.46, 18.00
18.00, 31.64
3.00, 30.45
15.46, 31.64

Min, Max
3.0, 31.6
15.5, 18.0
18.0, 31.6
3.0, 30.5
3.0, 98.1

Change from

Baseline

n
3
2
2
3
6

Mean
−7.67
1.73
−8.26
−1.01
−4.13

(SD)
(10.655)
(2.133)
(11.993)
(8.085)
(8.236)

Median
−10.33
1.73
−8.26
3.24
−2.52

Q1, Q3
−16.74, 4.07
0.22, 3.24
−16.74, 0.22
−10.33, 4.07
−10.33, 3.24

Min, Max
−16.7, 4.1
0.2, 3.2
−16.7, 0.2
−10.3, 4.1
−16.7, 4.1

Percent Change

from Baseline

n
3
2
2
3
6

Mean
−32.23
13.88
−16.67
−11.86
−12.34

(SD)
(46.499)
(17.857)
(25.347)
(57.113)
(38.098)

Median
−34.60
13.88
−16.67
15.41
−1.92

Q1, Q3
−77.50, 15.41
1.25, 26.50
−34.60, 1.25
−77.50, 26.50
−34.60, 15.41

Min, Max
−77.5, 15.4
1.3, 26.5
−34.6, 1.3
−77.5, 26.5
−77.5, 26.5

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

2
1
1

Mean

271.54
58.57
90.00

(SD)

(369.051)

Median

271.54
58.57
90.00

Q1, Q3

10.58, 532.50
58.57, 58.57
90.00, 90.00

Min, Max

10.6, 532.5
58.6, 58.6
90.0, 90.0

Average

Duration

n

2
1
1

Mean

412.29
38.75
63.00

(SD)

(574.575)

Median

412.29
38.75
63.00

Q1, Q3

6.00, 818.57
38.75, 38.75
63.00, 63.00

Min, Max

6.0, 818.6
38.8, 38.8
63.0, 63.0

Change from

Baseline

n

2
1
1

Mean

140.74
−19.82
−27.00

(SD)

(205.524)

Median

140.74
−19.82
−27.00

Q1, Q3

−4.58, 286.07
−19.82, −19.82
−27.00, −27.00

Min, Max

−4.6, 286.1
−19.8, −19.8
−27.0, −27.0

Percent Change

from Baseline

n

2
1
1

Mean

5.21
−33.84
−30.00

(SD)

(68.610)

Median

5.21
−33.84
−30.00

Q1, Q3

−43.31, 53.72
−33.84, −33.84
−30.00, −30.00

Min, Max

−43.3, 53.7
−33.8, −33.8
−30.0, −30.0

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean

74.29
58.57
90.00
172.91

(SD)

(22.223)

(241.938)

Median

74.29
58.57
90.00
74.29

Q1, Q3

58.57, 90.00
58.57, 58.57
90.00, 90.00
34.58, 311.25

Min, Max

58.6, 90.0
58.6, 58.6
90.0, 90.0
10.6, 532.5

Average

Duration

n

2
1
1
4

Mean

50.88
38.75
63.00
231.58

(SD)

(17.147)

(392.024)

Median

50.88
38.75
63.00
50.88

Q1, Q3

38.75, 63.00
38.75, 38.75
63.00, 63.00
22.38, 440.79

Min, Max

38.8, 63.0
38.8, 38.8
63.0, 63.0
6.0, 818.6

Change from

Baseline

n

2
1
1
4

Mean

−23.41
−19.82
−27.00
58.67

(SD)

(5.076)

(151.891)

Median

−23.41
−19.82
−27.00
−12.20

Q1, Q3

−27.00, −19.82
−19.82, −19.82
−27.00, −27.00
−23.41, 140.74

Min, Max

−27.0, −19.8
−19.8, −19.8
−27.0, −27.0
−27.0, 286.1

Percent Change

from Baseline

n

2
1
1
4

Mean

−31.92
−33.84
−30.00
−13.36

(SD)

(2.716)

(45.068)

Median

−31.92
−33.84
−30.00
−31.92

Q1, Q3

−33.84, −30.00
−33.84, −33.84
−30.00, −30.00
−38.57, 11.86

Min, Max

−33.8, −30.0
−33.8, −33.8
−30.0, −30.0
−43.3, 53.7

TABLE B-4

Average Duration of Weekly Symptomatic RP Attacks Change and Percent Change

from Baseline (Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Average duration (minutes) of weekly symptomatic RP attacks is defined as the total duration

of symptomatic RP attacks divided by total number of symptomatic RP attacks within the last 7

days of the dosing period (excluding the last dosing day). Baseline is calculated as total

duration of symptomatic RP attacks during the last 7 days of screening period (excluding the

first dosing day) divided by the total number of symptomatic RP attacks. Only symptomatic RP

attacks, defined as RP attacks with patient reported finger color changes associated with at

least one symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
48.38
19.86

17.78
12.22
56.42

(SD)

(9.232)

(66.350)

Median
48.38
19.86

17.78
12.22
56.42

Q1, Q3
48.38, 48.38
13.33, 26.39

17.78, 17.78
12.22, 12.22
9.50, 103.33

Min, Max
48.4, 48.4
13.3, 26.4

17.8, 17.8
12.2, 12.2
9.5, 103.3

Average

Duration

n
1
2

1
1
1

Mean
31.64
16.73

18.00
15.46
98.08

(SD)

(19.413)

Median
31.64
16.73

18.00
15.46
98.08

Q1, Q3
31.64, 31.64
3.00, 30.45

18.00, 18.00
15.46, 15.46
98.08, 98.08

Min, Max
31.6, 31.6
3.0, 30.5

18.0, 18.0
15.5, 15.5
98.1, 98.1

Change from

Baseline

n
1
2

1
1
1

Mean
−16.74
−3.13

0.22
3.24
−5.26

(SD)

(10.182)

Median
−16.74
−3.13

0.22
3.24
−5.26

Q1, Q3
−16.74, −16.74
−10.33, 4.07

0.22, 0.22
3.24, 3.24
−5.26, −5.26

Min, Max
−16.7, −16.7
−10.3, 4.1

0.2, 0.2
3.2, 3.2
−5.3, −5.3

Percent Change

from Baseline

n
1
2

1
1
1

Mean
−34.60
−31.05

1.25
26.50
−5.09

(SD)

(65.695)

Median
−34.60
−31.05

1.25
26.50
−5.09

Q1, Q3
−34.60, −34.60
−77.50, 15.41

1.25, 1.25
26.50, 26.50
−5.09, −5.09

Min, Max
−34.6, −34.6
−77.5, 15.4

1.3, 1.3
26.5, 26.5
−5.1, −5.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
29.37
15.00
33.08
17.31
32.99

(SD)
(17.713)
(3.928)
(21.640)
(7.878)
(33.738)

Median
26.39
15.00
33.08
13.33
17.78

Q1, Q3
13.33, 48.38
12.22, 17.78
17.78, 48.38
12.22, 26.39
12.22, 48.38

Min, Max
13.3, 48.4
12.2, 17.8
17.8, 48.4
12.2, 26.4
9.5, 103.3

Average

Duration

n
3
2
2
3
6

Mean
21.70
16.73
24.82
16.31
32.77

(SD)
(16.205)
(1.795)
(9.647)
(13.747)
(33.692)

Median
30.45
16.73
24.82
15.46
24.23

Q1, Q3
3.00, 31.64
15.46, 18.00
18.00, 31.64
3.00, 30.45
15.46, 31.64

Min, Max
3.0, 31.6
15.5, 18.0
18.0, 31.6
3.0, 30.5
3.0, 98.1

Change from

Baseline

n
3
2
2
3
6

Mean
−7.67
1.73
−8.26
−1.01
−4.13

(SD)
(10.655)
(2.133)
(11.993)
(8.085)
(8.236)

Median
−10.33
1.73
−8.26
3.24
−2.52

Q1, Q3
−16.74, 4.07
0.22, 3.24
−16.74, 0.22
−10.33, 4.07
−10.33, 3.24

Min, Max
−16.7, 4.1
0.2, 3.2
−16.7, 0.2
−10.3, 4.1
−16.7, 4.1

Percent Change

from Baseline

n
3
2
2
3
6

Mean
−32.23
13.88
−16.67
−11.86
−12.34

(SD)
(46.499)
(17.857)
(25.347)
(57.113)
(38.098)

Median
−34.60
13.88
−16.67
15.41
−1.92

Q1, Q3
−77.50, 15.41
1.25, 26.50
−34.60, 1.25
−77.50, 26.50
−34.60, 15.41

Min, Max
−77.5, 15.4
1.3, 26.5
−34.6, 1.3
−77.5, 26.5
−77.5, 26.5

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

1
1
1

Mean

10.58
58.57
90.00

(SD)

Median

10.58
58.57
90.00

Q1, Q3

10.58, 10.58
58.57, 58.57
90.00, 90.00

Min, Max

10.6, 10.6
58.6, 58.6
90.0, 90.0

Average

Duration

n

1
1
1

Mean

6.00
38.75
63.00

(SD)

Median

6.00
38.75
63.00

Q1, Q3

6.00, 6.00
38.75, 38.75
63.00, 63.00

Min, Max

6.0, 6.0
38.8, 38.8
63.0, 63.0

Change from

Baseline

n

1
1
1

Mean

−4.58
−19.82
−27.00

(SD)

Median

−4.58
−19.82
−27.00

Q1, Q3

−4.58, −4.58
−19.82, −19.82
−27.00, −27.00

Min, Max

−4.6, −4.6
−19.8, −19.8
−27.0, −27.0

Percent Change

from Baseline

n

1
1
1

Mean

−43.31
−33.84
−30.00

(SD)

Median

−43.31
−33.84
−30.00

Q1, Q3

−43.31, −43.31
−33.84, −33.84
−30.00, −30.00

Min, Max

−43.3, −43.3
−33.8, −33.8
−30.0, −30.0

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean

74.29
58.57
90.00
53.05

(SD)

(22.223)

(39.995)

Median

74.29
58.57
90.00
58.57

Q1, Q3

58.57, 90.00
58.57, 58.57
90.00, 90.00
10.58, 90.00

Min, Max

58.6, 90.0
58.6, 58.6
90.0, 90.0
10.6, 90.0

Average

Duration

n

2
1
1
3

Mean

50.88
38.75
63.00
35.92

(SD)

(17.147)

(28.605)

Median

50.88
38.75
63.00
38.75

Q1, Q3

38.75, 63.00
38.75, 38.75
63.00, 63.00
6.00, 63.00

Min, Max

38.8, 63.0
38.8, 38.8
63.0, 63.0
6.0, 63.0

Change from

Baseline

n

2
1
1
3

Mean

−23.41
−19.82
−27.00
−17.13

(SD)

(5.076)

(11.447)

Median

−23.41
−19.82
−27.00
−19.82

Q1, Q3

−27.00, −19.82
−19.82, −19.82
−27.00, −27.00
−27.00, −4.58

Min, Max

−27.0, −19.8
−19.8, −19.8
−27.0, −27.0
−27.0, −4.6

Percent Change

from Baseline

n

2
1
1
3

Mean

−31.92
−33.84
−30.00
−35.72

(SD)

(2.716)

(6.849)

Median

−31.92
−33.84
−30.00
−33.84

Q1, Q3

−33.84, −30.00
−33.84, −33.84
−30.00, −30.00
−43.31, −30.00

Min, Max

−33.8, −30.0
−33.8, −33.8
−30.0, −30.0
−43.3, −30.0

TABLE B-5

Average Duration of Weekly RP Attacks (All Attacks) Change and

Percent Change from Baseline. ITT Population - Part A.

Average duration (minutes) of weekly RP attacks is defined as the total duration

of RP attacks divided by total number of symptomatic RP attacks within the last 7

days of the dosing period (excluding the last dosing day). Baseline is calculated

as total duration of RP attacks during the last 7 days of screening period

(excluding the first dosing day) divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
40.00
17.81
320.46
36.16
46.96
56.42

(SD)

(10.165)
(437.753)
(25.999)
(49.294)
(66.350)

Median
40.00
17.81
320.46
36.16
46.96
56.42

Q1, Q3
40.00, 40.00
10.63, 25.00
10.92, 630.00
17.78, 54.55
12.11, 81.82
9.50, 103.33

Min, Max
40.0, 40.0
10.6, 25.0
10.9, 630.0
17.8, 54.5
12.1, 81.8
9.5, 103.3

Average

Duration

n
1
2
2
2
2
1

Mean
31.52
16.73
412.26
26.08
38.50
92.33

(SD)

(19.413)
(574.612)
(11.432)
(34.267)

Median
31.52
16.73
412.26
26.08
38.50
92.33

Q1, Q3
31.52, 31.52
3.00, 30.45
5.95, 818.57
18.00, 34.17
14.27, 62.73
92.33, 92.33

Min, Max
31.5, 31.5
3.0, 30.5
5.9, 818.6
18.0, 34.2
14.3, 62.7
92.3, 92.3

Change from

Baseline

n
1
2
2
2
2
1

Mean
−8.48
−1.09
91.80
−10.08
−8.46
−11.00

(SD)

(9.249)
(136.858)
(14.567)
(15.028)

Median
−8.48
−1.09
91.80
−10.08
−8.46
−11.00

Q1, Q3
−8.48, −8.48
−7.63, 5.45
−4.98, 188.57
−20.38, 0.22
−19.09, 2.16
−11.00, −11.00

Min, Max
−8.5, −8.5
−7.6, 5.5
−5.0, 188.6
−20.4, 0.2
−19.1, 2.2
−11.0, −11.0

Percent Change

from Baseline

n
1
2
2
2
2
1

Mean
−21.20
−24.97
−7.81
−18.06
−2.74
−10.65

(SD)

(66.173)
(53.375)
(27.302)
(29.125)

Median
−21.20
−24.97
−7.81
−18.06
−2.74
−10.65

Q1, Q3
−21.20, −21.20
−71.76, 21.82
−45.55, 29.93
−37.36, 1.25
−23.33, 17.86
−10.65, −10.65

Min, Max
−21.2, −21.2
−71.8, 21.8
−45.6, 29.9
−37.4, 1.3
−23.3, 17.9
−10.6, −10.6

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean
25.21
41.56
37.44
32.39
90.51

(SD)
(14.689)
(32.775)
(18.517)
(33.580)
(181.698)

Median
25.00
36.16
40.00
18.55
25.00

Q1, Q3
10.63, 40.00
14.94, 68.18
17.78, 54.55
11.37, 53.41
10.92, 81.82

Min, Max
10.6, 40.0
12.1, 81.8
17.8, 54.5
10.6, 81.8
9.5, 630.0

Average

Duration

n
3
4
3
4
10

Mean
21.66
32.29
27.90
27.61
111.10

(SD)
(16.168)
(22.053)
(8.672)
(25.981)
(250.056)

Median
30.45
26.08
31.52
22.36
30.99

Q1, Q3
3.00, 31.52
16.13, 48.45
18.00, 34.17
8.63, 46.59
14.27, 62.73

Min, Max
3.0, 31.5
14.3, 62.7
18.0, 34.2
3.0, 62.7
3.0, 818.6

Change from

Baseline

n
3
4
3
4
10

Mean
−3.55
−9.27
−9.54
−4.77
12.49

(SD)
(7.809)
(12.119)
(10.342)
(11.043)
(62.441)

Median
−7.63
−9.43
−8.48
−2.73
−6.30

Q1, Q3
−8.48, 5.45
−19.73, 1.19
−20.38, 0.22
−13.36, 3.81
−11.00, 2.16

Min, Max
−8.5, 5.5
−20.4, 2.2
−20.4, 0.2
−19.1, 5.5
−20.4, 188.6

Percent Change

from Baseline

n
3
4
3
4
10

Mean
−23.71
−10.40
−19.10
−13.86
−13.90

(SD)
(46.842)
(24.686)
(19.390)
(43.671)
(32.469)

Median
−21.20
−11.04
−21.20
−2.74
−15.92

Q1, Q3
−71.76, 21.82
−30.35, 9.55
−37.36, 1.25
−47.55, 19.84
−37.36, 17.86

Min, Max
−71.8, 21.8
−37.4, 17.9
−37.4, 1.3
−71.8, 21.8
−71.8, 29.9

TABLE B-6

Average Duration of Weekly RP Attacks (All Attacks) Change and Percent

Change from Baseline (Excluding Outliers). ITT Population - Part A.

Average duration (minutes) of weekly RP attacks is defined as the total duration

of RP attacks divided by total number of symptomatic RP attacks within the last 7

days of the dosing period (excluding the last dosing day). Baseline is calculated

as total duration of RP attacks during the last 7 days of screening period

(excluding the first dosing day) divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
40.00
17.81
10.92
36.16
46.96
56.42

(SD)

(10.165)

(25.999)
(49.294)
(66.350)

Median
40.00
17.81
10.92
36.16
46.96
56.42

Q1, Q3
40.00, 40.00
10.63, 25.00
10.92, 10.92
17.78, 54.55
12.11, 81.82
9.50, 103.33

Min, Max
40.0, 40.0
10.6, 25.0
10.9, 10.9
17.8, 54.5
12.1, 81.8
9.5, 103.3

Average

Duration

n
1
2
1
2
2
1

Mean
31.52
16.73
5.95
26.08
38.50
92.33

(SD)

(19.413)

(11.432)
(34.267)

Median
31.52
16.73
5.95
26.08
38.50
92.33

Q1, Q3
31.52, 31.52
3.00, 30.45
5.95, 5.95
18.00, 34.17
14.27, 62.73
92.33, 92.33

Min, Max
31.5, 31.5
3.0, 30.5
5.9, 5.9
18.0, 34.2
14.3, 62.7
92.3, 92.3

Change from

Baseline

n
1
2
1
2
2
1

Mean
−8.48
−1.09
−4.98
−10.08
−8.46
−11.00

(SD)

(9.249)

(14.567)
(15.028)

Median
−8.48
−1.09
−4.98
−10.08
−8.46
−11.00

Q1, Q3
−8.48, −8.48
−7.63, 5.45
−4.98, −4.98
−20.38, 0.22
−19.09, 2.16
−11.00, −11.00

Min, Max
−8.5, −8.5
−7.6, 5.5
−5.0, −5.0
−20.4, 0.2
−19.1, 2.2
−11.0, −11.0

Percent Change

from Baseline

n
1
2
1
2
2
1

Mean
−21.20
−24.97
−45.55
−18.06
−2.74
−10.65

(SD)

(66.173)

(27.302)
(29.125)

Median
−21.20
−24.97
−45.55
−18.06
−2.74
−10.65

Q1, Q3
−21.20, −21.20
−71.76, 21.82
−45.55, −45.55
−37.36, 1.25
−23.33, 17.86
−10.65, −10.65

Min, Max
−21.2, −21.2
−71.8, 21.8
−45.6, −45.6
−37.4, 1.3
−23.3, 17.9
−10.6, −10.6

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
25.21
41.56
37.44
32.39
36.56

(SD)
(14.689)
(32.775)
(18.517)
(33.580)
(33.315)

Median
25.00
36.16
40.00
18.55
21.39

Q1, Q3
10.63, 40.00
14.94, 68.18
17.78, 54.55
11.37, 53.41
10.92, 54.55

Min, Max
10.6, 40.0
12.1, 81.8
17.8, 54.5
10.6, 81.8
9.5, 103.3

Average

Duration

n
3
4
3
4
9

Mean
21.66
32.29
27.90
27.61
32.49

(SD)
(16.168)
(22.053)
(8.672)
(25.981)
(28.765)

Median
30.45
26.08
31.52
22.36
30.45

Q1, Q3
3.00, 31.52
16.13, 48.45
18.00, 34.17
8.63, 46.59
14.27, 34.17

Min, Max
3.0, 31.5
14.3, 62.7
18.0, 34.2
3.0, 62.7
3.0, 92.3

Change from

Baseline

n
3
4
3
4
9

Mean
−3.55
−9.27
−9.54
−4.77
−7.08

(SD)
(7.809)
(12.119)
(10.342)
(11.043)
(8.937)

Median
−7.63
−9.43
−8.48
−2.73
−7.63

Q1, Q3
−8.48, 5.45
−19.73, 1.19
−20.38, 0.22
−13.36, 3.81
−11.00, 0.22

Min, Max
−8.5, 5.5
−20.4, 2.2
−20.4, 0.2
−19.1, 5.5
−20.4, 5.5

Percent Change

from Baseline

n
3
4
3
4
9

Mean
−23.71
−10.40
−19.10
−13.86
−18.77

(SD)
(46.842)
(24.686)
(19.390)
(43.671)
(30.318)

Median
−21.20
−11.04
−21.20
−2.74
−21.20

Q1, Q3
−71.76, 21.82
−30.35, 9.55
−37.36, 1.25
−47.55, 19.84
−37.36, 1.25

Min, Max
−71.8, 21.8
−37.4, 17.9
−37.4, 1.3
−71.8, 21.8
−71.8, 21.8

TABLE B-7

Average Duration of Weekly RP Attacks (All Attacks) Change and Percent

Change from Baseline by Baseline RCS. ITT Population - Part A.

Average duration (minutes) of weekly RP attacks is defined as the total duration

of RP attacks divided by total number of symptomatic RP attacks within the last 7

days of the dosing period (excluding the last dosing day). Baseline is calculated

as total duration of RP attacks during the last 7 days of screening period

(excluding the first dosing day) divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
40.00
17.81

17.78
12.11
56.42

(SD)

(10.165)

(66.350)

Median
40.00
17.81

17.78
12.11
56.42

Q1, Q3
40.00, 40.00
10.63, 25.00

17.78, 17.78
12.11, 12.11
9.50, 103.33

Min, Max
40.0, 40.0
10.6, 25.0

17.8, 17.8
12.1, 12.1
9.5, 103.3

Average

Duration

n
1
2

1
1
1

Mean
31.52
16.73

18.00
14.27
92.33

(SD)

(19.413)

Median
31.52
16.73

18.00
14.27
92.33

Q1, Q3
31.52, 31.52
3.00, 30.45

18.00, 18.00
14.27, 14.27
92.33, 92.33

Min, Max
31.5, 31.5
3.0, 30.5

18.0, 18.0
14.3, 14.3
92.3, 92.3

Change from

Baseline

n
1
2

1
1
1

Mean
−8.48
−1.09

0.22
2.16
−11.00

(SD)

(9.249)

Median
−8.48
−1.09

0.22
2.16
−11.00

Q1, Q3
−8.48, −8.48
−7.63, 5.45

0.22, 0.22
2.16, 2.16
−11.00, −11.00

Min, Max
−8.5, −8.5
−7.6, 5.5

0.2, 0.2
2.2, 2.2
−11.0, −11.0

Percent Change

from Baseline

n
1
2

1
1
1

Mean
−21.20
−24.97

1.25
17.86
−10.65

(SD)

(66.173)

Median
−21.20
−24.97

1.25
17.86
−10.65

Q1, Q3
−21.20, −21.20
−71.76, 21.82

1.25, 1.25
17.86, 17.86
−10.65, −10.65

Min, Max
−21.2, −21.2
−71.8, 21.8

1.3, 1.3
17.9, 17.9
−10.6, −10.6

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
25.21
14.94
28.89
15.91
31.19

(SD)
(14.689)
(4.011)
(15.713)
(7.907)
(33.561)

Median
25.00
14.94
28.89
12.11
17.78

Q1, Q3
10.63, 40.00
12.11, 17.78
17.78, 40.00
10.63, 25.00
10.63, 40.00

Min, Max
10.6, 40.0
12.1, 17.8
17.8, 40.0
10.6, 25.0
9.5, 103.3

Average

Duration

n
3
2
2
3
6

Mean
21.66
16.13
24.76
15.91
31.60

(SD)
(16.168)
(2.640)
(9.561)
(13.801)
(31.601)

Median
30.45
16.13
24.76
14.27
24.23

Q1, Q3
3.00, 31.52
14.27, 18.00
18.00, 31.52
3.00, 30.45
14.27, 31.52

Min, Max
3.0, 31.5
14.3, 18.0
18.0, 31.5
3.0, 30.5
3.0, 92.3

Change from

Baseline

n
3
2
2
3
6

Mean
−3.55
1.19
−4.13
0.00
−3.21

(SD)
(7.809)
(1.371)
(6.152)
(6.803)
(6.688)

Median
−7.63
1.19
−4.13
2.16
−3.70

Q1, Q3
−8.48, 5.45
0.22, 2.16
−8.48, 0.22
−7.63, 5.45
−8.48, 2.16

Min, Max
−8.5, 5.5
0.2, 2.2
−8.5, 0.2
−7.6, 5.5
−11.0, 5.5

Percent Change

from Baseline

n
3
2
2
3
6

Mean
−23.71
9.55
−9.97
−10.70
−10.45

(SD)
(46.842)
(11.742)
(15.871)
(52.923)
(34.218)

Median
−21.20
9.55
−9.97
17.86
−4.70

Q1, Q3
−71.76, 21.82
1.25, 17.86
−21.20, 1.25
−71.76, 21.82
−21.20, 17.86

Min, Max
−71.8, 21.8
1.3, 17.9
−21.2, 1.3
−71.8, 21.8
−71.8, 21.8

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

2
1
1

Mean

320.46
54.55
81.82

(SD)

(437.753)

Median

320.46
54.55
81.82

Q1, Q3

10.92, 630.00
54.55, 54.55
81.82, 81.82

Min, Max

10.9, 630.0
54.5, 54.5
81.8, 81.8

Average

Duration

n

2
1
1

Mean

412.26
34.17
62.73

(SD)

(574.612)

Median

412.26
34.17
62.73

Q1, Q3

5.95, 818.57
34.17, 34.17
62.73, 62.73

Min, Max

5.9, 818.6
34.2, 34.2
62.7, 62.7

Change from

Baseline

n

2
1
1

Mean

91.80
−20.38
−19.09

(SD)

(136.858)

Median

91.80
−20.38
−19.09

Q1, Q3

−4.98, 188.57
−20.38, −20.38
−19.09, −19.09

Min, Max

−5.0, 188.6
−20.4, −20.4
−19.1, −19.1

Percent Change

from Baseline

n

2
1
1

Mean

−7.81
−37.36
−23.33

(SD)

(53.375)

Median

−7.81
−37.36
−23.33

Q1, Q3

−45.55, 29.93
−37.36, −37.36
−23.33, −23.33

Min, Max

−45.6, 29.9
−37.4, −37.4
−23.3, −23.3

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean

68.18
54.55
81.82
194.32

(SD)

(19.285)

(291.916)

Median

68.18
54.55
81.82
68.18

Q1, Q3

54.55, 81.82
54.55, 54.55
81.82, 81.82
32.73, 355.91

Min, Max

54.5, 81.8
54.5, 54.5
81.8, 81.8
10.9, 630.0

Average

Duration

n

2
1
1
4

Mean

48.45
34.17
62.73
230.35

(SD)

(20.195)

(392.830)

Median

48.45
34.17
62.73
48.45

Q1, Q3

34.17, 62.73
34.17, 34.17
62.73, 62.73
20.06, 440.65

Min, Max

34.2, 62.7
34.2, 34.2
62.7, 62.7
5.9, 818.6

Change from

Baseline

n

2
1
1
4

Mean

−19.73
−20.38
−19.09
36.03

(SD)

(0.911)

(101.932)

Median

−19.73
−20.38
−19.09
−12.03

Q1, Q3

−20.38, −19.09
−20.38, −20.38
−19.09, −19.09
−19.73, 91.80

Min, Max

−20.4, −19.1
−20.4, −20.4
−19.1, −19.1
−20.4, 188.6

Percent Change

from Baseline

n

2
1
1
4

Mean

−30.35
−37.36
−23.33
−19.08

(SD)

(9.919)

(33.937)

Median

−30.35
−37.36
−23.33
−30.35

Q1, Q3

−37.36, −23.33
−37.36, −37.36
−23.33, −23.33
−41.46, 3.30

Min, Max

−37.4, −23.3
−37.4, −37.4
−23.3, −23.3
−45.6, 29.9

TABLE B-8

Average Duration of Weekly RP Attacks (All Attacks) Change and Percent

Change from Baseline (Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Average duration (minutes) of weekly RP attacks is defined as the total duration of RP

attacks divided by total number of symptomatic RP attacks within the last 7 days of the

dosing period (excluding the last dosing day). Baseline is calculated as total duration

of RP attacks during the last 7 days of screening period (excluding the first dosing day)

divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
40.00
17.81

17.78
12.11
56.42

(SD)

(10.165)

(66.350)

Median
40.00
17.81

17.78
12.11
56.42

Q1, Q3
40.00, 40.00
10.63, 25.00

17.78, 17.78
12.11, 12.11
9.50, 103.33

Min, Max
40.0, 40.0
10.6, 25.0

17.8, 17.8
12.1, 12.1
9.5, 103.3

Average Duration

n
1
2

1
1
1

Mean
31.52
16.73

18.00
14.27
92.33

(SD)

(19.413)

Median
31.52
16.73

18.00
14.27
92.33

Q1, Q3
31.52, 31.52
3.00, 30.45

18.00, 18.00
14.27, 14.27
92.33, 92.33

Min, Max
31.5, 31.5
3.0, 30.5

18.0, 18.0
14.3, 14.3
92.3, 92.3

Change from Baseline

n
1
2

1
1
1

Mean
−8.48
−1.09

0.22
2.16
−11.00

(SD)

(9.249)

Median
−8.48
−1.09

0.22
2.16
−11.00

Q1, Q3
−8.48, −8.48
−7.63, 5.45

0.22, 0.22
2.16, 2.16
−11.00, −11.00

Min, Max
−8.5, −8.5
−7.6, 5.5

0.2, 0.2
2.2, 2.2
−11.0, −11.0

Percent Change from Baseline

n
1
2

1
1
1

Mean
−21.20
−24.97

1.25
17.86
−10.65

(SD)

(66.173)

Median
−21.20
−24.97

1.25
17.86
−10.65

Q1, Q3
−21.20, −21.20
−71.76, 21.82

1.25, 1.25
17.86, 17.86
−10.65, −10.65

Min, Max
−21.2, −21.2
−71.8, 21.8

1.3, 1.3
17.9, 17.9
−10.6, −10.6

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean (SD)
25.21
14.94
28.89
15.91
31.19

(14.689)
(4.011)
(15.713)
(7.907)
(33.561)

Median
25.00
14.94
28.89
12.11
17.78

Q1, Q3
10.63, 40.00
12.11, 17.78
17.78, 40.00
10.63, 25.00
10.63, 40.00

Min, Max
10.6, 40.0
12.1, 17.8
17.8, 40.0
10.6, 25.0
9.5, 103.3

Average Duration

n
3
2
2
3
6

Mean (SD)
21.66
16.13
24.76
15.91
31.60

(16.168)
(2.640)
(9.561)
(13.801)
(31.601)

Median
30.45
16.13
24.76
14.27
24.23

Q1, Q3
3.00, 31.52
14.27, 18.00
18.00, 31.52
3.00, 30.45
14.27, 31.52

Min, Max
3.0, 31.5
14.3, 18.0
18.0, 31.5
3.0, 30.5
3.0, 92.3

Change from Baseline

n
3
2
2
3
6

Mean (SD)
−3.55
1.19
−4.13
0.00
−3.21

(7.809)
(1.371)
(6.152)
(6.803)
(6.688)

Median
−7.63
1.19
−4.13
2.16
−3.70

Q1, Q3
−8.48, 5.45
0.22, 2.16
−8.48, 0.22
−7.63, 5.45
−8.48, 2.16

Min, Max
−8.5, 5.5
0.2, 2.2
−8.5, 0.2
−7.6, 5.5
−11.0, 5.5

Percent Change from Baseline

n
3
2
2
3
6

Mean (SD)
−23.71
9.55
−9.97
−10.70
−10.45

(46.842)
(11.742)
(15.871)
(52.923)
(34.218)

Median
−21.20
9.55
−9.97
17.86
−4.70

Q1, Q3
−71.76, 21.82
1.25, 17.86
−21.20, 1.25
−71.76, 21.82
−21.20, 17.86

Min, Max
−71.8, 21.8
1.3, 17.9
−21.2, 1.3
−71.8, 21.8
−71.8, 21.8

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n

1
1
1

Mean

10.92
54.55
81.82

(SD)

Median

10.92
54.55
81.82

Q1, Q3

10.92, 10.92
54.55, 54.55
81.82, 81.82

Min, Max

10.9, 10.9
54.5, 54.5
81.8, 81.8

Average Duration

n

1
1
1

Mean

5.95
34.17
62.73

(SD)

Median

5.95
34.17
62.73

Q1, Q3

5.95, 5.95
34.17, 34.17
62.73, 62.73

Min, Max

5.9, 5.9
34.2, 34.2
62.7, 62.7

Change from Baseline

n

1
1
1

Mean

−4.98
−20.38
−19.09

(SD)

Median

−4.98
−20.38
−19.09

Q1, Q3

−4.98, −4.98
−20.38, −20.38
−19.09, −19.09

Min, Max

−5.0, −5.0
−20.4, −20.4
−19.1, −19.1

Percent Change from Baseline

n

1
1
1

Mean

−45.55
−37.36
−23.33

(SD)

Median

−45.55
−37.36
−23.33

Q1, Q3

−45.55, −45.55
−37.36, −37.36
−23.33, −23.33

Min, Max

−45.6, −45.6
−37.4, −37.4
−23.3, −23.3

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean

68.18
54.55
81.82
49.10

(SD)

(19.285)

(35.760)

Median

68.18
54.55
81.82
54.55

Q1, Q3

54.55, 81.82
54.55, 54.55
81.82, 81.82
10.92, 81.82

Min, Max

54.5, 81.8
54.5, 54.5
81.8, 81.8
10.9, 81.8

Average Duration

n

2
1
1
3

Mean

48.45
34.17
62.73
34.28

(SD)

(20.195)

(28.390)

Median

48.45
34.17
62.73
34.17

Q1, Q3

34.17, 62.73
34.17, 34.17
62.73, 62.73
5.95, 62.73

Min, Max

34.2, 62.7
34.2, 34.2
62.7, 62.7
5.9, 62.7

Change from Baseline

n

2
1
1
3

Mean

−19.73
−20.38
−19.09
−14.82

(SD)

(0.911)

(8.545)

Median

−19.73
−20.38
−19.09
−19.09

Q1, Q3

−20.38, −19.09
−20.38, −20.38
−19.09, −19.09
−20.38, −4.98

Min, Max

−20.4, −19.1
−20.4, −20.4
−19.1, −19.1
−20.4, −5.0

Percent Change from Baseline

n

2
1
1
3

Mean

−30.35
−37.36
−23.33
−35.42

(SD)

(9.919)

(11.237)

Median

−30.35
−37.36
−23.33
−37.36

Q1, Q3

−37.36, −23.33
−37.36, −37.36
−23.33, −23.33
−45.55, −23.33

Min, Max

−37.4, −23.3
−37.4, −37.4
−23.3, −23.3
−45.6, −23.3

TABLE C-1

Average Severity of Weekly Symptomatic RP Attacks Changeand Percent

Change from Baseline. ITT Population - Part A.

Average severity (0-10) of weekly symptomatic RP attacks is defined as the

total severity scores of symptomatic RP attacks divided by total number of

symptomatic RP attacks within the last 7 days of the dosing period (excluding

the last dosing day). Baseline is calculated as total severity scores of symptomatic

RP attacks during the last 7 days of screening period (excluding the first dosing day)

divided by the total number of symptomatic RP attacks. Only symptomatic RP attacks, defined

as RP attacks with patient reported finger color changes associated with at least one

symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
3.49
3.74
7.68
5.99
5.56
3.82

(SD)

(1.430)
(2.398)
(0.520)
(1.823)
(0.055)

Median
3.49
3.74
7.68
5.99
5.56
3.82

Q1, Q3
3.49, 3.49
2.73, 4.75
5.98, 9.38
5.62, 6.36
4.27, 6.84
3.78, 3.86

Min, Max
3.5, 3.5
2.7, 4.8
6.0, 9.4
5.6, 6.4
4.3, 6.8
3.8, 3.9

Average Severity

n
1
2
2
2
2
2

Mean
3.77
2.30
7.08
4.06
4.51
3.43

(SD)

(0.141)
(3.406)
(1.644)
(0.774)
(0.601)

Median
3.77
2.30
7.08
4.06
4.51
3.43

Q1, Q3
3.77, 3.77
2.20, 2.40
4.67, 9.48
2.90, 5.23
3.96, 5.06
3.00, 3.85

Min, Max
3.8, 3.8
2.2, 2.4
4.7, 9.5
2.9, 5.2
4.0, 5.1
3.0, 3.9

Change from Baseline

n
1
2
2
2
2
2

Mean
0.28
−1.44
−0.60
−1.93
−1.05
−0.39

(SD)

(1.571)
(1.008)
(1.124)
(1.049)
(0.656)

Median
0.28
−1.44
−0.60
−1.93
−1.05
−0.39

Q1, Q3
0.28, 0.28
−2.55, −0.33
−1.32, 0.11
−2.72, −1.13
−1.79, −0.31
−0.86, 0.07

Min, Max
0.3, 0.3
−2.6, −0.3
−1.3, 0.1
−2.7, −1.1
−1.8, −0.3
−0.9, 0.1

Percent Change from Baseline

n
1
2
2
2
2
2

Mean
8.05
−32.85
−10.43
−33.11
−16.64
−10.20

(SD)

(29.464)
(16.377)
(21.645)
(13.424)
(17.040)

Median
8.05
−32.85
−10.43
−33.11
−16.64
−10.20

Q1, Q3
8.05, 8.05
−53.68, −12.02
−22.01, 1.16
−48.42, −17.81
−26.14, −7.15
−22.25, 1.85

Min, Max
8.0, 8.0
−53.7, −12.0
−22.0, 1.2
−48.4, −17.8
−26.1, −7.2
−22.2, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean
3.66
5.77
5.16
4.65
5.19

(SD)
(1.021)
(1.123)
(1.489)
(1.700)
(1.902)

Median
3.49
5.99
5.62
4.51
4.75

Q1, Q3
2.73, 4.75
4.94, 6.60
3.49, 6.36
3.50, 5.80
3.78, 6.36

Min, Max
2.7, 4.8
4.3, 6.8
3.5, 6.4
2.7, 6.8
2.7, 9.4

Average Severity

n
3
4
3
4
11

Mean
2.79
4.29
3.97
3.40
4.23

(SD)
(0.855)
(1.080)
(1.175)
(1.354)
(2.016)

Median
2.40
4.51
3.77
3.18
3.85

Q1, Q3
2.20, 3.77
3.43, 5.14
2.90, 5.23
2.30, 4.51
2.90, 5.06

Min, Max
2.2, 3.8
2.9, 5.2
2.9, 5.2
2.2, 5.1
2.2, 9.5

Change from Baseline

n
3
4
3
4
11

Mean
−0.87
−1.49
−1.19
−1.24
−0.96

(SD)
(1.490)
(1.023)
(1.502)
(1.114)
(1.052)

Median
−0.33
−1.46
−1.13
−1.06
−0.86

Q1, Q3
−2.55, 0.28
−2.26, −0.72
−2.72, 0.28
−2.17, −0.32
−1.79, 0.07

Min, Max
−2.6, 0.3
−2.7, −0.3
−2.7, 0.3
−2.6, −0.3
−2.7, 0.3

Percent Change from Baseline

n
3
4
3
4
11

Mean
−19.22
−24.88
−19.39
−24.75
−18.04

(SD)
(31.490)
(17.512)
(28.267)
(20.904)
(19.728)

Median
−12.02
−21.97
−17.81
−19.08
−17.81

Q1, Q3
−53.68, 8.05
−37.28, −12.48
−48.42, 8.05
−39.91, −9.58
−26.14, 1.16

Min, Max
−53.7, 8.0
−48.4, −7.2
−48.4, 8.0
−53.7, −7.2
−53.7, 8.0

TABLE C-2

Average Severity of Weekly Symptomatic RP Attacks Change and Percent Change

from Baseline (Excluding Outliers). ITT Population - Part A.

Average severity (0-10) of weekly symptomatic RP attacks is defined as the total

severity scores of symptomatic RP attacks divided by total number of symptomatic

RP attacks within the last 7 days of the dosing period (excluding the last dosing day).

Baseline is calculated as total severity scores of symptomatic RP attacks during the last 7 days

of screening period (excluding the first dosing day) divided by the total number of symptomatic RP attacks.

Only symptomatic RP attacks, defined as RP attacks with patient reported finger color changes associated

with at least one symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
3.49
3.74
5.98
5.99
5.56
3.82

(SD)

(1.430)

(0.520)
(1.823)
(0.055)

Median
3.49
3.74
5.98
5.99
5.56
3.82

Q1, Q3
3.49, 3.49
2.73, 4.75
5.98, 5.98
5.62, 6.36
4.27, 6.84
3.78, 3.86

Min, Max
3.5, 3.5
2.7, 4.8
6.0, 6.0
5.6, 6.4
4.3, 6.8
3.8, 3.9

Average Severity

n
1
2
1
2
2
2

Mean
3.77
2.30
4.67
4.06
4.51
3.43

(SD)

(0.141)

(1.644)
(0.774)
(0.601)

Median
3.77
2.30
4.67
4.06
4.51
3.43

Q1, Q3
3.77, 3.77
2.20, 2.40
4.67, 4.67
2.90, 5.23
3.96, 5.06
3.00, 3.85

Min, Max
3.8, 3.8
2.2, 2.4
4.7, 4.7
2.9, 5.2
4.0, 5.1
3.0, 3.9

Change from Baseline

n
1
2
1

2

Mean
0.28
−1.44
−1.32
−1.93
−1.05
−0.39

(SD)

(1.571)

(1.124)
(1.049)
(0.656)

Median
0.28
−1.44
−1.32
−1.93
−1.05
−0.39

Q1, Q3
0.28, 0.28
−2.55, −0.33
−1.32, −1.32
−2.72, −1.13
−1.79, −0.31
−0.86, 0.07

Min, Max
0.3, 0.3
−2.6, −0.3
−1.3, −1.3
−2.7, −1.1
−1.8, −0.3
−0.9, 0.1

Percent Change from Baseline

n
1
2
1
2
2
2

Mean
8.05
−32.85
−22.01
−33.11
−16.64
−10.20

(SD)

(29.464)

(21.645)
(13.424)
(17.040)

Median
8.05
−32.85
−22.01
−33.11
−16.64
−10.20

Q1, Q3
8.05, 8.05
−53.68, −12.02
−22.01, −22.01
−48.42, −17.81
−26.14, −7.15
−22.25, 1.85

Min, Max
8.0, 8.0
−53.7, −12.0
−22.0, −22.0
−48.4, −17.8
−26.1, −7.2
−22.2, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
3.66
5.77
5.16
4.65
4.77

(SD)
(1.021)
(1.123)
(1.489)
(1.700)
(1.370)

Median
3.49
5.99
5.62
4.51
4.51

Q1, Q3
2.73, 4.75
4.94, 6.60
3.49, 6.36
3.50, 5.80
3.78, 5.98

Min, Max
2.7, 4.8
4.3, 6.8
3.5, 6.4
2.7, 6.8
2.7, 6.8

Average Severity

n
3
4
3
4
10

Mean
2.79
4.29
3.97
3.40
3.70

(SD)
(0.855)
(1.080)
(1.175)
(1.354)
(1.068)

Median
2.40
4.51
3.77
3.18
3.81

Q1, Q3
2.20, 3.77
3.43, 5.14
2.90, 5.23
2.30, 4.51
2.90, 4.67

Min, Max
2.2, 3.8
2.9, 5.2
2.9, 5.2
2.2, 5.1
2.2, 5.2

Change from Baseline

n
3
4
3
4
10

Mean
−0.87
−1.49
−1.19
−1.24
−1.07

(SD)
(1.490)
(1.023)
(1.502)
(1.114)
(1.044)

Median
−0.33
−1.46
−1.13
−1.06
−1.00

Q1, Q3
−2.55, 0.28
−2.26, −0.72
−2.72, 0.28
−2.17, −0.32
−1.79, −0.31

Min, Max
−2.6, 0.3
−2.7, −0.3
−2.7, 0.3
−2.6, −0.3
−2.7, 0.3

Percent Change from Baseline

n
3
4
3
4
10

Mean
−19.22
−24.88
−19.39
−24.75
−19.96

(SD)
(31.490)
(17.512)
(28.267)
(20.904)
(19.683)

Median
−12.02
−21.97
−17.81
−19.08
−19.91

Q1, Q3
−53.68, 8.05
−37.28, −12.48
−48.42, 8.05
−39.91, −9.58
−26.14, −7.15

Min, Max
−53.7, 8.0
−48.4, −7.2
−48.4, 8.0
−53.7, −7.2
−53.7, 8.0

TABLE C-3

Average Severity of Weekly Symptomatic RP Attacks Change and

Percent Change from Baseline by Baseline RCS. ITT Population - Part A.

Average severity (0-10) of weekly symptomatic RP attacks is defined as the

total severity scores of symptomatic RP attacks divided by total number of symptomatic

RP attacks within the last 7 days of the dosing period (excluding the last dosing day).

Baseline is calculated as total severity scores of symptomatic RP attacks during the last 7 days

of screening period (excluding the first dosing day) divided by the total number of symptomatic RP attacks.

Only symptomatic RP attacks, defined as RP attacks with patient reported finger color changes associated

with at least one symptom (pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
3.49
3.74

5.62
4.27
3.82

(SD)

(1.430)

(0.055)

Median
3.49
3.74

5.62
4.27
3.82

Q1, Q3
3.49, 3.49
2.73, 4.75

5.62, 5.62
4.27, 4.27
3.78, 3.86

Min, Max
3.5, 3.5
2.7, 4.8

5.6, 5.6
4.3, 4.3
3.8, 3.9

Average Severity

n
1
2

1
1
2

Mean
3.77
2.30

2.90
3.96
3.43

(SD)

(0.141)

(0.601)

Median
3.77
2.30

2.90
3.96
3.43

Q1, Q3
3.77, 3.77
2.20, 2.40

2.90, 2.90
3.96, 3.96
3.00, 3.85

Min, Max
3.8, 3.8
2.2, 2.4

2.9, 2.9
4.0, 4.0
3.0, 3.9

Change from Baseline

n
1
2

1
1
2

Mean
0.28
−1.44

−2.72
−0.31
−0.39

(SD)

(1.571)

(0.656)

Median
0.28
−1.44

−2.72
−0.31
−0.39

Q1, Q3
0.28, 0.28
−2.55, −0.33

−2.72, −2.72
−0.31, −0.31
−0.86, 0.07

Min, Max
0.3, 0.3
−2.6, −0.3

−2.7, −2.7
−0.3, −0.3
−0.9, 0.1

Percent Change from Baseline

n
1
2

1
1
2

Mean
8.05
−32.85

−48.42
−7.15
−10.20

(SD)

(29.464)

(17.040)

Median
8.05
−32.85

−48.42
−7.15
−10.20

Q1, Q3
8.05, 8.05
−53.68, −12.02

−48.42, −48.42
−7.15, −7.15
−22.25, 1.85

Min, Max
8.0, 8.0
−53.7, −12.0

−48.4, −48.4
−7.2, −7.2
−22.2, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
3.66
4.94
4.56
3.91
4.07

(SD)
(1.021)
(0.959)
(1.507)
(1.056)
(0.929)

Median
3.49
4.94
4.56
4.27
3.86

Q1, Q3
2.73, 4.75
4.27, 5.62
3.49, 5.62
2.73, 4.75
3.49, 4.75

Min, Max
2.7, 4.8
4.3, 5.6
3.5, 5.6
2.7, 4.8
2.7, 5.6

Average Severity

n
3
2
2
3
7

Mean
2.79
3.43
3.34
2.85
3.15

(SD)
(0.855)
(0.751)
(0.616)
(0.964)
(0.717)

Median
2.40
3.43
3.34
2.40
3.00

Q1, Q3
2.20, 3.77
2.90, 3.96
2.90, 3.77
2.20, 3.96
2.40, 3.85

Min, Max
2.2, 3.8
2.9, 4.0
2.9, 3.8
2.2, 4.0
2.2, 4.0

Change from Baseline

n
3
2
2
3
7

Mean
−0.87
−1.51
−1.22
−1.06
−0.92

(SD)
(1.490)
(1.709)
(2.124)
(1.290)
(1.229)

Median
−0.33
−1.51
−1.22
−0.33
−0.33

Q1, Q3
−2.55, 0.28
−2.72, −0.31
−2.72, 0.28
−2.55, −0.31
−2.55, 0.07

Min, Max
−2.6, 0.3
−2.7, −0.3
−2.7, 0.3
−2.6, −0.3
−2.7, 0.3

Percent Change from Baseline

n
3
2
2
3
7

Mean
−19.22
−27.79
−20.18
−24.28
−19.09

(SD)
(31.490)
(29.181)
(39.929)
(25.577)
(23.925)

Median
−12.02
−27.79
−20.18
−12.02
−12.02

Q1, Q3
−53.68, 8.05
−48.42, −7.15
−48.42, 8.05
−53.68, −7.15
−48.42, 1.85

Min, Max
−53.7, 8.0
−48.4, −7.2
−48.4, 8.0
−53.7, −7.2
−53.7, 8.0

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n

2
1
1

Mean

7.68
6.36
6.84

(SD)

(2.398)

Median

7.68
6.36
6.84

Q1, Q3

5.98, 9.38
6.36, 6.36
6.84, 6.84

Min, Max

6.0, 9.4
6.4, 6.4
6.8, 6.8

Average Severity

n

2
1
1

Mean

7.08
5.23
5.06

(SD)

(3.406)

Median

7.08
5.23
5.06

Q1, Q3

4.67, 9.48
5.23, 5.23
5.06, 5.06

Min, Max

4.7, 9.5
5.2, 5.2
5.1, 5.1

Change from Baseline

n

2
1
1

Mean

−0.60
−1.13
−1.79

(SD)

(1.008)

Median

−0.60
−1.13
−1.79

Q1, Q3

−1.32, 0.11
−1.13, −1.13
−1.79, −1.79

Min, Max

−1.3, 0.1
−1.1, −1.1
−1.8, −1.8

Percent Change from Baseline

n

2
1
1

Mean

−10.43
−17.81
−26.14

(SD)

(16.377)

Median

−10.43
−17.81
−26.14

Q1, Q3

−22.01, 1.16
−17.81, −17.81
−26.14, −26.14

Min, Max

−22.0, 1.2
−17.8, −17.8
−26.1, −26.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean

6.60
6.36
6.84
7.14

(SD)

(0.345)

(1.531)

Median

6.60
6.36
6.84
6.60

Q1, Q3

6.36, 6.84
6.36, 6.36
6.84, 6.84
6.17, 8.11

Min, Max

6.4, 6.8
6.4, 6.4
6.8, 6.8
6.0, 9.4

Average Severity

n

2
1
1
4

Mean

5.14
5.23
5.06
6.11

(SD)

(0.120)

(2.263)

Median

5.14
5.23
5.06
5.14

Q1, Q3

5.06, 5.23
5.23, 5.23
5.06, 5.06
4.86, 7.35

Min, Max

5.1, 5.2
5.2, 5.2
5.1, 5.1
4.7, 9.5

Change from Baseline

n

2
1
1
4

Mean

−1.46
−1.13
−1.79
−1.03

(SD)

(0.464)

(0.809)

Median

−1.46
−1.13
−1.79
−1.22

Q1, Q3

−1.79, −1.13
−1.13, −1.13
−1.79, −1.79
−1.55, −0.51

Min, Max

−1.8, −1.1
−1.1, −1.1
−1.8, −1.8
−1.8, 0.1

Percent Change from Baseline

n

2
1
1
4

Mean

−21.97
−17.81
−26.14
−16.20

(SD)

(5.888)

(12.059)

Median

−21.97
−17.81
−26.14
−19.91

Q1, Q3

−26.14, −17.81
−17.81, −17.81
−26.14, −26.14
−24.07, −8.33

Min, Max

−26.1, −17.8
−17.8, −17.8
−26.1, −26.1
−26.1, 1.2

TABLE C-4

Average Severity of Weekly Symptomatic RP Attacks Change and Percent

Change from Baseline (Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Average severity (0-10) of weekly symptomatic RP attacks is defined as the total severity

scores of symptomatic RP attacks divided by total number of symptomatic RP attacks within the

last 7 days of the dosing period (excluding the last dosing day). Baseline is calculated as total

severity scores of symptomatic RP attacks during the last 7 days of screening period (excluding the

first dosing day) divided by the total number of symptomatic RP attacks. Only symptomatic RP attacks,

defined as RP attacks with patient reported finger color changes associated with at least one symptom

(pain, numbness, tingling), were included in the derivations.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
3.49
3.74

5.62
4.27
3.82

(SD)

(1.430)

(0.055)

Median
3.49
3.74

5.62
4.27
3.82

Q1, Q3
3.49, 3.49
2.73, 4.75

5.62, 5.62
4.27, 4.27
3.78, 3.86

Min, Max
3.5, 3.5
2.7, 4.8

5.6, 5.6
4.3, 4.3
3.8, 3.9

Average Severity

n
1
2

1
1
2

Mean
3.77
2.30

2.90
3.96
3.43

(SD)

(0.141)

(0.601)

Median
3.77
2.30

2.90
3.96
3.43

Q1, Q3
3.77, 3.77
2.20, 2.40

2.90, 2.90
3.96, 3.96
3.00, 3.85

Min, Max
3.8, 3.8
2.2, 2.4

2.9, 2.9
4.0, 4.0
3.0, 3.9

Change from Baseline

n
1
2

1
1
2

Mean
0.28
−1.44

−2.72
−0.31
−0.39

(SD)

(1.571)

(0.656)

Median
0.28
−1.44

−2.72
−0.31
−0.39

Q1, Q3
0.28, 0.28
−2.55, −0.33

−2.72, −2.72
−0.31, −0.31
−0.86, 0.07

Min, Max
0.3, 0.3
−2.6, −0.3

−2.7, −2.7
−0.3, −0.3
−0.9, 0.1

Percent Change from Baseline

n
1
2

1
1
2

Mean
8.05
−32.85

−48.42
−7.15
−10.20

(SD)

(29.464)

(17.040)

Median
8.05
−32.85

−48.42
−7.15
−10.20

Q1, Q3
8.05, 8.05
−53.68, −12.02

−48.42, −48.42
−7.15, −7.15
−22.25, 1.85

Min, Max
8.0, 8.0
−53.7, −12.0

−48.4, −48.4
−7.2, −7.2
−22.2, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
3.66
4.94
4.56
3.91
4.07

(SD)
(1.021)
(0.959)
(1.507)
(1.056)
(0.929)

Median
3.49
4.94
4.56
4.27
3.86

Q1, Q3
2.73, 4.75
4.27, 5.62
3.49, 5.62
2.73, 4.75
3.49, 4.75

Min, Max
2.7, 4.8
4.3, 5.6
3.5, 5.6
2.7, 4.8
2.7, 5.6

Average Severity

n
3
2
2
3
7

Mean
2.79
3.43
3.34
2.85
3.15

(SD)
(0.855)
(0.751)
(0.616)
(0.964)
(0.717)

Median
2.40
3.43
3.34
2.40
3.00

Q1, Q3
2.20, 3.77
2.90, 3.96
2.90, 3.77
2.20, 3.96
2.40, 3.85

Min, Max
2.2, 3.8
2.9, 4.0
2.9, 3.8
2.2, 4.0
2.2, 4.0

Change from Baseline

n
3
2
2
3
7

Mean
−0.87
−1.51
−1.22
−1.06
−0.92

(SD)
(1.490)
(1.709)
(2.124)
(1.290)
(1.229)

Median
−0.33
−1.51
−1.22
−0.33
−0.33

Q1, Q3
−2.55, 0.28
−2.72, −0.31
−2.72, 0.28
−2.55, −0.31
−2.55, 0.07

Min, Max
−2.6, 0.3
−2.7, −0.3
−2.7, 0.3
−2.6, −0.3
−2.7, 0.3

Percent Change from Baseline

n
3
2
2
3
7

Mean
−19.22
−27.79
−20.18
−24.28
−19.09

(SD)
(31.490)
(29.181)
(39.929)
(25.577)
(23.925)

Median
−12.02
−27.79
−20.18
−12.02
−12.02

Q1, Q3
−53.68, 8.05
−48.42, −7.15
−48.42, 8.05
−53.68, −7.15
−48.42, 1.85

Min, Max
−53.7, 8.0
−48.4, −7.2
−48.4, 8.0
−53.7, −7.2
−53.7, 8.0

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n

1
1
1

Mean

5.98
6.36
6.84

(SD)

Median

5.98
6.36
6.84

Q1, Q3

5.98, 5.98
6.36, 6.36
6.84, 6.84

Min, Max

6.0, 6.0
6.4, 6.4
6.8, 6.8

Average Severity

n

1
1
1

Mean

4.67
5.23
5.06

(SD)

Median

4.67
5.23
5.06

Q1, Q3

4.67, 4.67
5.23, 5.23
5.06, 5.06

Min, Max

4.7, 4.7
5.2, 5.2
5.1, 5.1

Change from Baseline

n

1
1
1

Mean

−1.32
−1.13
−1.79

(SD)

Median

−1.32
−1.13
−1.79

Q1, Q3

−1.32, −1.32
−1.13, −1.13
−1.79, −1.79

Min, Max

−1.3, −1.3
−1.1, −1.1
−1.8, −1.8

Percent Change from Baseline

n

1
1
1

Mean

−22.01
−17.81
−26.14

(SD)

Median

−22.01
−17.81
−26.14

Q1, Q3

−22.01, −22.01
−17.81, −17.81
−26.14, −26.14

Min, Max

−22.0, −22.0
−17.8, −17.8
−26.1, −26.1

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean

6.60
6.36
6.84
6.39

(SD)

(0.345)

(0.432)

Median

6.60
6.36
6.84
6.36

Q1, Q3

6.36, 6.84
6.36, 6.36
6.84, 6.84
5.98, 6.84

Min, Max

6.4, 6.8
6.4, 6.4
6.8, 6.8
6.0, 6.8

Average Severity

n

2
1
1
3

Mean

5.14
5.23
5.06
4.98

(SD)

(0.120)

(0.286)

Median

5.14
5.23
5.06
5.06

Q1, Q3

5.06, 5.23
5.23, 5.23
5.06, 5.06
4.67, 5.23

Min, Max

5.1, 5.2
5.2, 5.2
5.1, 5.1
4.7, 5.2

Change from Baseline

n

2
1
1
3

Mean

−1.46
−1.13
−1.79
−1.41

(SD)

(0.464)

(0.339)

Median

−1.46
−1.13
−1.79
−1.32

Q1, Q3

−1.79, −1.13
−1.13, −1.13
−1.79, −1.79
−1.79, −1.13

Min, Max

−1.8, −1.1
−1.1, −1.1
−1.8, −1.8
−1.8, −1.1

Percent Change from Baseline

n

2
1
1
3

Mean

−21.97
−17.81
−26.14
−21.98

(SD)

(5.888)

(4.164)

Median

−21.97
−17.81
−26.14
−22.01

Q1, Q3

−26.14, −17.81
−17.81, −17.81
−26.14, −26.14
−26.14, −17.81

Min, Max

−26.1, −17.8
−17.8, −17.8
−26.1, −26.1
−26.1, −17.8

TABLE C-5

Average Severity of Weekly RP Attacks (All Attacks)

Change and Percent Change from Baseline. ITT Population - Part A.

Average severity (0-10) of weekly RP attacks is defined as the total

severity scores of RP attacks divided by total number of RP attacks

within the last 7 days of the dosing period (excluding the last dosing day).

Baseline is calculated as total severity scores of RP attacks during the last

7 days of screening period (excluding the first dosing day) divided by the

total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
3.03
3.37
7.49
5.92
5.36
3.82

(SD)

(1.087)
(2.457)
(0.421)
(1.746)
(0.055)

Median
3.03
3.37
7.49
5.92
5.36
3.82

Q1, Q3
3.03, 3.03
2.60, 4.14
5.75, 9.23
5.62, 6.22
4.12, 6.59
3.78, 3.86

Min, Max
3.0, 3.0
2.6, 4.1
5.8, 9.2
5.6, 6.2
4.1, 6.6
3.8, 3.9

Average

Severity

n
1
2
2
2
2
2

Mean
3.05
2.30
7.02
3.90
4.39
3.37

(SD)

(0.141)
(3.479)
(1.414)
(0.943)
(0.676)

Median
3.05
2.30
7.02
3.90
4.39
3.37

Q1, Q3
3.05, 3.05
2.20, 2.40
4.56, 9.48
2.90, 4.90
3.73, 5.06
2.89, 3.85

Min, Max
3.0, 3.0
2.2, 2.4
4.6, 9.5
2.9, 4.9
3.7, 5.1
2.9, 3.9

Change from

Baseline

n
1
2
2
2
2
2

Mean
0.02
−1.07
−0.47
−2.02
−0.96
−0.45

(SD)

(1.229)
(1.022)
(0.993)
(0.804)
(0.732)

Median
0.02
−1.07
−0.47
−2.02
−0.96
−0.45

Q1, Q3
0.02, 0.02
−1.94, −0.20
−1.19, 0.25
−2.72, −1.32
−1.53, −0.39
−0.97, 0.07

Min, Max
0.0, 0.0
−1.9, −0.2
−1.2, 0.3
−2.7, −1.3
−1.5, −0.4
−1.0, 0.1

Percent Change

from Baseline

n
1
2
2
2
2
2

Mean
0.55
−27.26
−8.97
−34.81
−16.40
−11.58

(SD)

(27.673)
(16.585)
(19.248)
(9.657)
(18.995)

Median
0.55
−27.26
−8.97
−34.81
−16.40
−11.58

Q1, Q3
0.55, 0.55
−46.83, −7.69
−20.69, 2.76
−48.42, −21.20
−23.23, −9.57
−25.01, 1.85

Min, Max
0.5, 0.5
−46.8, −7.7
−20.7, 2.8
−48.4, −21.2
−23.2, −9.6
−25.0, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean
3.26
5.64
4.96
4.36
4.99

(SD)
(0.793)
(1.087)
(1.694)
(1.651)
(1.918)

Median
3.03
5.92
5.62
4.13
4.14

Q1, Q3
2.60, 4.14
4.87, 6.40
3.03, 6.22
3.36, 5.36
3.78, 6.22

Min, Max
2.6, 4.1
4.1, 6.6
3.0, 6.2
2.6, 6.6
2.6, 9.2

Average

Severity

n
3
4
3
4
11

Mean
2.55
4.15
3.62
3.35
4.09

(SD)
(0.443)
(1.022)
(1.114)
(1.328)
(2.036)

Median
2.40
4.31
3.05
3.06
3.73

Q1, Q3
2.20, 3.05
3.31, 4.98
2.90, 4.90
2.30, 4.39
2.89, 4.90

Min, Max
2.2, 3.0
2.9, 5.1
2.9, 4.9
2.2, 5.1
2.2, 9.5

Change from

Baseline

n
3
4
3
4
11

Mean
−0.71
−1.49
−1.34
−1.02
−0.90

(SD)
(1.071)
(0.957)
(1.370)
(0.850)
(0.944)

Median
−0.20
−1.42
−1.32
−0.96
−0.97

Q1, Q3
−1.94, 0.02
−2.13, −0.86
−2.72, 0.02
−1.73, −0.30
−1.53, 0.02

Min, Max
−1.9, 0.0
−2.7, −0.4
−2.7, 0.0
−1.9, −0.2
−2.7, 0.3

Percent Change

from Baseline

n
3
4
3
4
11

Mean
−17.99
−25.60
−23.02
−21.83
−17.95

(SD)
(25.311)
(16.357)
(24.534)
(18.046)
(17.879)

Median
−7.69
−22.21
−21.20
−16.40
−20.69

Q1, Q3
−46.83, 0.55
−35.82, −15.38
−48.42, 0.55
−35.03, −8.63
−25.01, 0.55

Min, Max
−46.8, 0.5
−48.4, −9.6
−48.4, 0.5
−46.8, −7.7
−48.4, 2.8

TABLE C-6

Average Severity of Weekly RP Attacks (All Attacks) Change and Percent

Change from Baseline (Excluding Outliers). ITT Population - Part A.

Average severity (0-10) of weekly RP attacks is defined as the total severity scores of RP attacks divided

by total number of RP attacks within the last 7 days of the dosing period (excluding the last dosing day).

Baseline is calculated as total severity scores of RP attacks during the last 7 days of screening

period (excluding the first dosing day) divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
3.03
3.37
5.75
5.92
5.36
3.82

(SD)

(1.087)

(0.421)
(1.746)
(0.055)

Median
3.03
3.37
5.75
5.92
5.36
3.82

Q1, Q3
3.03, 3.03
2.60, 4.14
5.75, 5.75
5.62, 6.22
4.12, 6.59
3.78, 3.86

Min, Max
3.0, 3.0
2.6, 4.1
5.8, 5.8
5.6, 6.2
4.1, 6.6
3.8, 3.9

Average

Severity

n
1
2
1
2
2
2

Mean
3.05
2.30
4.56
3.90
4.39
3.37

(SD)

(0.141)

(1.414)
(0.943)
(0.676)

Median
3.05
2.30
4.56
3.90
4.39
3.37

Q1, Q3
3.05, 3.05
2.20, 2.40
4.56, 4.56
2.90, 4.90
3.73, 5.06
2.89, 3.85

Min, Max
3.0, 3.0
2.2, 2.4
4.6, 4.6
2.9, 4.9
3.7, 5.1
2.9, 3.9

Change from

Baseline

n
1
2
1
2
2
2

Mean
0.02
−1.07
−1.19
−2.02
−0.96
−0.45

(SD)

(1.229)

(0.993)
(0.804)
(0.732)

Median
0.02
−1.07
−1.19
−2.02
−0.96
−0.45

Q1, Q3
0.02, 0.02
−1.94, −0.20
−1.19, −1.19
−2.72, −1.32
−1.53, −0.39
−0.97, 0.07

Min, Max
0.0, 0.0
−1.9, −0.2
−1.2, −1.2
−2.7, −1.3
−1.5, −0.4
−1.0, 0.1

Percent Change

from Baseline

n
1
2
1
2
2
2

Mean
0.55
−27.26
−20.69
−34.81
−16.40
−11.58

(SD)

(27.673)

(19.248)
(9.657)
(18.995)

Median
0.55
−27.26
−20.69
−34.81
−16.40
−11.58

Q1, Q3
0.55, 0.55
−46.83, −7.69
−20.69, −20.69
−48.42, −21.20
−23.23, −9.57
−25.01, 1.85

Min, Max
0.5, 0.5
−46.8, −7.7
−20.7, −20.7
−48.4, −21.2
−23.2, −9.6
−25.0, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
3.26
5.64
4.96
4.36
4.57

(SD)
(0.793)
(1.087)
(1.694)
(1.651)
(1.377)

Median
3.03
5.92
5.62
4.13
4.13

Q1, Q3
2.60, 4.14
4.87, 6.40
3.03, 6.22
3.36, 5.36
3.78, 5.75

Min, Max
2.6, 4.1
4.1, 6.6
3.0, 6.2
2.6, 6.6
2.6, 6.6

Average

Severity

n
3
4
3
4
10

Mean
2.55
4.15
3.62
3.35
3.55

(SD)
(0.443)
(1.022)
(1.114)
(1.328)
(1.027)

Median
2.40
4.31
3.05
3.06
3.39

Q1, Q3
2.20, 3.05
3.31, 4.98
2.90, 4.90
2.30, 4.39
2.89, 4.56

Min, Max
2.2, 3.0
2.9, 5.1
2.9, 4.9
2.2, 5.1
2.2, 5.1

Change from

Baseline

n
3
4
3
4
10

Mean
−0.71
−1.49
−1.34
−1.02
−1.02

(SD)
(1.071)
(0.957)
(1.370)
(0.850)
(0.910)

Median
−0.20
−1.42
−1.32
−0.96
−1.08

Q1, Q3
−1.94, 0.02
−2.13, −0.86
−2.72, 0.02
−1.73, −0.30
−1.53, −0.20

Min, Max
−1.9, 0.0
−2.7, −0.4
−2.7, 0.0
−1.9, −0.2
−2.7, 0.1

Percent Change

from Baseline

n
3
4
3
4
10

Mean
−17.99
−25.60
−23.02
−21.83
−20.02

(SD)
(25.311)
(16.357)
(24.534)
(18.046)
(17.400)

Median
−7.69
−22.21
−21.20
−16.40
−20.95

Q1, Q3
−46.83, 0.55
−35.82, −15.38
−48.42, 0.55
−35.03, −8.63
−25.01, −7.69

Min, Max
−46.8, 0.5
−48.4, −9.6
−48.4, 0.5
−46.8, −7.7
−48.4, 1.9

TABLE C-7

Average Severity of Weekly RP Attacks (All Attacks) Change and

Percent Change from Baseline by Baseline RCS. ITT Population - Part A.

Average severity (0-10) of weekly RP attacks is defined as the total severity scores

of RP attacks divided by total number of RP attacks within the last 7 days of the dosing

period (excluding the last dosing day). Baseline is calculated as total severity scores of

RP attacks during the last 7 days of screening period (excluding the first dosing day)

divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
3.03
3.37

5.62
4.12
3.82

(SD)

(1.087)

(0.055)

Median
3.03
3.37

5.62
4.12
3.82

Q1, Q3
3.03, 3.03
2.60, 4.14

5.62, 5.62
4.12, 4.12
3.78, 3.86

Min, Max
3.0, 3.0
2.6, 4.1

5.6, 5.6
4.1, 4.1
3.8, 3.9

Average

Severity

n
1
2

1
1
2

Mean
3.05
2.30

2.90
3.73
3.37

(SD)

(0.141)

(0.676)

Median
3.05
2.30

2.90
3.73
3.37

Q1, Q3
3.05, 3.05
2.20, 2.40

2.90, 2.90
3.73, 3.73
2.89, 3.85

Min, Max
3.0, 3.0
2.2, 2.4

2.9, 2.9
3.7, 3.7
2.9, 3.9

Change from

Baseline

n
1
2

1
1
2

Mean
0.02
−1.07

−2.72
−0.39
−0.45

(SD)

(1.229)

(0.732)

Median
0.02
−1.07

−2.72
−0.39
−0.45

Q1, Q3
0.02, 0.02
−1.94, −0.20

−2.72, −2.72
−0.39, −0.39
−0.97, 0.07

Min, Max
0.0, 0.0
−1.9, −0.2

−2.7, −2.7
−0.4, −0.4
−1.0, 0.1

Percent Change

from Baseline

n
1
2

1
1
2

Mean
0.55
−27.26

−48.42
−9.57
−11.58

(SD)

(27.673)

(18.995)

Median
0.55
−27.26

−48.42
−9.57
−11.58

Q1, Q3
0.55, 0.55
−46.83, −7.69

−48.42, −48.42
−9.57, −9.57
−25.01, 1.85

Min, Max
0.5, 0.5
−46.8, −7.7

−48.4, −48.4
−9.6, −9.6
−25.0, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
3.26
4.87
4.33
3.62
3.88

(SD)
(0.793)
(1.061)
(1.832)
(0.883)
(0.960)

Median
3.03
4.87
4.33
4.12
3.86

Q1, Q3
2.60, 4.14
4.12, 5.62
3.03, 5.62
2.60, 4.14
3.03, 4.14

Min, Max
2.6, 4.1
4.1, 5.6
3.0, 5.6
2.6, 4.1
2.6, 5.6

Average

Severity

n
3
2
2
3
7

Mean
2.55
3.31
2.97
2.78
3.00

(SD)
(0.443)
(0.585)
(0.105)
(0.830)
(0.616)

Median
2.40
3.31
2.97
2.40
2.90

Q1, Q3
2.20, 3.05
2.90, 3.73
2.90, 3.05
2.20, 3.73
2.40, 3.73

Min, Max
2.2, 3.0
2.9, 3.7
2.9, 3.0
2.2, 3.7
2.2, 3.9

Change from

Baseline

n
3
2
2
3
7

Mean
−0.71
−1.56
−1.35
−0.84
−0.88

(SD)
(1.071)
(1.646)
(1.937)
(0.952)
(1.074)

Median
−0.20
−1.56
−1.35
−0.39
−0.39

Q1, Q3
−1.94, 0.02
−2.72, −0.39
−2.72, 0.02
−1.94, −0.20
−1.94, 0.02

Min, Max
−1.9, 0.0
−2.7, −0.4
−2.7, 0.0
−1.9, −0.2
−2.7, 0.1

Percent Change

from Baseline

n
3
2
2
3
7

Mean
−17.99
−28.99
−23.94
−21.36
−19.30

(SD)
(25.311)
(27.470)
(34.624)
(22.073)
(21.249)

Median
−7.69
−28.99
−23.94
−9.57
−9.57

Q1, Q3
−46.83, 0.55
−48.42, −9.57
−48.42, 0.55
−46.83, −7.69
−46.83, 0.55

Min, Max
−46.8, 0.5
−48.4, −9.6
−48.4, 0.5
−46.8, −7.7
−48.4, 1.9

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

2
1
1

Mean

7.49
6.22
6.59

(SD)

(2.457)

Median

7.49
6.22
6.59

Q1, Q3

5.75, 9.23
6.22, 6.22
6.59, 6.59

Min, Max

5.8, 9.2
6.2, 6.2
6.6, 6.6

Average

Severity

n

2
1
1

Mean

7.02
4.90
5.06

(SD)

(3.479)

Median

7.02
4.90
5.06

Q1, Q3

4.56, 9.48
4.90, 4.90
5.06, 5.06

Min, Max

4.6, 9.5
4.9, 4.9
5.1, 5.1

Change from

Baseline

n

2
1
1

Mean

−0.47
−1.32
−1.53

(SD)

(1.022)

Median

−0.47
−1.32
−1.53

Q1, Q3

−1.19, 0.25
−1.32, −1.32
−1.53, −1.53

Min, Max

−1.2, 0.3
−1.3, −1.3
−1.5, −1.5

Percent Change

from Baseline

n

2
1
1

Mean

−8.97
−21.20
−23.23

(SD)

(16.585)

Median

−8.97
−21.20
−23.23

Q1, Q3

−20.69, 2.76
−21.20, −21.20
−23.23, −23.23

Min, Max

−20.7, 2.8
−21.2, −21.2
−23.2, −23.2

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg
20 mg

and
and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
4

Mean

6.40
6.22
6.59
6.95

(SD)

(0.264)

(1.559)

Median

6.40
6.22
6.59
6.40

Q1, Q3

6.22, 6.59
6.22, 6.22
6.59, 6.59
5.99, 7.91

Min, Max

6.2, 6.6
6.2, 6.2
6.6, 6.6
5.8, 9.2

Average

Severity

n

2
1
1
4

Mean

4.98
4.90
5.06
6.00

(SD)

(0.113)

(2.330)

Median

4.98
4.90
5.06
4.98

Q1, Q3

4.90, 5.06
4.90, 4.90
5.06, 5.06
4.73, 7.27

Min, Max

4.9, 5.1
4.9, 4.9
5.1, 5.1
4.6, 9.5

Change from

Baseline

n

2
1
1
4

Mean

−1.42
−1.32
−1.53
−0.95

(SD)

(0.150)

(0.813)

Median

−1.42
−1.32
−1.53
−1.25

Q1, Q3

−1.53, −1.32
−1.32, −1.32
−1.53, −1.53
−1.42, −0.47

Min, Max

−1.5, −1.3
−1.3, −1.3
−1.5, −1.5
−1.5, 0.3

Percent Change

from Baseline

n

2
1
1
4

Mean

−22.21
−21.20
−23.23
−15.59

(SD)

(1.435)

(12.283)

Median

−22.21
−21.20
−23.23
−20.95

Q1, Q3

−23.23, −21.20
−21.20, −21.20
−23.23, −23.23
−22.21, −8.97

Min, Max

−23.2, −21.2
−21.2, −21.2
−23.2, −23.2
−23.2, 2.8

TABLE C-8

Average Severity of Weekly RP Attacks (All Attacks) Change and Percent Change

from Baseline (Excluding Outliers) by Baseline RCS. ITT Population - Part A.

Average severity (0-10) of weekly RP attacks is defined as the total severity scores of RP attacks

divided by total number of RP attacks within the last 7 days of the dosing period (excluding the last

dosing day). Baseline is calculated as total severity scores of RP attacks during the last 7 days

of screening period (excluding the first dosing day) divided by the total number of RP attacks.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2

1
1
2

Mean
3.03
3.37

5.62
4.12
3.82

(SD)

(1.087)

(0.055)

Median
3.03
3.37

5.62
4.12
3.82

Q1, Q3
3.03, 3.03
2.60, 4.14

5.62, 5.62
4.12, 4.12
3.78, 3.86

Min, Max
3.0, 3.0
2.6, 4.1

5.6, 5.6
4.1, 4.1
3.8, 3.9

Average

Severity

n
1
2

1
1
2

Mean
3.05
2.30

2.90
3.73
3.37

(SD)

(0.141)

(0.676)

Median
3.05
2.30

2.90
3.73
3.37

Q1, Q3
3.05, 3.05
2.20, 2.40

2.90, 2.90
3.73, 3.73
2.89, 3.85

Min, Max
3.0, 3.0
2.2, 2.4

2.9, 2.9
3.7, 3.7
2.9, 3.9

Change from

Baseline

n
1
2

1
1
2

Mean
0.02
−1.07

−2.72
−0.39
−0.45

(SD)

(1.229)

(0.732)

Median
0.02
−1.07

−2.72
−0.39
−0.45

Q1, Q3
0.02, 0.02
−1.94, −0.20

−2.72, −2.72
−0.39, −0.39
−0.97, 0.07

Min, Max
0.0, 0.0
−1.9, −0.2

−2.7, −2.7
−0.4, −0.4
−1.0, 0.1

Percent Change

from Baseline

n
1
2

1
1
2

Mean
0.55
−27.26

−48.42
−9.57
−11.58

(SD)

(27.673)

(18.995)

Median
0.55
−27.26

−48.42
−9.57
−11.58

Q1, Q3
0.55, 0.55
−46.83, −7.69

−48.42, −48.42
−9.57, −9.57
−25.01, 1.85

Min, Max
0.5, 0.5
−46.8, −7.7

−48.4, −48.4
−9.6, −9.6
−25.0, 1.9

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg
20 mg

and
and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
2
2
3
7

Mean
3.26
4.87
4.33
3.62
3.88

(SD)
(0.793)
(1.061)
(1.832)
(0.883)
(0.960)

Median
3.03
4.87
4.33
4.12
3.86

Q1, Q3
2.60, 4.14
4.12, 5.62
3.03, 5.62
2.60, 4.14
3.03, 4.14

Min, Max
2.6, 4.1
4.1, 5.6
3.0, 5.6
2.6, 4.1
2.6, 5.6

Average

Severity

n
3
2
2
3
7

Mean
2.55
3.31
2.97
2.78
3.00

(SD)
(0.443)
(0.585)
(0.105)
(0.830)
(0.616)

Median
2.40
3.31
2.97
2.40
2.90

Q1, Q3
2.20, 3.05
2.90, 3.73
2.90, 3.05
2.20, 3.73
2.40, 3.73

Min, Max
2.2, 3.0
2.9, 3.7
2.9, 3.0
2.2, 3.7
2.2, 3.9

Change from

Baseline

n
3
2
2
3
7

Mean
−0.71
−1.56
−1.35
−0.84
−0.88

(SD)
(1.071)
(1.646)
(1.937)
(0.952)
(1.074)

Median
−0.20
−1.56
−1.35
−0.39
−0.39

Q1, Q3
−1.94, 0.02
−2.72, −0.39
−2.72, 0.02
−1.94, −0.20
−1.94, 0.02

Min, Max
−1.9, 0.0
−2.7, −0.4
−2.7, 0.0
−1.9, −0.2
−2.7, 0.1

Percent Change

from Baseline

n
3
2
2
3
7

Mean
−17.99
−28.99
−23.94
−21.36
−19.30

(SD)
(25.311)
(27.470)
(34.624)
(22.073)
(21.249)

Median
−7.69
−28.99
−23.94
−9.57
−9.57

Q1, Q3
−46.83, 0.55
−48.42, −9.57
−48.42, 0.55
−46.83, −7.69
−46.83, 0.55

Min, Max
−46.8, 0.5
−48.4, −9.6
−48.4, 0.5
−46.8, −7.7
−48.4, 1.9

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n

1
1
1

Mean

5.75
6.22
6.59

(SD)

Median

5.75
6.22
6.59

Q1, Q3

5.75, 5.75
6.22, 6.22
6.59, 6.59

Min, Max

5.8, 5.8
6.2, 6.2
6.6, 6.6

Average

Severity

n

1
1
1

Mean

4.56
4.90
5.06

(SD)

Median

4.56
4.90
5.06

Q1, Q3

4.56, 4.56
4.90, 4.90
5.06, 5.06

Min, Max

4.6, 4.6
4.9, 4.9
5.1, 5.1

Change from

Baseline

n

1
1
1

Mean

−1.19
−1.32
−1.53

(SD)

Median

−1.19
−1.32
−1.53

Q1, Q3

−1.19, −1.19
−1.32, −1.32
−1.53, −1.53

Min, Max

−1.2, −1.2
−1.3, −1.3
−1.5, −1.5

Percent Change

from Baseline

n

1
1
1

Mean

−20.69
−21.20
−23.23

(SD)

Median

−20.69
−21.20
−23.23

Q1, Q3

−20.69, −20.69
−21.20, −21.20
−23.23, −23.23

Min, Max

−20.7, −20.7
−21.2, −21.2
−23.2, −23.2

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n

2
1
1
3

Mean

6.40
6.22
6.59
6.19

(SD)

(0.264)

(0.419)

Median

6.40
6.22
6.59
6.22

Q1, Q3

6.22, 6.59
6.22, 6.22
6.59, 6.59
5.75, 6.59

Min, Max

6.2, 6.6
6.2, 6.2
6.6, 6.6
5.8, 6.6

Average

Severity

n

2
1
1
3

Mean

4.98
4.90
5.06
4.84

(SD)

(0.113)

(0.254)

Median

4.98
4.90
5.06
4.90

Q1, Q3

4.90, 5.06
4.90, 4.90
5.06, 5.06
4.56, 5.06

Min, Max

4.9, 5.1
4.9, 4.9
5.1, 5.1
4.6, 5.1

Change from

Baseline

n

2
1
1
3

Mean

−1.42
−1.32
−1.53
−1.35

(SD)

(0.150)

(0.172)

Median

−1.42
−1.32
−1.53
−1.32

Q1, Q3

−1.53, −1.32
−1.32, −1.32
−1.53, −1.53
−1.53, −1.19

Min, Max

−1.5, −1.3
−1.3, −1.3
−1.5, −1.5
−1.5, −1.2

Percent Change

from Baseline

n

2
1
1
3

Mean

−22.21
−21.20
−23.23
−21.71

(SD)

(1.435)

(1.341)

Median

−22.21
−21.20
−23.23
−21.20

Q1, Q3

−23.23, −21.20
−21.20, −21.20
−23.23, −23.23
−23.23, −20.69

Min, Max

−23.2, −21.2
−21.2, −21.2
−23.2, −23.2
−23.2, −20.7

Tables D-1 and D-2 include Raynaud's Condition Score (RCS) data.

TABLE D-1

Average Daily RCS Change and Percent Change from Baseline. ITT Population - Part A.

Average daily RCS is defined as the total RCS divided by the number of days with available

diary data during the dosing period. Baseline is calculated as the total RCS divided by the

number of days with available diary data during the screening period. If there were

multiple daily RCS scores, the latest daily RCS was used.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
(N = 2)
(N = 2)
(N = 2)

Baseline

n
1
2
2
2
2
2

Mean
2.74
3.35
7.72
4.73
6.01
3.18

(SD)

(0.778)
(2.378)
(2.660)
(3.445)
(0.089)

Median
2.74
3.35
7.72
4.73
6.01
3.18

Q1, Q3
2.74, 2.74
2.80, 3.90
6.04, 9.40
2.85, 6.61
3.58, 8.45
3.12, 3.24

Min, Max
2.7, 2.7
2.8, 3.9
6.0, 9.4
2.9, 6.6
3.6, 8.5
3.1, 3.2

Average

Daily RCS

n
1
2
2
2
2
2

Mean
1.76
2.90
7.05
2.77
4.30
2.71

(SD)

(1.730)
(3.672)
(2.025)
(1.112)
(0.507)

Median
1.76
2.90
7.05
2.77
4.30
2.71

Q1, Q3
1.76, 1.76
1.68, 4.13
4.46, 9.65
1.34, 4.20
3.52, 5.09
2.35, 3.07

Min, Max
1.8, 1.8
1.7, 4.1
4.5, 9.7
1.3, 4.2
3.5, 5.1
2.4, 3.1

Change from

Baseline

n
1
2
2
2
2
2

Mean
−0.98
−0.45
−0.67
−1.96
−1.71
−0.47

(SD)

(0.953)
(1.294)
(0.635)
(2.333)
(0.418)

Median
−0.98
−0.45
−0.67
−1.96
−1.71
−0.47

Q1, Q3
−0.98, −0.98
−1.12, 0.22
−1.58, 0.25
−2.41, −1.51
−3.36, −0.06
−0.77, −0.18

Min, Max
−1.0, −1.0
−1.1, 0.2
−1.6, 0.3
−2.4, −1.5
−3.4, −0.1
−0.8, −0.2

Percent Change

from Baseline

n
1
2
2
2
2
2

Mean
−35.74
−17.16
−11.76
−44.79
−20.71
−15.03

(SD)

(32.420)
(20.390)
(11.766)
(26.931)
(13.569)

Median
−35.74
−17.16
−11.76
−44.79
−20.71
−15.03

Q1, Q3
−35.74, −35.74
−40.08, 5.77
−26.18, 2.66
−53.11, −36.47
−39.75, −1.67
−24.62, −5.43

Min, Max
−35.7, −35.7
−40.1, 5.8
−26.2, 2.7
−53.1, −36.5
−39.8, −1.7
−24.6, −5.4

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 3)
(N = 4)
(N = 3)
(N = 4)
(N = 11)

Baseline

n
3
4
3
4
11

Mean
3.15
5.37
4.07
4.68
4.79

(SD)
(0.652)
(2.620)
(2.203)
(2.554)
(2.427)

Median
2.80
5.09
2.85
3.74
3.58

Q1, Q3
2.74, 3.90
3.21, 7.53
2.74, 6.61
3.19, 6.18
2.85, 6.61

Min, Max
2.7, 3.9
2.9, 8.5
2.7, 6.6
2.8, 8.5
2.7, 9.4

Average

Daily RCS

n
3
4
3
4
11

Mean
2.52
3.54
2.43
3.60
3.75

(SD)
(1.389)
(1.602)
(1.545)
(1.438)
(2.324)

Median
1.76
3.86
1.76
3.82
3.52

Q1, Q3
1.68, 4.13
2.43, 4.65
1.34, 4.20
2.60, 4.61
1.76, 4.46

Min, Max
1.7, 4.1
1.3, 5.1
1.3, 4.2
1.7, 5.1
1.3, 9.7

Change from

Baseline

n
3
4
3
4
11

Mean
−0.63
−1.84
−1.64
−1.08
−1.05

(SD)
(0.740)
(1.404)
(0.723)
(1.627)
(1.133)

Median
−0.98
−1.96
−1.51
−0.59
−0.98

Q1, Q3
−1.12, 0.22
−2.89, −0.79
−2.41, −0.98
−2.24, 0.08
−1.58, −0.06

Min, Max
−1.1, 0.2
−3.4, −0.1
−2.4, −1.0
−3.4, 0.2
−3.4, 0.3

Percent Change

from Baseline

n
3
4
3
4
11

Mean
−23.35
−32.75
−41.77
−18.93
−23.15

(SD)
(25.311)
(21.937)
(9.825)
(24.420)
(20.211)

Median
−35.74
−38.11
−36.47
−20.71
−26.18

Q1, Q3
−40.08, 5.77
−46.43, −19.07
−53.11, −35.74
−39.92, 2.05
−39.75, −1.67

Min, Max
−40.1, 5.8
−53.1, −1.7
−53.1, −35.7
−40.1, 5.8
−53.1, 5.8

TABLE D-2

Average Daily RCS Change and Percent Change from

Baseline (Excluding Outliers). ITT Population - Part A.

Average daily RCS is defined as the total RCS divided by the

number of days with available diary data during the dosing period.

Baseline is calculated as the total RCS divided by the number of days

with available diary data during the screening period. If there were

multiple daily RCS scores, the latest daily RCS was used.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 1)
(N = 2)
(N = 2)
5 mg (N = 2)
5 mg (N = 2)
(N = 2)

Baseline

n
1
2
1
2
2
2

Mean
2.74
3.35
6.04
4.73
6.01
3.18

(SD)

(0.778)

(2.660)
(3.445)
(0.089)

Median
2.74
3.35
6.04
4.73
6.01
3.18

Q1, Q3
2.74, 2.74
2.80, 3.90
6.04, 6.04
2.85, 6.61
3.58, 8.45
3.12, 3.24

Min, Max
2.7, 2.7
2.8, 3.9
6.0, 6.0
2.9, 6.6
3.6, 8.5
3.1, 3.2

Average Daily RCS

n
1
2
1
2
2
2

Mean
1.76
2.90
4.46
2.77
4.30
2.71

(SD)

(1.730)

(2.025)
(1.112)
(0.507)

Median
1.76
2.90
4.46
2.77
4.30
2.71

Q1, Q3
1.76, 1.76
1.68, 4.13
4.46, 4.46
1.34, 4.20
3.52, 5.09
2.35, 3.07

Min, Max
1.8, 1.8
1.7, 4.1
4.5, 4.5
1.3, 4.2
3.5, 5.1
2.4, 3.1

Change from Baseline

n
1
2
1
2
2
2

Mean
−0.98
−0.45
−1.58
−1.96
−1.71
−0.47

(SD)

(0.953)

(0.635)
(2.333)
(0.418)

Median
−0.98
−0.45
−1.58
−1.96
−1.71
−0.47

Q1, Q3
−0.98, −0.98
−1.12, 0.22
−1.58, −1.58
−2.41, −1.51
−3.36, −0.06
−0.77, −0.18

Min, Max
−1.0, −1.0
−1.1, 0.2
−1.6, −1.6
−2.4, −1.5
−3.4, −0.1
−0.8, −0.2

Percent Change from Baseline

n
1
2
1
2
2
2

Mean
−35.74
−17.16
−26.18
−44.79
−20.71
−15.03

(SD)

(32.420)

(11.766)
(26.931)
(13.569)

Median
−35.74
−17.16
−26.18
−44.79
−20.71
−15.03

Q1, Q3
−35.74, −35.74
−40.08, 5.77
−26.18, −26.18
−53.11, −36.47
−39.75, −1.67
−24.62, −5.43

Min, Max
−35.7, −35.7
−40.1, 5.8
−26.2, −26.2
−53.1, −36.5
−39.8, −1.7
−24.6, −5.4

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Pooled
Cilnidipine
Cilnidipine

Pooled
Cilnidipine +
10 mg +
20 mg +
All

Cilnidipine
Tadalafil
Tadalafil
Tadalafil
Participants

Statistics
(N = 3)
(N = 4)
5 mg (N = 3)
5 mg (N = 4)
(N = 11)

Baseline

n
3
4
3
4
10

Mean
3.15
5.37
4.07
4.68
4.33

(SD)
(0.652)
(2.620)
(2.203)
(2.554)
(1.987)

Median
2.80
5.09
2.85
3.74
3.41

Q1, Q3
2.74, 3.90
3.21, 7.53
2.74, 6.61
3.19, 6.18
2.85, 6.04

Min, Max
2.7, 3.9
2.9, 8.5
2.7, 6.6
2.8, 8.5
2.7, 8.5

Average Daily RCS

n
3
4
3
4
10

Mean
2.52
3.54
2.43
3.60
3.16

(SD)
(1.389)
(1.602)
(1.545)
(1.438)
(1.320)

Median
1.76
3.86
1.76
3.82
3.29

Q1, Q3
1.68, 4.13
2.43, 4.65
1.34, 4.20
2.60, 4.61
1.76, 4.20

Min, Max
1.7, 4.1
1.3, 5.1
1.3, 4.2
1.7, 5.1
1.3, 5.1

Change from Baseline

n
3
4
3
4
10

Mean
−0.63
−1.84
−1.64
−1.08
−1.17

(SD)
(0.740)
(1.404)
(0.723)
(1.627)
(1.105)

Median
−0.98
−1.96
−1.51
−0.59
−1.05

Q1, Q3
−1.12, 0.22
−2.89, −0.79
−2.41, −0.98
−2.24, 0.08
−1.58, −0.18

Min, Max
−1.1, 0.2
−3.4, −0.1
−2.4, −1.0
−3.4, 0.2
−3.4, 0.2

Percent Change from Baseline

n
3
4
3
4
10

Mean
−23.35
−32.75
−41.77
−18.93
−25.73

(SD)
(25.311)
(21.937)
(9.825)
(24.420)
(19.300)

Median
−35.74
−38.11
−36.47
−20.71
−30.96

Q1, Q3
−40.08, 5.77
−46.43, −19.07
−53.11, −35.74
−39.92, 2.05
−39.75, −5.43

Min, Max
−40.1, 5.8
−53.1, −1.7
−53.1, −35.7
−40.1, 5.8
−53.1, 5.8

Results and Discussion

The study treatment is well-tolerated and no adverse events or serious adverse events have been reported in any treated patients.

All cilnidipine and cilnidipine plus tadalafil treated patients (n=7) showed a decrease in the weekly frequency of Raynaud attacks in a population of both milder and more severe disease based on Raynaud Condition Scores at baseline. In 6 of 7 of these patients the average frequency of Raynaud's attacks decreased more than 25%, a clinically meaningful improvement. This improvement was not seen in patients treated with tadalafil alone, who demonstrated an increase in attack frequency.

When considering attacks reported by patients as their typical attacks, all pooled cilnidipine monotherapy or cilnidipine plus tadalafil treated patients (n=7) achieved the primary endpoint of the study producing a 25% or greater reduction in weekly attack frequency (−31 to −40%).

In patients with less severe disease at baseline, as delineated by a baseline Raynaud Condition Score of <5.0, all cilnidipine and cilnidipine plus tadalafil treated patients (n=5) demonstrated a reduction in the weekly frequency of attacks by at least 25% (range 28%-44% reduction).

In patients with more severe disease at baseline, as delineated by a Raynaud Condition Score of >5.0., (n=2) two of two cilnidipine plus tadalafil treated patients demonstrated a reduction in the weekly frequency of attacks but in only one of these patients was the reduction greater than the 25% threshold (43% reduction). Tadalafil monotherapy also increased the frequency of attacks in the one treated patient who had a baseline RCS>5.0.

When considering attacks reported by the patient as their typical Raynaud attacks, a dose response was seen (n=3) with the reduction in weekly frequency of attacks increasing to 46% from 28%, with an increase in dose from 10 mg to 20 mg of cilnidipine.

When considering attacks reported by the patient as their typical Raynaud attacks, in patients with more severe disease at baseline as determined by a baseline RCS>5.0, on average, cilnidipine plus tadalafil treated patients (cilnidipine at either 10 mg or 20 mg) had a significant reduction in the weekly frequency of attacks (−30%)

While tadalafil monotherapy at a 5 mg dose in this small sample of patients (n=2) seemed ineffective (frequency of attacks increased) adding this same dose of tadalafil to cilnidipine seemed to increase benefit with reductions in frequency, severity of attacks, duration of attacks and on RCS scores.

When considering attacks reported by the patient as their typical Raynaud attacks, pooled datasets of all cilnidipine monotherapy patients (n=3) (at either 10 or 20 mg daily) or all pooled cilnidipine plus tadalafil treated patients (n=4), or pooled cilnidipine 10 mg with or without tadalafil (n=3) or pooled cilnidipine 20 mg with or without tadalafil, all met the study primary endpoint of a reduction of at least 25% or greater in the weekly frequency of attacks (−33 to −40%)

Assessing the effect of treatment on the duration of Raynaud attacks, all cilnidipine or cilnidipine plus tadalafil treated patients (n=7) demonstrated a decrease greater than that seen in placebo treated patients. Tadalafil monotherapy patients (n=2) saw on average an increase in the duration of their reported attacks during treatment. Of the 7 cilnidipine or cilnidipine plus tadalafil treated patients, this reduction exceeded a 25% threshold in 4 of 7 patients treated. In the single placebo patient who complied with the study protocol, duration decreased only 5%. Pooled cilnidipine plus tadalafil treated patients (n=4) had a 24.3% average reduction in duration of attacks during treatment. The ability of cilnidipine to decrease duration of attacks occurred regardless of whether disease was mild or severe at baseline as determined by RCS score at baseline.

When considering the severity of attacks as reported by patients, a dose response appears to be present with 20 mg reducing severity more than 10 mg of cilnidipine as monotherapy (n=3). Cilnidipine plus tadalafil (n=4) decreased severity more than tadalafil monotherapy (n=2). Cilnidipine plus tadalafil treated patients (n=4) had a 26% reduction in severity as reported with attacks. The reduction in severity appeared to be slightly greater in patients with milder disease (RCS<5.0, (n=2), −31%) than patients with more severe disease (RCS>5.0, n=2, −22%). In patients with more severe disease at baseline (RCS>5.0, adding cilnidipine to tadalafil produced a greater reduction in severity than treating with tadalafil alone (n=2 for cilnidipine plus tadalafil, 22.2% reduction in severity, n=2 for tadalafil monotherapy, 6.3% reduction in severity.

The benefit of adding tadalafil to cilnidipine in combination appears to be seen in its effect on RCS during the study. At both 10 mg and 20 mg doses of cilnidipine, the reduction in RCS was greater in combination with tadalafil 5 mg. (n=3 cilnidipine monotherapy versus n=4 cilnidipine plus tadalafil dual therapy). 3 of 4 cilnidipine plus tadalafil treated patients achieved a clinically meaningful >25% reduction in their baseline RCS while on treatment. A result this positive has not been seen in previous drug trials in this population and the FDA considers improvements in RCS scores to be an approvable endpoint for a treatment for these patients.

Example 4. Two-Phase, Phase 2 Study, Assessing the Safety of Cilnidipine in SSc-RP and Dose Effect of a Combination of Cilnidipine and Tadalafil

Introduction: A two-phase, phase 2 study, evaluation the safety of cilnidipine in SSc-RP and determination of whether a dose effect existed for cilnidipine at two doses, and whether addition of tadalafil to these doses complemented efficacy and its effect on safety.

Summary of Methods and Protocol:
Part A

Part A of the trial employed a dose-finding, parallel arm design. A total of 27 patients were randomized into one of 6 prespecified treatment arms. In this part, the objective is to determine the appropriate dosage of cilnidipine and tadalafil, as well as their combination, for further evaluation.

Part B

Part B, is designed as a prospective, double-blind, randomized, placebo-controlled, two-way crossover trial. Double-blind, placebo-controlled, 2-way crossover assessed the safety and efficacy of cilnidipine 20 mg (the dose selected in Part A). A total of 38 participants (19 in each sequence) with a diagnosis of SSc-RP were randomized into one of two prespecified treatment sequences in a 2-way crossover design.

Interventions

The study evaluated the following interventions: cilnidipine at doses of 10 mg and 20 mg, tadalafil at a dose of 5 mg, administered once daily, as well as placebo.

Medication Dispensation and Diary Maintenance

Study medication and matching placebo were provided to patients in kits at the time of randomization, following the screening process. Participants were instructed to maintain a daily electronic diary using a cell-phone based case report form (CRF). If necessary, patients were allowed to supplement the electronic diary with a paper record.

Treatment and Assessment

Patients received the assigned intervention for a duration of two weeks. Subsequently, they returned to the clinic for assessments. After treatment discontinuation, patients were followed up for safety purposes.

Concomitant Medications

Throughout the study, patients were permitted to continue their current stable doses of medications prescribed for the management of Raynaud's and other concurrent conditions.

Study Endpoints

The study evaluated multiple endpoints, including the weekly frequency of Raynaud's attacks (primary endpoint), Raynaud Condition Score (RCS), pain severity, attack duration, Scleroderma Health Assessment Questionnaire (SHAQ), Patient-Reported Outcome (PRO), UCLA Gastrointestinal Tract (GIT) 2.0 assessment for gastrointestinal dysfunction, endothelial function assessed by Endo-PAT, thermography, and pharmacokinetics (PK).

Detailed Protocol:
Detailed Summary

A randomized, double-blind, placebo-controlled phase 2a study to assess the safety and efficacy of cilnidipine (10 mg and 20 mg) alone and in combination with 5 mg tadalafil in participants with diagnosis of secondary Raynaud's disease, also referred to as reconnoiter-1: randomized evaluation of the benefit of cilnidipine dose on the nature, observational indices, temperature changes, and overall effect in secondary Raynaud's disease.

Overall Study Design

A schematic of the study design is provided in FIG. 9. This is a randomized, double-blind, placebo-controlled Phase 2a study that assessed the safety and efficacy of cilnidipine alone and in combination with tadalafil, in participants who have frequent attacks of secondary RP mostly resulting from SSc. Oversight for the study will be provided by a DSMB.

Participants underwent a screening period beginning up to 10 days prior to randomization. The initial screening and capacity was conducted via phone at the start of the screening period with eligibility finalized prior to randomization on Day 0. Participants were required to provide informed consent in a 2-step process at screening (commencement of diary use will be considered implied consent for the screening period) and at randomization (Day 0) before undertaking any study-specific procedures or assessments. Only participants who met all of the inclusion and none of the exclusion criteria were be randomized.

The study consists of two parts.

Part A—double-blind, placebo-controlled, parallel-group, dose selection, will assess the safety and efficacy of two doses of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil. A total of 27 participants were randomized to one of six prespecified treatment arms. Refer to FIG. 9 for treatment arms in Part A of the study. Dosing lasted for 12 (±2) days in which participants self-administered daily doses of assigned treatment in the morning. Each participant took one capsule and one tablet to blind the active therapy being received. Study visits and assessments occurred as delineated in the SoA presented in FIG. 2.

The data obtained and reviewed from 27 participants enrolled in Part A was sufficient to 1) confirm safety, tolerability, and potential efficacy of cilnidipine in patients with SSc-RP and 2) select the cilnidipine dose (20 mg) for Part B for continued evaluation of efficacy, safety, and tolerability. The Committee also agreed that the co-administration of tadalafil with cilnidipine did not provide significant additional benefit to the higher dose of cilnidipine chosen and may add some minor adverse events; therefore, the Committee recommended modifying Part B to a 2-way crossover design (CIL 20>placebo, placebo>CIL 20).

Part B—Double-blind, placebo-controlled, 2-way crossover assessed the safety and efficacy of cilnidipine 20 mg (the dose selected in Part A). A total of 38 participants (19 in each sequence) with a diagnosis of SSc-RP were randomized into one of two prespecified treatment sequences in a 2-way crossover design.

Refer to FIG. 9 for treatment sequences in Part B of the study. Each participant underwent two dosing periods in which they received a different treatment each dosing period followed by a 4 (±1) day washout period. Each dosing period lasted for 12 (±2) days in which participants self-administered daily doses of assigned treatment in the morning. At all dosing periods, each participant took one tablet to blind the active therapy being received. Study visits and assessments occurred as delineated in the SoA presented in FIGS. 4A and 4B.

For both Part A and B of the study, participants were required to visit the clinic on last day of each dosing period (i.e., day 10 to 14) to return/dispense study drug and conduct in person study assessments. Participants were dispensed with 2 weeks' worth of study drug to be taken at home for the following dosing period; overage from the prior dosing period was also collected.

Patients were assessed for the occurrence of efficacy endpoints for each dosing period via the patient reported diary and the in-clinic visit. Safety information was collected from randomization until patient follow-up was complete (28+3 days after the last dosing period) and assessed for each dosing period.

Dose Selection, Sample Size Confirmation and Safety Oversight

The role of the DSMB, was set out in a DSMB Charter. The DSMB conducted a review of the efficacy and safety data from Part A of the study. The first review occurred after approximately 50% of the participants completed the study. Subsequent reviews occurred as needed prior to commencement of Part B of the study to assess the risk: benefit of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil.

Following review of the efficacy and safety data from Part A, the DSMB were to make the following recommendations:

- 1. Select the dose of cilnidipine (10 mg or 20 mg) to be studied in Part B of the study
- 2. Confirm the sample size estimates for Part B of the study.
  
  Serious adverse events will be monitored (by the DSMB in Part A and Drug Safety Officer in Part B) on an ongoing basis throughout the study.

Efficacy and safety data from the 27 participants who completed Part A were included in the analyses. The benefit/risk profile demonstrated and recommended that the study proceed directly to Part B (powered crossover phase) without full completion of Part A. That the data from Part A is sufficient to 1) confirm safety, tolerability, and potential efficacy of cilnidipine in patients with SSc-RP and 2) select the cilnidipine dose (20 mg) for Part B for continued evaluation of efficacy, safety, and tolerability. The Committee also agreed that the co-administration of tadalafil with cilnidipine did not provide significant additional benefit to the higher dose of cilnidipine chosen and may add some minor adverse events; therefore, the Committee recommended modifying Part B to a 2-way crossover design (CIL 20>placebo, placebo>CIL 20).

Participants received study treatment (cilnidipine 20 mg or placebo tablet) in a blinded fashion. Each dosing period lasted for 12 days (±2 days) in which participants took daily doses of assigned treatment in the morning. The schematic for dosing is presented for Part A (Table S1) and Part B (Table S2) below and FIG. 9.

TABLE S0

Part A Demographic data

Pooled

Cilnidipine
All Cilnidipine
Placebo

only (n = 7)
(n = 16)
(n = 4)

Mean Age (SD)
59.9
(13.8)
61.8
(11.1)
49
(7.8)

SSc Diagnosis
86%
88%
100%

Presence of GI sx
57%
81%
75%

Hx Diabetes
14.3%
12.5%
25%

Hx CAD
0%
0%
0%

Hx HTN
0%
0%
0%

Abnl ANA
100%
(n = 6)
92%
(n = 13)
75%

CRP/ESR levels elevated
0%
0%
33%
(n-3)

Smoking Hx
28.6%
31%
75%

TABLE S1

Part A, Double-blind, Parallel-group, Dose Selection

Arm
N
Treatment

A
6
P

B
6
C10

C
6
C20

D
6
T05

E
6
C10 + T05

F
6
C20 + T05

Abbreviations: C = cilnidipine, P = placebo, T = tadalafil, N = number of participants, C10 = C 10 mg, C20 = C 20 mg; T05 = T 5 mg.

TABLE S2

Part B, Double-blind, Placebo-controlled, 2-way crossover

Sequence

Dosing
Dosing

Number
N
Period 1
Period 2

1
19
P
C20

2
19
C20
P

Abbreviations: C20 = cilnidipine 20 mg, P = placebo, N = number of participants

Number of Participants (Planned): Up to 65 participants will be enrolled in this study: 27 (revised from 36 based on DSMB recommendation) in the parallel-group dose selection phase (Part A) and 38 in the 2-way crossover phase (Part B). Participants who complete Part A without any major protocol deviations or compliance issues were invited to participate in Part B. Participants needed to consent and meet all eligibility criteria again in order to be randomized into Part B. Dropouts will not be replaced.

Diagnosis and Main Criteria for Inclusion:

Participants aged 18-90 years and diagnosed with severe secondary Raynaud's disease (Raynaud's Condition Score [RCS]≥20 and at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion) mostly resulting from SSc and exhibiting regular and frequent RP attacks (averaging at least one attack per day) during the screening period.

Investigational Product, Dosage and Mode of Administration:
Cilnidipine

For Part A, Cilnidipine 10 mg and cilnidipine 20 mg for oral administration, were provided to the site in cartons containing 16 tablets sealed in blister packs.

For Part B, Cilnidipine 20 mg (the dose selected in Part A) were provided to the site in cartons containing 16 tablets sealed in blister packs.

Tadalafil

For Part A, Tadalafil 5 mg, for oral administration was over encapsulated (and back filled with inert capsule filler consisting of only maize starch and pre-gelatinized maize starch, so that the internal tablet cannot be detected) and provided in bottles containing 16 capsules to the site. Tadalafil was not provided for Part B.

Medications were dispensed during the preceding in-clinic study visit for self-administration by the participant once daily in the morning for a 12 (±2) day period. The duration of the Dosing period was confirmed by the study staff when the in-clinic study visit was scheduled.

Investigational Plan
Study Rationale

No cure exists for patients suffering with SSc. The exact cause is unknown, however SSc is thought to result from a combination of factors, including autoimmune, genetic, and environmental triggers. Symptoms can include painful episodes in the extremities with color changes of the fingers or toes (e.g., RP), digital ulcers, skin thickening or hardening, capillary changes (assessed using nailfold capillaroscopy), swelling of the hands or legs, and general pain. Available therapies only provide symptomatic treatment with limited efficacy and safety. New treatments are needed to better manage the symptoms and directly address the underlying disease processes of SSc-RP. This study evaluated the efficacy and safety of cilnidipine (Profervia®) monotherapy compared to placebo for the treatment of patients with secondary RP primarily due to SSc; the study also included evaluation of combination therapy of cilnidipine and tadalafil to determine if the combination of cilnidipine with a low dose of the PDE5 inhibitor tadalafil provided additional or synergistic benefits for the study patients.

The pharmacology and safety profile of cilnidipine make it a potentially more efficacious and safe treatment for SSc than the currently available medications, with the added potential benefits of diminishing the major symptoms of the disease including improvement of Raynaud's attacks (reduction of frequency and severity), as well as possibly addressing and improving the underlying pathologic processes contributing to disease progression, including fibrosis and endothelial/vascular dysfunction. It is further anticipated that the pharmacokinetic profile of cilnidipine make it better suited for the treatment of SSc-RP patients than other currently approved CCBs, since peak blood levels of the drug after oral dosing are reached within 2 hours, which is more rapidly than other CCBs.

Dosage Rationale
Cilnidipine

Cilnidipine is approved for the treatment of hypertension in Japan, India, China, and South Korea in doses of 5 mg up to 20 mg. It is taken orally, once a day, usually in the morning. First approved in Japan in 1995, there is greater than 25 years of safety experience at these doses.

Cilnidipine's pharmacokinetics, with a more rapid time to achieve maximal plasma concentrations (2 hour T_max) than the CCBs amlodipine (10 hours) or extended release nifedipine (3 hours), may increase cilnidipine's suitability for treating Raynaud's symptoms in SSc patients compared to other CCBs, in that these symptoms commonly occur early in the day. Cilnidipine is also dosed once daily compared to nifedipine's three times a day dosing schedule.

Duration of Treatment:

Part A, Double-blind, Parallel-group, Dose Selection: Participants enrolled participated for up to 29 (5) days:

- Screening: up to 10 days (−3 days)
- Treatment: 12 (±2) days
- Follow-up: 7 days (+3 days)

Part B, Double-blind, Placebo-controlled, 2-way crossover: Participants enrolled participated for up to 63 days (±8 days):

- Screening: up to 10 days (−3 days)
- Treatment: 28 days (two days each lasting for 12 (±2) days, separated by a 4 (±1) day washout period)
- Follow-up: 28 days (+3 days)
- Reference Therapy, Dosage, and Mode of Administration:
- Placebo: Placebo tablets (matching cilnidipine) and placebo capsules (matching tadalafil, Part A only), for oral administration, were provided to the site.

Study Objectives and Endpoints
Objectives
Primary Efficacy Objectives:

The primary efficacy objective of the study was to evaluate the effect of cilnidipine on the frequency of weekly RP attacks compared with placebo in participants with SSc-RP.

Secondary Efficacy Objectives:

The secondary efficacy objective of the study was to evaluate the effect of cilnidipine on all the clinical features of SSc-RP, including symptoms and disability associated with SSc in addition to RP.

Safety Objectives:

The safety objective of the study was to evaluate the safety of cilnidipine compared to placebo in participants with SSc-RP.

Exploratory Objectives:

To assess the impact of treatment on 1) endothelial function and 2) severity and impact of Raynaud's phenomenon, in participants with SSc-RP

To evaluate the efficacy and safety of combination therapy (cilnidipine 10 mg and mg, in combination with tadalafil) on all efficacy and safety endpoints (Part A only)

Primary Efficacy Endpoint:

Percentage change from baseline in frequency of weekly RP attacks.

Secondary Efficacy Endpoints:

- Change from baseline in frequency of weekly RP attacks.
- Change from Baseline in average duration of weekly RP attacks.
- Change from Baseline in average severity of weekly RP attacks.
- Change from Baseline in average daily RCS.
- Change from baseline in highest (most severe) pain score recorded during weekly RP attacks.
- Change from baseline in average pain score recorded during weekly RP attacks.
- Change from baseline in net digital ulcer burden.
- Change from baseline in distal-dorsal difference (DDD) of the affected index finger sites.
- Change from baseline in participant quality of life and other aspects of scleroderma disease measured using the Scleroderma Health Assessment Questionnaire (SHAQ).
- Change from baseline in participant gastrointestinal symptoms (of sclerosis) as assessed with the UCLA SCTC GIT 2.0 questionnaire.
- Change from baseline in Raynaud-visual analog scale (VAS).
- Change from baseline in physician assessment of disease.
- Measurement of cilnidipine drug levels taken 2 to 6 hours following the last dose.
- The time to reach maximum degree of efficacy (in days) compared to baseline.
- The time to return to baseline symptom severity after termination of dosing.
- Impact of daily ambient temperature on symptomatic RP attacks.
- Use of rescue medications for breakthrough symptoms.

Exploratory Efficacy Endpoints:

- Change from baseline in endothelial function as measured by reactive hyperemia index (RHI) using Endo-PAT
- Change from baseline in novel patient-reported outcomes (ASRAP score) which assesses the severity and impact of RP in SSc (Part B).
- Change from baseline in combination endpoint (frequency of weekly RP attacks and ASRAP score) (Part B).
- Change from baseline in reported ocular symptoms (Part B)
- Effect of combination therapy (Cilnidipine 10 mg+Tadalafil 5 mg, and Cilnidipine 20 mg+Tadalafil 5 mg) on all efficacy endpoints (Part A only).

Safety Endpoints:

- Incidence of treatment emergent adverse events (AEs) and serious adverse events (SAEs), including clinically significant vital signs. For Part A safety will be assessed from the time of randomization until 7 days following the last protocol dose. For Part B, participants will be followed for 28 days from the last study dose.
- Serious adverse events will be monitored by a DSMB (Part A) and Drug Safety Officer (Part B) on an ongoing basis throughout the study.
- Adverse events will be coded using the MedDRA and summarized by SOC, PT, and treatment group.

Statistical Methods:

Part A data was analyzed in exploratory fashion to support cilnidipine dose selection and treatment effect check for sample size confirmation for Part B. For Part B data, mixed effects model was used for analysis of the continuous efficacy endpoints in the crossover design. For nominal data, Chi-square tests were applied. Generalized Estimating Equations method were used, as appropriate, for adjusting for potential confounding factors. Safety endpoints were summarized by treatment group. No multiple comparison adjustment were used to control alpha for the multiple comparisons.

Statistical Analyses:

Data from Part A and Part B was analyzed separately. The primary and secondary efficacy analyses were based on the Modified Intent-To-Treat (mITT) population. Analyses based on the Intent-To-Treat (ITT) and PP population for Part B were considered secondary and confirmatory. All safety analyses were performed on the safety population. Subgroup analyses were also performed.

Additional exploratory analyses may be performed and will be documented in the statistical analysis plan. Any deviation from planned analyses described in this protocol will also be documented in the statistical analysis plan. Data was summarized by treatment group for treatment effect comparison according to crossover design; participants receiving each treatment were pooled from all periods. Baseline was be defined as screening assessments for change from baseline analyses for all periods.

Sample Size Calculation:

The sample size for Part B was calculated based on the available data from Part A at the time of protocol specified data review Assuming a 2-sided 0.05 alpha for the comparison of cilnidipine 20 mg versus placebo, between-participants standard deviation (SD) of 35, a correlation between the two measurements on the same participant of 0.2, and a 25% dropout rate, it is estimated that a total sample size of 38 participants (19 in each treatment sequence) was needed to obtain complete data from 28 participants (14 in each treatment sequence), for ≥80% power to detect a decrease of 25 in percentage change from baseline in weekly RP attacks in a 2×2 crossover design.

Pharmacokinetics and Pharmacodynamics
Pharmacokinetics

Cilnidipine achieves maximal plasma concentration in about 2 hours, which is more rapid than other CCBs (e.g., amlodipine at 10 hours or extended use nifedipine at 3 hours), which may increase cilnidipine's suitability for treating SSc patients. See S3 for a summary of pharmacokinetic (PK) parameters for cilnidipine.

TABLE S3

PK Parameters for 10 mg Cilnidipine,

Healthy Volunteers, single oral dose

Pharmacokinetic Parameters
Mean

C_max(ng/mL)
8.9
(±4.2)

T_max(hr)
2
(0.5-5)

AUC_last(ng*hr/mL)
37.0
(±17.9)

AUC_inf(ng*h/mL)
41.2
(±20.4)

CL/F (L/hr)
304.7
(±147.5)

T_1/2(hr)
7.5
(±1.0)

Source: Lee, et al., Drug Des Devel Ther. 2014; 8: 1781-1788. 2014

*Mean (±standard deviation), except for T_maxfor which median (minimum-maximum) is presented. Abbreviations: AUC_inf= area under the plasma concentration time curve from time zero extrapolated to infinity. AUC_last= area under the plasma concentration time curve to the last observation. C_max= maximum plasma concentration. CL/F = apparent clearance. T_max= time to reach C_max.

Pharmacodynamics

The mechanism of action of cilnidipine offers unique potential benefits for SSc participants that differentiate it from other dihydropyridine CCBs. In hypertensive patients, cilnidipine has been shown to have similar equipotent efficacy when compared to other calcium channel antagonist hypertensive treatments, while exhibiting a better safety profile. This is due to cilnidipine's N-type Ca channel selectivity, in addition to its L-type Ca channel activity.

Currently approved CCBs have primarily L-channel Ca activity and little or no N-type activity. Because of its improved safety profile, cilnidipine can be dosed at higher dose levels than other non-N-selective CCBs, engendering greater efficacy in reducing blood pressure.

Unlike other CCBs, cilnidipine with its primarily N-type Ca channel activity also inhibits sympathetic nervous system activity, dilates venules in addition to arterioles, improves endothelial structure and function, and may provide analgesic effects. Cilnidipine has also demonstrated anti-fibrotic effects in nonclinical studies as well as additional renal and cardiovascular effects in clinical studies. Cilnidipine also is a potent inhibitor of the purinergic P2X7R pathway, and studies have shown that fibroblasts from patients with SSc show upregulation of this receptor and that it promotes a fibrogenic phenotype in their fibroblasts. These additional pharmacodynamic properties of cilnidipine address several key factors of SSc and may provide superior treatment for SSc participants than currently available treatments. This is a first in human (FIH) study of cilnidipine and tadalafil combination. No clinical studies of cilnidipine and tadalafil combination have been conducted to date. However, based on the clinical use of CCBs in combination with PDE5 inhibitors, no drug-drug interaction is expected.

Safety Criteria for Stopping or Unblinding Treatment

- Symptoms of possible allergic phenomena: rash, hives, urticaria, changes in breathing or wheezing.
- Systolic BP (SBP)<90 mmHg
- Reduction in BP (relative to baseline values) considered to be significant in the opinion of the Investigator on an absolute basis or consistent with symptoms (dizziness, light-headedness) suggestive of being related to reduction in BP.
- Two separate SBP measurements of <90 mmHg, taken at rest (where baseline SBP exceeded 110 mmHg), even in the absence of symptoms, shall be considered sufficient reason to unblind the study for that patient.
- Dizziness, when going from a recumbent to standing position and/or if accompanied by a reduction in BP.
- Dizziness in the absence of a reduction in BP should be considered on an individual participant basis, as to its relative degree of severity, as to whether the participant continues in the study.
- Unexpected adverse event or reaction.

Study Termination

The study will be completed as planned unless:

- New information or other evaluation regarding the safety of the study medication indicates a change in the known risk/benefit profile for the compound, such that the risk/benefit is no longer acceptable for participants participating in the study. This may be determined by the Sponsor, the Investigator, the HREC or regulatory authorities.
- The study is terminated by the Sponsor for administrative reasons.

4. Participant Population

The study was conducted in participants aged 18-90 years, diagnosed with severe secondary Raynaud's disease (RCS≥20 and at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion) mostly resulting from SSc (defined by consensus criteria 2013 American College of Rheumatology [ACR]) and exhibiting a frequency of attacks (at least one per day) during the screening period.

Women of childbearing potential were included and are subject to contraceptive requirements during the study from screening until study completion, including the follow-up period, and for at least 30 days after the last dose of study drug (see Section 4.2). Women of childbearing potential must demonstrate negative pregnancy testing at screening. This is in line with regulatory Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (US FDA Guidance document, January 2010).

Number of Participants

Up to 76 participants could be enrolled in this study. Thirty-six participants were planned for the parallel-group dose selection phase (Part A), however following the DSMB recommendation to proceed directly to Part B (the powered cross-over phase), Part A was stopped early with 27 participants randomized. In Part B, 38 participants were be randomized in a 2-way crossover design. Participants who completed Part A without any major protocol deviations or compliance issues were invited to participate in Part B. Following completion of Part A, participants would need to provide written informed consent and meet all eligibility criteria again in order to be randomized into Part B. Sample size assumptions account for a dropout rate of 25%, therefore dropouts will not be replaced.

Participant Inclusion Criteria

To be eligible for this study, a participant had to meet all of the following inclusion criteria:

- 1. Male or female participants, aged 18 to 90 years (inclusive at the time of informed consent).
- 2. Severe secondary Raynaud's disease (with patient reported RCS at baseline of ≥20) based on ACR criteria mostly resulting from SSc.
- 3. Regular and frequent Raynaud's attacks (averaging at least one attack per day) during the screening week (in participants with at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion).
- 4. Willingness to complete the daily diary entry's during the screening period.
- 5. Participants must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.
- 6. Willingness to forego therapies for Raynaud's during study participation is preferred (except for selective serotonin reuptake inhibitors such as fluoxetine which should not be discontinued) Ongoing treatment with CCBs and other routine therapies for SSc-RP is permitted however, if it is not clinically feasible to stop therapy, the participant has been on a stable dose for the last 2 months and meets all eligibility criteria. Rescue therapy (with acetaminophen, nonsteroidal anti-inflammatory drug [NSAIDs], other codeine analgesics, fluoxetine, angiotensin II receptor blockers (ARBs) such as losartan) or CCBs will be allowed to manage breakthrough symptoms of SSc-RP but must be documented).
- 7. Participants who are on a stable dose (no change in the last 2 months) of a CCB for hypertension or PDE5 inhibitors for pulmonary hypertension may continue these agents at this stable dose as long as they meet other inclusion criteria during screening.
- 8. Have agreed not to use (or initiate treatment with) other investigational therapies or unapproved therapies during the course of the study outside of protocol allowances for rescue medication (such medications include but are not limited to: nitroglycerin, topical creams, fenoldopam, nimodipine, amlodipine, fluoxetine, pregabalin, gabapentin, verapamil, sildenafil, tadalafil, vardenafil).
- 9. Women of childbearing potential (WOCBP) who have agreed to use an effective method of contraception during the study and for 30 days after the last study dose. Acceptable methods of birth control in this study include oral contraceptive, barrier control, or implanted devices. A woman must agree not to donate eggs (ova; oocytes) for purposes of reproduction for at least 30 days after last dose of study drug.
- 10. Post-menopausal females, aged over 45 years who have not had a period for at least 12 months, and are not using hormonal contraception, or females documented as permanently sterile (e.g., bilateral tubal ligation; hysterectomy, bilateral salpingectomy).
- 11. Negative urine pregnancy test on randomization day (WOCBP only).
- 12. All sexually active men whose partner is a WOCBP (due to potential risk of drug exposure through the ejaculate) who agree to a barrier method of birth control during the study and for 30 days after the last dose of the study drug. All men must agree not to donate sperm for at least 30 days after receiving last dose of study drug.
- 13. Participants must have clinical laboratory values within normal range as specified by the testing laboratory at their most recent pre-screening sample, unless deemed not clinically significant by the Investigator or delegate. Lab sample may be within the last 2 months as long as there have been no significant clinical changes since the last labs and no new medications (e.g., Diuretics) have been introduced that are known to be associated with changes in clinical chemistry or hematology values (e.g., potassium with diuretics or cyclosporine associated with aplastic anemia).

Participant Exclusion Criteria

A participant who met any of the following exclusion criteria were excluded from the study:

- 1. Primary Raynaud's disease.
- 2. History of Raynaud's attacks of sufficient severity as to require in-patient hospitalization (within the last 6 months).
- 3. The SBP of <95 mm Hg during randomization visit (Day 0).
- 4. Participants with an allergy to dihydropyridine CCBs that results in clinical findings such as profound hypotension, hives, rash, urticaria, wheezing and changes in breathing (Common treatment limiting adverse events [AEs] that occur with CCBs nifedipine and amlodipine such as edema, headache, heart rate changes, tachycardia, fatigue, constipation, flushing, drowsiness, dizziness should not limit enrollment into this study).
- 5. History of other chronic pain condition that could confound recording of pain scores during the study period.
- 6. Any prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that in the opinion of the Investigator(s), would contraindicate administration of the study medication, or interfere with the study evaluations, or interfere with the participant's ability to comply with the study protocol.
- 7. Cognitive or language difficulties that would impair completion of the study assessments.
- 8. Use of any investigational product (IP) or investigational medical device or participation in investigational drug studies within 30 days prior to enrollment in the study.
- 9. Those receiving nitrates (nitro-dur, nitroglycerin) or similar agents that have vasodilatory effects (e.g., nicorandil) prescribed to treat angina, alpha blockers, PDE inhibitors, prostacyclins or endothelin antagonists for whom dose is not stable for >2 months
- 10. History of orthostatic hypertension, dizziness or fainting spells, acute coronary or cerebrovascular event within 3 months of study enrollment.
- 11. History of major thoracic, abdominal, or vascular surgery within 6 months of study enrollment; History of sympathectomy in the hand which is symptomatic for RP.
- 12. Severe cardiomyopathy, severe valvular heart disease, chronic kidney disease (CKD) stage 3 or greater, evidence of malignancy, end stage lung disease.
- 13. Pregnant or lactating women.
- 14. Women of childbearing potential (WOCBP) unable to comply with contraceptive requirements during the study period.
- 15. Males with partners who are WOCBP and are unable to comply with the contraceptive requirements during the study.
- 16. History of drug (including recreational use of inhaled amyl nitrates or party poppers) or excess alcohol use that in the opinion of the Investigator(s) would affect the participant's ability to reliably participate in the study. NHMRC guidelines for regular alcohol consumption in healthy adults are no more than 10 standard drinks per week and no more than four standard drinks on any one day.
- 17. Heavy smokers of tobacco products of any type (defined as >10 cigarettes per day). Light smokers who agree to keep their smoking stable for the duration of their trial participation are eligible.

Screen Failures

Screen failures were defined as participants who consent to participate in the clinical study but were not subsequently randomized in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes screen failure details and eligibility criteria. Participants who withdrew from the study, for any reason, prior to randomization were considered screen failures. Individuals who did not meet the criteria for participation in this study (screen failure) could be re-screened following a one month waiting period. Re-screened participants should be assigned a new participant number.

Participant Replacement

All participants who were randomized were followed and included in the primary ITT analysis. Dropouts were not replaced.

Participant Withdrawal Criteria

Participants could withdraw their consent to participate in the study at any time. If a participant withdrew consent, the date and reason for consent withdrawal should have been documented. Participants were encouraged to remain in the clinic to complete all necessary assessments and until the Investigator deems that it is safe to be discharged. Participant data was included in the analysis up to the date of the withdrawal of consent. Apart from withdrawal of consent, reasons for early termination of individual participants can include:

- Protocol deviations or participant non-compliance (must be specified on the appropriate eCRF)
- Serious or severe AEs
- Administrative decision by the Investigator or the Sponsor
- Death
- Other (must be specified).

The primary reason for withdrawal were identified and recorded on the appropriate eCRF, along with the date of withdrawal.

In accordance with applicable regulations, a participant had the right to withdraw from the study, at any time and for any reason, without prejudice to future medical care. If a participant was withdrawn because of an AE, the Investigator must arrange for the participant to have appropriate follow-up care until the AE was resolved or stabilized. Unresolved AEs were followed until the last scheduled Follow-up/End of Study (EOS) visit or until the Investigator(s) determine that further follow-up was no longer indicated. In addition to AEs, other reasons for removal of participants from the study included, but were not limited to, withdrawal of consent, administrative decision by the Investigator or the Sponsor, protocol deviation, or participant noncompliance.

If a participant asked or decided to withdraw from the study, all efforts were made to complete and report the observations, especially those related to the listed primary and secondary objectives, as thoroughly as possible up to the date of withdrawal. Wherever possible, the tests and evaluations, including those listed for the EOS/follow-up visit, should have been performed for all participants who discontinue prior to the completion of the study.

Treatments
Cilnidipine

Cilnidipine is an orally administered dihydropyridine calcium channel blocker (CCB) that dilates blood vessels, increases blood flow, inhibits sympathetic nervous system activity, and improves endothelial structure and function. Please refer to IB for more information on composition of cilnidipine tablet.

Cilnidipine is commercially available and should be used only in accordance with this study protocol and IB. Cilnidipine 10 mg and 20 mg oral tablets will be provided to the site in cartons containing 16 tablets sealed in blister packs.

Tadalafil

Tadalafil for oral administration belong to a class of medications called PDE5 inhibitors.

Tadalafil is commercially available and should be used only in accordance with this study protocol. Please refer to the pharmacy manual and product information sheet for more information on composition and storage information for tadalafil. Tadalafil will be over encapsulated (and back filled with inert capsule filler consisting only of maize starch and pre-gelatinized maize starch, so that the internal tablet cannot be detected) and provided in bottles containing 16 capsules to the site.

Reference Products

Placebo tablets (matching cilnidipine) and placebo capsules (matching tadalafil) for oral administration will be provided for this study.

Dosage and Treatment Periods

In Part A, each participant took daily one capsule and one tablet to blind the active therapy being received. In Part B, each participant took one tablet daily. All medications for each dosing period (each dosing period will last for 12 days [±2 days]) were dispensed during the preceding in-clinic visit and then self-administered by the participant once daily, orally, in the morning.

If a participant accidentally missed a dose, they should have been advised to take the dose on the same day as soon as they realized. Only one dose should be taken each day. If more than one dose is lost, the participant should notify the study staff so that their in-clinic visit can be adjusted if needed.

Part A, Double-blind, Parallel-group, Dose Selection Study drug was self-administered daily for 12 (±2) days. Each participant received only one treatment. Please refer to FIG. 2 for more details.

Part B, double-blind, placebo-controlled, 2-way crossover study drug was self-administered daily in two dosing periods separated by a four-day (±1) washout period.

Each participant received a different treatment during each dosing period, with a total of two treatments received. Please refer to FIGS. 4A and 4B for more detail.

Method of Assigning Participants to Treatment
Randomization

A randomization list was prepared using a statistical software package by a Biostatistician. Each participant was provided with a unique screening number post-documentation of informed consent. Once deemed eligible, the participant was assigned a sequential randomization number prior to first dosing. Participants who consented to screening but then withdrew from the study or fail eligibility, for any reason, prior to randomization were considered screen failures.

Participants who completed Part A without any major protocol deviations or compliance issues were invited to participate in Part B. Those who consented to be rescreened for Part B were provided with a second unique screening number. If deemed eligible, the participant was assigned a sequential randomization number specific to Part B.

Concomitant Medications

All medications, including over the counter medications, vitamins, and herbal supplements, taken during the screening period was reviewed by the Investigator to determine whether these medications render the participant as suitable for inclusion in the study.

Concomitant medications of interest were captured electronically from the start of the screening period until study completion.

Treatment prior to enrollment with therapies for SSc-RP including but not limited to CCBs, nitroglycerin, topical creams fenoldopam, nimodipine, fluoxetine, pregabalin, gabapentin, sildenafil, tadalafil, vardenafil were permitted. In order to be eligible, participants had to be willing to forego these therapies for SSc-RP at the start of the screening period and for the duration of the study. Participants who were on a stable dose (no change in dose in prior 2 months) of a CCB for hypertension or sildenafil for pulmonary hypertension could continue these agents at this stable dose as long as they met other inclusion criteria during screening. Similarly, participants who were receiving CCBs to manage their symptoms of SSc-RP and were unwilling to stop treatment for the duration of the study were still eligible if the participant's dose had been stable for the past 2 months. During the study participants were able to decrease the dosage of their prior CCB for safety reasons only; no increase in dosage was allowed during the study period. The use of any other IP or investigational medical device within 30 days prior to screening is prohibited.

Prior therapy or concomitant therapy (after study drug administration) with any medications, including both prescription and non-prescription drugs should have been discussed with the Investigator and Sponsor's MM before study drug administration, except in the case of necessary treatment of AEs or where appropriate medical care necessitates that therapy should begin before the Investigator can consult with the Sponsor's MM.

Rescue Medicine

Medications required as rescue therapy can be taken to manage breakthrough symptoms of SSc-RP but must have been recorded in the participant Diary. First-line therapy may include acetaminophen, NSAIDs, or other codeine-based analgesics. These rescue medications could have been taken for the duration of symptoms of a Raynaud's attack. For participants in whom first-line rescue therapy was not effective, additional rescue medication therapy could started per Investigator discretion and could include fluoxetine, ARBs such as losartan or CCBs. Rescue therapy should continue as long as clinically needed during an acute attack, but then patients should have returned to the pre-rescue study medication regimen. All participants receiving rescue therapy should have continued in the study undergoing subsequent dosing periods through study completion.

Treatment Compliance

All doses were self-administered by participants remote from study sites (at home). For each dosing period, participants were dispensed with two weeks' worth of study medication and were asked to return the unused study medication on the last day of each dosing period at the time of in-clinic visit. The treatment compliance was noted by the Investigator(s) during the in-clinic visit.

Blinding

This study was double-blind. To maintain the blind, all study medication was provided to the site in a blinded fashion. Cilnidipine tablets and matching placebo were supplied in cartons containing 16 tablets sealed in blister packs, identical in appearance. Tadalafil was provided in an over encapsulated form. The capsules, tadalafil, and placebo were identical in appearance and weight and were supplied in bottles containing 16 capsules. Each study drug was labeled with a unique ID number. The interactive voice response system (IVRS) will have access to the treatment arm assignment for each individual ID number.

In the Event of an Emergency: Unblinding a Code

It is recognized that, in the course of clinical practice, it may be necessary for the treating physician to have knowledge of the treatment assignment to ensure the safety of a study participant. This circumstance is extraordinary and will likely impact a minor fraction of the enrolled participants. Unblinding was done via the IVRS. The treating physician is encouraged to contact the Sponsor MM in this circumstance. The Sponsor and DSMB will monitor all episodes of unblinding very carefully.

Study Schedule

The SoAs for Part A and Part B of the study are provided in FIG. 2 and FIGS. 4A and 4B. Where possible, assessments were conducted in order of least invasive to most invasive. This study consists of four periods:

- Screening period (begins with initial participant contact through participant completion of the screening Diary)
- Randomization period (from the time participant eligibility is confirmed and the participant randomized until immediately before the 1^stdose of study drug)
- Procedural period (from the first dose of study drug in the first dosing period until the last day of dosing)
- Follow-up period (from the end of the procedural period through completion of follow-up for safety i.e., 7 days for Part A and 28 days for Part B).

Part A—Double-Blind, Placebo-Controlled, Parallel-Group, Dose Selection

In Part A, the procedural period required only one dosing period i.e. participants received only one treatment during the procedural period. Within the procedural period for Part A there were two sub-periods:

- Daily at home dosing (first ten to fourteen days of the dosing period)
- In-clinic visit (the last day of the dosing period that occurs on Day 12 [±2 days]).

Part B Double-Blind, Placebo-Controlled, 2-Way Crossover

In Part B, the procedural period required two dosing periods i.e., participants will receive two different treatments in a 2-way crossover design. Within the procedural period for Part B there were two sub-periods associated with each dosing period/treatment received:

- Daily at home dosing (first ten to fourteen days of the dosing period)
- In-clinic visit (the last day of the dosing period that occurs on Day 12 [±2 days]) One washout period (four days of no dosing) is required between each dosing period).

Screening (Day −10 to Day −1)

Prior to enrolling in the study, and before performance of any procedures, potential participants were contacted via phone to discuss the details of the study and assess their eligibility and willingness to comply with all study procedures and duration. A copy of the Informed Consent Form (ICF) was emailed to the patient in conjunction with this discussion. If the participant seemed eligible and was interested in participating in the screening period, then they were asked to start using a diary to record the daily clinical features and symptoms of their SSc-RP for the next 7 to 10 days. Commencement of diary use was considered implied consent for the screening period, the data from which was used to confirm eligibility and future baseline analyses assuming the participant is randomized.

During screening, the Diary collected the following data to confirm eligibility and serve as the baseline measure for efficacy endpoints should the participant be randomized:

- Number of daily Raynaud's attacks
- Duration of each attack
- Symptoms of each attack, including numbness, pain, tingling, color changes
- Severity of each attack (all symptoms of the attack to be considered including tingling, numbness, pain, color changes)
- Location of participant during each attack (inside/outside)
- Pain score of each attack—using 11-point Likert scale, a validated pain scale which can be used to record intensity of pain.
- Daily RCS—a validated outcome measure used to assess the level of difficulty experienced due to RP each day.

Rescue medications taken to manage breakthrough symptoms of SSc-RP (including acetaminophen, NSAIDs, other codeine-based medicines, fluoxetine, ARBs such as losartan, CCBs) as well as other concomitant medications was also captured and assessed during screening.

Randomization Day (Day 0)

Participants were scheduled to visit the clinic for randomization (Day 0) assessments between days 7 to 10 of the screening period. Only participants who seemed eligible based on Diary compliance and frequency of RP attacks were requested to visit clinic for randomization. During the visit the participant were provided with another copy of the ICF. Prior to being asked to sign the consent form, participants were given time to review study information and ask any questions.

After the consent form is signed and the following assessments was carried out:

- Medical history/demographics
- Previous/concomitant medications
- Vital signs
- Physician's Assessment of Disease (including RP, scleroderma, ulcers, ocular symptoms, overall health)
- Pregnancy test
- Review of daily participant dairy
- SHAQ which includes Raynaud's VAS to be completed by the participant with review by physician designee
- Assessment of gastrointestinal symptoms (of sclerosis) using the UCLA SCTC GIT 2.0 questionnaire, to be completed by the participant with review by physician designee
- Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) questionnaire to be completed by the participant with review by physician designee (Part B)
- Digital ulcer assessment
- Thermography
- Endo-PAT
- Blood sample for PK
- Inclusion/Exclusion
- Randomization
- AE/SAE reporting
- Dispensing study medication

Note: The data collected for assessments that are performed first time on randomization (Day 0) visit (vital signs, digital ulcer assessment, and Endo-PAT) served as baseline measure for efficacy endpoints for those assessments.

Routine hospital tests including hematology, biochemistry, inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), antibody status (serum anti-topoisomerase [anti-Scl 70]) and nailfold capillaroscopy should have been conducted as clinically indicated per standard of care but are not required per protocol. If conducted, results were collected in the eCRF and used to describe the severity of disease in the baseline demographic and disease data.

Dosing Periods
Daily at Home Dosing (12 Days (+2 Days))

During the dosing period, participants were required to self-administer the assigned study medication once daily in the morning at home. Participants were also required to complete their Diary daily to capture the clinical features and symptoms of their SSc-RP, and report concomitant medications including rescue therapy (if any).

In-Clinic Visit (Last Day of the Dosing Period)

Participants were required to visit the clinic following each dosing period—dosing day 10 to Day 14. The day of the in-clinic visit was considered the last day of dosing in each dosing period. After taking their last dose of study medication in the morning at home, the following assessments/procedures took place during the in-clinic visit by the physician or designee, with results recorded in the eCRF:

- Vital signs
- Blood sample for PK
- Daily participant E-dairy review for the most recent dosing sequence
- Scleroderma Health Assessment Questionnaire (SHAQ) which includes Raynaud's VAS to be completed by the participant with review by physician designee
- Assessment of gastrointestinal symptoms (of sclerosis) using the UCLA SCTC GIT 2.0 questionnaire, to be completed by the participant with review by physician designee
- Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) questionnaire, to be completed by the participant with review by physician designee (Part B)
- Physician's Assessment of Disease (including RP, scleroderma, ulcers, ocular symptoms, overall health)
- Concomitant medications
- Thermography (for two most symptomatic areas in terms of Raynaud's)
- Endothelial dysfunction (Endo-PAT)
- AE/SAE reporting
- Dispensing/returning study medication

Note: On the last clinic visit at the end of last dosing period (dosing period 1 for Part A and dosing period 2 for Part B), pregnancy test was performed for WOCBP.

Washout Period

In Part B, each dosing period was separated by a 4-day (±1 day) washout period. The washout period commenced the day after the in-clinic visit during which participants did not take any study medication. During the washout period, participants were required to complete the daily participant Diary, reporting their symptoms of SSc-RP, and use of any concomitant medications. Once the 4-day washout was completed the participant commenced the daily at home dosing for the study medication dispensed at the previous in-clinic visit. No washout period was required after the second and final in-clinic visit. After this visit participants will proceed directly to follow-up.

Follow-up

All Participants were followed for 7 days following completion of the final dosing period for their symptoms of SSc-RP, during which time they were requested to continue to complete their patient Diary. Participants will also be requested to report use of any concomitant medications and any AEs/SAEs during the Follow-up period. Participants in Part B were followed for AEs/SAEs until 28 days following the last dose of study medication. Follow-up of AEs/SAEs ceased at 7 days for participants in Part A. This visit marks the end of participation in this study.

Early Termination (If Applicable)

Participants who withdrew early from the study were encouraged to return to the clinic for an EOS assessment. The following procedures were conducted:

- Participants were requested to complete the Diary for 7 days following termination
- Participants were requested to report use of concomitant medications of interest for 7 days following termination
- Participants were requested to report any AEs/SAEs for 7 (Part A) to 28 (Part B) days following termination. This visit marks the end of participation for participants that withdraw early from the study.

Pharmacokinetic Assessments
Blood Sample Collection

When possible, one 4 mL blood sample was obtained during each in-clinic visit within 2 to 6 hours of last dose of study drug in that dosing period as delineated in the SoA (FIG. 2 and FIGS. 4A and 4B). The level of cilnidipine in blood was measured following last dose of the dosing period. Sample handling details was provided in the PK manual. The actual collection time of each sample must be recorded in the source data documentation, on the collection tube and in the eCRF.

Efficacy Assessments
Efficacy Parameters

Study procedures should have been completed as delineated in the SoAs (FIG. 2 and FIGS. 4A and 4B).

Diary

The Sponsor-developed participant-informed Diary was used in this study to record data. Participant was required to keep and fill the Diary daily as delineated in the SoAs (FIG. 2 and FIGS. 4A and 4B).

The relevant metrics measured by this tool daily are:

- Study medication
- SSc-RP symptoms (Reporting an attack including duration of attack)
- Severity of the attack considering all symptoms of the attack e.g., tingling, numbness, pain, color changes (VAS 0-10 cm scale)
- Participant's location at the time of the attack (inside home/outside home)
- Selecting symptoms experienced during the attack (tingling, numbness, pain, color changes, other)
- Pain rating during the attack (11-point Likert scale)
- The RCS based on how much difficulty participants had with Raynaud's today, how many attacks the participant had, and how long they lasted. Participants will also be asked to consider how much pain, numbness, or other symptoms the Raynaud's caused in fingers (including painful sores), and how much the Raynaud's alone affected the use of hands today (VAS 0-10 cm scale).
  
  Metrics Measured at the In-Clinic Visit (Once in a Dosing Period) were:
- Digital ulcer severity (VAS 0-10 cm scale)—Applicable only if participant had digital ulcers.
- Scleroderma Health Assessment Questionnaire which includes Raynaud's VAS measuring participant quality of life over the past 7 days
- UCLA SCTC GIT 2.0 questionnaire, assessing gastrointestinal symptoms (of sclerosis) over the past 7 days.
- Assessment of Systemic sclerosis-associated Raynaud's Phenomenon (ASRAP) questionnaire, measuring participant experience with Raynaud's symptoms over the past 7 days.

Note: Digital ulcer severity (VAS 0-10 cm scale), SHAQ, UCLA SCTC GIT 2.0 and ASRAP questionnaire was done on paper in-clinic. External temperature was a fed into the Diary database based on participant's location.

Physician Assessment of Disease

The Physician will assess the below at each in-clinic visit, details of which were recorded in the eCRF.

- Rating severity of participant's Raynaud's disease
- Rating severity of participant's scleroderma symptoms
- Rating severity of participant's ulcers how many ulcers, how many considered new, for each ulcer: location and diameter of the ulcer
- Rating overall health of participant for past week
- Any ocular symptoms, and the nature of these symptoms as ocular manifestations are common in patients with SSc (Kozikowska 2020), and range in incidence and prevalence from over 80% having symptoms of dry eye disease, and >75% having eyelid symptoms and conjunctival symptoms in >70% of patients.
- Patient symptoms were recorded in severity with the patient asked to rate any ocular symptoms or discomfort or pain on a 0-10 scale and the physician will record these answers in the eCRF. AE/SAE reporting.

Drug accountability, including dispensing and returning of the study medication was also be recorded at each visit.

Scleroderma Health Assessment Questionnaire (SHAQ)

The standard, validated, patient reported outcome measures tool for SSc patients, the SHAQ, was collected at the time points specified in the study schedules (FIG. 2 and FIGS. 4A and 4B) to assess the participant's quality of life. The SHAQ included a Raynaud's VAS that will also be reported separately.

UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0)

The standard, validated, patient reported outcome measures tool for SSc patients, the UCLA SCTC GIT 2.0 was collected at the time points specified in the study schedules (FIG. 2 and FIGS. 4A and 4B) to assess gastrointestinal symptoms (of sclerosis).

Assessment of Systemic Sclerosis-associated Raynaud's Phenomenon (ASRAP) A novel patient-reported outcome (PRO) questionnaire was completed by the participant at the time points specified in the Part B study schedule FIGS. 4A and 4B), to assess the severity and impact on daily life of RP in SSc.

Thermography

Thermography assessments were performed at the time points specified in the study schedules (FIG. 2 and FIGS. 4A and 4B). Thermography was conducted on the most severely impacted digits identified at screening; the participant must be indoors for at least 30 minutes prior to the test to give the body time to equilibrate. Photos were taken with the help of Fluor thermographic camera of these two areas at times specified in SoAs.

Endothelial Dysfunction (Endo-PAT)

Assessments for endothelial dysfunction were performed using Endo-PAT at timepoints specified in the study schedules (FIG. 2 and FIGS. 4A and 4B). The Endo-PAT is a diagnostic device used to assess endothelial vasodilator function in a rapid and non-invasive fashion. The below points were considered before assessment is started:

- 1. Prior to the study, the participant should fast for at least 4 hours, and should refrain from caffeine, vitamins or medications that might affect vascular tone for at least 8 hours. The participant must reconfirm their abstinence from tobacco and may use the restroom prior to the assessment.
- 2. The Endo-PAT assessment should be conducted in a quiet, dimly lit, temperature-controlled (25° C. for at least 30 minutes) exam room to reduce fluctuations in vascular tone.
- 3. Cell phones or paging devices should be silenced, and restrictive clothing that could interfere with blood flow to the arms should be removed. The participant should also remove watches, rings, or other jewelry on the hands or fingers.
- 4. Participant's fingers should be inspected for any deformities or injuries that could affect the study. The probes should not be placed on a finger that is cut or injured. Fingernails should not extend more than 5 mm or ⅕ of an inch beyond the tip of the finger tissue.
- 5. The index finger is recommended for the study; however, if this finger is unsuitable, a different digit (except the thumb) may be used, as long as the same finger is used on both hands.
- 6. The participant should be supine and comfortable for 15 minutes so as to attain a cardiovascular steady state.

Safety Assessments
Safety Parameters

Study procedures should have been completed as delineated in the SoA (FIG. 2 and FIGS. 4A and 4B). Any unscheduled procedures required for urgent evaluation of safety concerns took precedence over all routine scheduled procedures.

Demographic/Medical History

Medical history (including alcohol and smoking status), date of birth, age (calculated), weight, sex, ethnicity, and race was recorded at randomization (Day 0) visit.

Vital Signs

Vital signs (SBP, DBP, pulse rate, temperature) were measured at the time points specified in the SoA (FIG. 2 and FIGS. 4A and 4B) with participants resting for at least 5 minutes in a supine position. When the time of vital signs measurement coincides with a blood draw, the vital signs were taken before the scheduled blood draw where possible, ensuring the blood draw is within the window specified in the protocol. Additional vital signs may be performed at other times if deemed necessary.

Laboratory Assessments

Routine hospital laboratory tests including hematology, biochemistry, inflammatory markers (CRP and ESR), and antibody status (Scl-70) should have been conducted as clinically indicated per standard of care but are not required per protocol. If conducted, results were collected in the eCRF and used to describe the severity of disease in the baseline demographic and disease data. Additional clinical laboratory tests could have been performed at other times when deemed necessary, based on the participant's clinical condition.

Pregnancy Testing

A urine pregnancy test was performed at the randomization (Day 0) visit and on the last clinic visit at the end of last dosing period for WOCBP only.

Adverse and Serious Adverse Events

In this study, AEs and SAEs were reported for all participants from the time of randomization until the completion of the Follow-up/EOS visit. Adverse events that were ongoing at the EOS visit were marked as Not Recovered/Not resolved on the AE eCRF page (see Section 9.4.4). The Investigator did full AE review during in-clinic visit. All spontaneously volunteered and enquired for, as well as observed AEs, were recorded in the participant's medical records and the eCRF.

Complications of the Disease Under Study

Clinical features and symptoms of SSc-RP were recorded as endpoints in the electronic data collection tools provided by the Sponsor, as well as in the source documents and should not be reported as AEs.

Definition of Adverse Events

Events Meeting the Definition of an AE Include:

- Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition
- New conditions detected or diagnosed after study drug administration that occur during the reporting periods, even though it may have been present prior to the start of the study
- Signs, symptoms, or the clinical sequelae of a suspected interaction
- Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or concomitant medications (overdose per se will not be reported as an AE/SAE).
  
  Events that do not Meet the Definition of an AE Include:
- Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure should be reported as an AE if it meets the criteria of an AE
- Situations where an untoward medical occurrence did not occur (e.g., social and/or convenience admission to a hospital)
- Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

If there is evidence of an AE through report or observation, the Investigator or designee evaluated further and recorded the following information:

- Time of onset and resolution
- Severity
- Seriousness
- Causality/relation to study treatment
- Action taken regarding study drug
- Action taken regarding AE
- Outcome.

Severity of an Adverse Event

Severity of AEs were graded by the Investigator as one of:

- Mild (Grade 1): A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living.
- Moderate (Grade 2): A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant.
- Severe (Grade 3): A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention.
- Life-threatening (Grade 4): A type of AE that places the participant at immediate risk of death.
- Death (Grade 5): Events that result in death.

Causal Relationship of an Adverse Event

The Investigator assessed the relationship between study drug and the occurrence of each AE. The Investigator's assessment of the relationship of each AE to study drug was recorded in the source documents and the eCRF. Alternative causes, such as medical history, concomitant therapy, other risk factors, and the temporal relationship of the event to the study drug were considered and investigated, when appropriate. The following definitions are general guidelines to help assign grade of attribution:

- Not related: The event is clearly related to other factors such as the participant's environment or clinical state, therapeutic interventions or concomitant drugs administered to the participant. This is especially so when an event occurs prior to the commencement of treatment with the study drug.
- Unlikely: The temporal association, participant history, and/or circumstances are such that the study drug is not likely to have had an association with the observed event. Other conditions, including concurrent illness, progression, or expression of the disease state, or reaction to a concomitant drug administered appear to explain the event.
- Possible: The event follows a reasonable temporal sequence from the time of study drug administration or follows a known response to the study drug but could have been produced by other factors such as the participant's clinical state, other therapeutic interventions, or concomitant drugs administered to the participant.
- Probable: The event follows a reasonable temporal sequence from the time of study drug administration and follows a known response to the study drug and cannot be reasonably explained by other factors such as the participant's clinical state, other therapeutic interventions, or concomitant drugs administered to the participant.
- Definite: The event follows a reasonable temporal sequence from the time of study drug administration or control abates upon discontinuation or cannot be explained by known characteristics of the participant's clinical state.
  
  Action Taken with Investigational Products

Should the Investigator need to alter the administration of the study drug from the procedure described in the protocol due to the wellbeing and safety of the participant then the action taken was recorded on the AE eCRF page, as one of the following options:

- Dose Reduced
- Drug Interrupted
- Drug Withdrawn
- Not Applicable
- Other.

Outcome

Outcome of an AE was recorded on the AE eCRF as follows:

- Recovered/Resolved
- Recovering/Resolving
- Recovered/Resolved with Sequelae
- Not Recovered/Not Resolving
- Fatal
- Unknown.

Definition of Serious Adverse Event

An SAE is an AE occurring during any study phase (i.e. baseline, treatment, washout, or follow-up), and at any dose of the study drug (active or placebo), that fulfilled one or more of the following:

- Resulted in death
- Was immediately life-threatening
- Required in participant hospitalization or prolongation of existing hospitalization
- Resulted in persistent or significant disability or incapacity
- Resulted in a congenital abnormality or birth defect.
- Is an important medical event that jeopardized the participant or required medical intervention to prevent one of the outcomes listed above.

Important medical events that may not be one of the above were considered an SAE by the Investigator when, based upon appropriate medical judgment, they were considered clinically significant and jeopardized the participant, or required medical or surgical intervention to prevent one of the outcomes listed above.

An AE was considered “life-threatening” if, in the opinion of either the Investigator or the Sponsor, its occurrence placed the participant at immediate risk of death. It did not include an AE that, had it occurred in a more severe form, might have caused death.

Notification of a Serious Adverse Event

All SAEs, regardless of relationship to the study drug, during the period starting from the time of randomization through to the EOS were recorded in the eCRF. The Investigator did full SAE review during in-clinic visit. All SAEs were recorded in the participant's medical records and the eCRF.

Once the Investigator became aware of an SAE, they reported it to the SAE to Sponsor within 24 hours of knowledge of the event.

If requested, supporting de-identified source documents (e.g., hospital discharge summary, autopsy report when available, results of relevant diagnostic tests completed to evaluate the event) were also sent to the Sponsor.

A written SAE report included a full description of the event including the below parameters:

- Diagnosis or description of event
- Onset date
- Severity assessment
- Causal relationship to the IP
- Assessment of seriousness of the event
- Corrective treatment administered for the SAE
- Action taken related to study drug include the following: dose interruption, dose delay, dose reduction or study drug discontinuation
- Outcome of event and end date.

The Sponsor was responsible for notifying the relevant regulatory authorities of certain events. It was the Investigator's responsibility to notify the HREC of all SAEs in accordance with the HREC SAE reporting policy. The Investigator was also notified of all unexpected, serious, drug-related events that occur during the clinical study. The investigational site was responsible for notifying its HREC of these additional SAEs. Note: Disease progression was not considered a reportable event.

Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events and Serious Adverse Events

Abnormal laboratory findings or other abnormal assessments (e.g., vital signs) per se were not reported as AEs. However, those abnormal findings that are deemed clinically significant by the Investigator(s) and/or delegate or are associated with signs and/or symptoms were recorded as AEs if they met the definition of an AE (and recorded as an SAE if they meet the criteria of being serious) as previously described. Clinically significant abnormal laboratory or other abnormal findings that were detected after randomization or that were present at baseline and worsened after randomization are included as AEs (and SAEs if serious).

The Investigator(s) exercised medical and scientific judgment in deciding whether an abnormal laboratory finding, or other abnormal assessment was clinically significant. To be considered clinically significant, the abnormality needed to be associated with a clinically evident sign or symptom or be likely to result in an evident sign or symptom in the near term. A clinically significant laboratory abnormality in the absence of clinical symptoms may jeopardize the participant and may require intervention to prevent immediate consequences. For example, a markedly low serum glucose concentration may not be accompanied by coma or convulsions yet be of a magnitude to require glucose administration to prevent such sequelae.

Recording Adverse Events

Adverse events spontaneously reported by the participant and/or in response to an open question from the study personnel or revealed by observation were recorded in accordance with the Investigator's normal clinical practice and on the AE page of the eCRF during the study at the investigational site.

However, abnormal values that constitute an SAE or lead to discontinuation of administration of study drug must have been reported and recorded as an AE. The AE term must have been reported in standard medical terminology when possible. For each AE, the Investigator evaluated and reported the onset (date and time), resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused the participant to discontinue the study. AEs that occurred during the study must have been documented in the participant's medical record, on the AE eCRF and on the SAE report form. If an SAE report is completed, pertinent laboratory data should have been recorded on the SAE form, preferably with baseline values and copies of laboratory reports.

In addition, if the abnormal assessment meets the criteria for being serious, the SAE form must also have been completed. A diagnosis, if known, or clinical signs or symptoms if the diagnosis is unknown, rather than the clinically significant laboratory finding or abnormal assessment, should have been used to complete the AE/SAE page. If no diagnosis was known and clinical signs or symptoms were not present, then the abnormal finding should have been recorded.

Follow-up of Adverse Events and Serious Adverse Events

All AEs and SAEs were followed for the duration of the study. The Investigator was responsible for ensuring that follow-up includes any supplemental investigations as may be indicated to elucidate as completely as practical the nature and/or causality of the AE/SAE. This may include additional laboratory tests or investigations or consultation with other health care professionals.

The Sponsor may have requested that the Investigator perform or arrange for the conduct of supplemental measurements and/or evaluations. If a participant died during participation in the study or during a recognized Follow-up period, the Sponsor was provided with a copy of any post-mortem findings, including histopathology.

Pregnancy

Pregnancy testing was performed in all WOCBP as per the SoA and the pregnancy results should be captured in the eCRF. All WOCBP were instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during the study. Male participants contacted the Investigator immediately if they suspected they may have fathered a child during the study treatment period. When possible, the partner's pregnancies were followed (to term) to determine the outcome.

If a participant became pregnant during the clinical study, the Investigator reported the details on a pregnancy form to the Sponsor/assigned designee within 24 hours of knowledge of the pregnancy. Even though participants agreed to withdraw or terminate the clinical trial, the Investigator should have followed-up and documented the process and results of all the pregnancies.

If a male participant's female partner became pregnant while enrolled in the study, a pregnancy form should be completed. Abortions (spontaneous, accidental, or therapeutic) must also be reported to the Sponsor. Congenital anomalies/birth defects always meet SAE criteria, and should therefore, have been expeditiously reported as an SAE, using the previously described process for SAE reporting. A pregnancy form should also have been previously completed and will need to be updated to reflect the outcome of the pregnancy. The Investigator must have reported any pregnancy (including pregnancy of a male participant's partner), even if no AE has occurred, on a Pregnancy Report Form within 24 hours of the Investigator becoming aware of the pregnancy.

Study Drug Materials And Management
Study Drug Packaging and Labeling

The Sponsor is responsible for the preparation and labeling and providing details of batch numbers, safety, and stability data. The study drug was labeled in accordance with local regulatory requirements was shipped at a temperature below 25° C. within a dry place.

Study Drug Storage

Upon receipt, the study drug was stored at controlled room temperature (15° C. to 25° C.) in a tightly closed container. The drug was protected from excess heat and light and kept out of reach of children. The Investigator or designee was fully responsible for the security, accessibility, and storage of the study drug while it was at the investigational facility.

Administration

The Investigator or designee was responsible for the education of study staff and participants as to the correct administration of the study drug.

Study Drug Accountability

A record was maintained by the investigational site that will account for all dispensing and return of any used and unused study drug. At the end of the study, the study drug was reconciled, and a copy of the record given to the study monitor.

Study Drug Handling and Disposal

On completion of the study, any surplus study drug supplies were destroyed upon receipt of written approval from the Sponsor. Evidence of the destruction of any surplus study drug were supplied to the study monitor. If no supplies remain, this was documented in the dispensing record.

Statistics

Statistical methods were further outlined in the statistical analysis plan (SAP) and approved by the Sponsor. Procedures outlined in the SAP will supersede protocol specified statistical methods in the event of divergence.

Part A and Part B data was analyzed separately. Analysis of Part A data were mainly exploratory to support cilnidipine dose selection and treatment effect check for sample size confirmation for Part B. For Part B, the primary and secondary efficacy analyses were based on the mITT population. Analyses based on the ITT and PP population were considered secondary and confirmatory. All safety analyses were performed on the safety population.

In general, descriptive statistics (e.g., arithmetic mean, SD, median, minimum and maximum) were calculated for continuous safety data by treatment and protocol specified time point, while frequency summary (e.g., number of observed and percentage of each categories) were applied for categorical safety data by treatment and protocol specified time point.

Sample Size

Assuming a 2-sided 0.05 alpha for treatment (cilnidipine or combination therapy or tadalafil) versus placebo and without controlling alpha for the multiple efficacy comparisons, a sample size of eight participants in each paired comparison group (cilnidipine or combination therapy or tadalafil) was needed for 80% power in a 4×4 crossover design to detect a 25% difference at common SD of 0.5 (a moderate effect size) in percent change from baseline of Raynaud's attack per week. Assuming a 20% dropout rate for final efficacy analysis, ten participants in each group was planned. After reviewing the results from Part A: Run-in phase, the sample size for Part B may be adjusted.

Following from the decision of the committee to exclude tadalafil from Part B of the study, the design was changed to a two-treatments, two-periods (2×2) crossover. The sample size for Part B was calculated based on the available data from Part A at the time of the protocol specified data review. Assuming a 2-sided 0.05 alpha for the comparison of cilnidipine 20 mg versus placebo, a between-participants standard deviation (SD) of 35, a correlation between the two measurements on the same participant of 0.2, and a 25% dropout rate, it was estimated that a total sample size of 38 participants (19 in each treatment sequence) was needed, in order to obtain complete data from 28 participants (14 in each treatment sequence), for ≥80% power to detect a decrease of 25 in percentage change from baseline in weekly RP attacks in a 2×2 crossover design.

Analysis Populations

Participant inclusion into each population was determined prior to the final analysis.

Intent-To-Treat (ITT) Population

All participants who were entered into the study and completed screening, signed an informed consent for the study and randomized was included in the ITT population.

Modified Intent-To-Treat (mITT) Population

All participants who were entered into the study and complete screening, signed an informed consent for the study and randomized and have post-baseline attack data (primary endpoint data) was included in the mITT population.

Per Protocol Population

All participants who completed the study with all dosing periods (for Part B—at least 5 days of dosing within the last 7 days treatment) and met all eligibility criteria, and without any major/important protocol deviations, was included in the PP Analysis Population.

Pharmacokinetic Population

All participants who received any amount of active study drug and had sufficiently evaluable concentration time profile to allow determination of at least one PK parameter was included in the PK population. An evaluable PK profile was determined at the discretion of the pharmacokineticist following examination of participants with dosing or protocol deviations that could potentially affect the PK profile. The PK population was used for the summaries of all PK data.

Safety Population

All randomized participants who received study drug were included in Safety population and were classified according to the actual treatment received.

Statistical Methods
Participant Disposition

Participant disposition was analyzed using counts and percentages. The number and percentage of screened participants, enrolled participants, treated participants, participants discontinued from the study and study treatment, as well as the primary reason for discontinuation was analyzed and listed.

Demographics, Medical History, and Baseline Characteristics

Demography and baseline characteristics data was summarized using descriptive statistics. The following demographic variables were summarized by dose level: race, gender, age, height and weight, concomitant diseases (Hypertension, peripheral vascular disease, diabetes, CKD and stage, osteoporosis, history and type of heart arrhythmia). In addition, the following baseline characteristics of Raynauds Disease were summarized: age of onset, seasonality (months disease is worst), usual number of attacks/day, usual peak severity, baseline RCS assessment, how attacks are usually treated, how long attacks last in general, experience with other treatments both pharmacological and non-pharmacological.

Prior and Concomitant Medication

Prior and concomitant medications were coded using the most current version of the WHO drug dictionary available at the start of the study. Prior and concomitant medications were listed by participant and summarized by treatment using anatomical therapeutic chemical (ATC) and preferred name.

Treatment Compliance and Exposure

Treatment compliance and exposure were summarized and listed by treatment for all participants in the Safety population.

Analysis of Primary Endpoint

Percent change from baseline evaluation for frequency of weekly RP attacks were the primary efficacy endpoint. Data collected in the last 7 days of each dosing period were used for this analysis. Screening assessments were used as baseline for the analysis of all periods. No multiple comparison adjustment were used to control alpha for the multiple comparisons. Mixed effects model were used for analysis of the primary endpoint according to the crossover design. Other efficacy endpoints of continuous variables were analyzed using similar methodology. For nominal data, chi-square tests were applied. Generalized Estimating Equations method were used, as appropriate, for adjusting for potential confounding factors. In addition, the final analysis assessed whether in this study of severe Raynaud's disease participants, the minimally important difference, previously concluded of 14-15 points on the 100 point RCS scale had been achieved in the cilnidipine dose group. It also recorded the percentage of participants achieving a PASS (34 point difference from baseline on a 0-100 VAS) in each treatment group.

Analysis of Secondary Endpoints

The secondary endpoints of change from baseline evaluation were compared among treatment groups using mixed effects model. Kaplan-Meier method was used to evaluate time to event endpoints. To evaluate the impact of daily ambient temperature on symptomatic Raynaud's attack, logistic regression were used for temperature versus the occurrence of Raynaud's attack (Yes/No).

The effect of temperature on the severity score of Raynaud's attacks and difference of using rescue medication between treatment groups was evaluated by Chi-square test. The impact of therapy in sympathetic activity was assessed by mixed model for repeated measures.

Safety Analyses

All safety assessments, including AEs, laboratory evaluations, vital signs, and other safety assessments were analyzed using the Safety population.

Adverse Event

Adverse events were coded using the most current version of the MedDRA® Version 22.0 or higher. The analysis of AEs was based on the concept of treatment emergent AEs. Treatment emergent AEs were tabulated by treatment group and included the number of participants for whom the event occurred, the severity, and relationship to study drug. Treatment emergent AEs (TEAEs) leading to discontinuation and SAEs with onset after the start of study drug were also summarized. All AEs and SAEs (including those with onset or worsening before the start of study drug) through the end of the study were listed.

Laboratory Evaluations

Baseline laboratory evaluations were listed and summarized by treatment.

Vital Signs

Vital signs (BP [systolic and diastolic], pulse rate, and oral temperature) were listed and summarized by treatment and protocol specified collection time point. Observed and change from baseline were summarized at each protocol specified collection time point.

Other Safety Assessments

The following assessments were listed by participant:

- Pregnancy Test
- Raynaud's function assessment by physician.

Pharmacokinetics

Plasma concentrations and actual blood sampling times were listed by treatment and protocol specified time point and summarized using descriptive statistics number of measurements, arithmetic mean, SD, and % CV, geometric mean, minimum, median, and maximum—at each scheduled time point. Individual and mean plasma concentration-time profiles will also be presented graphically for each treatment.

Pharmacokinetic parameters were computed from the individual plasma concentrations using a non-compartmental approach.

Values for elimination rate constant (kel), elimination half-life (t^1/2), Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), apparent total clearance of the drug from plasma after oral administration (CL/F) or apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F) were not reported. Additional analyses were performed as deemed necessary upon review of the data.

Ethics
Ethics Review

The final study protocol, including the final version of the ICF, must be approved or given a favorable opinion in writing by an HREC as appropriate. The Investigator must submit written approval to the Sponsor before they can enroll any participant into the study.

The Principal Investigator (PI) was responsible for informing the HREC of any amendment to the protocol in accordance with local requirements. In addition, the HREC must approve all advertising used to recruit participants for the study. The protocol must be re-approved by the HREC upon receipt of amendments and annually, as local regulations require.

The PI was also responsible for providing the HREC with reports of any reportable serious adverse drug reactions from any other study conducted with the study drug (active). The Sponsor provided this information to the PI. Progress reports and notifications of serious adverse drug reactions were provided to the HREC according to local regulations and guidelines.

Ethical Conduct of the Study

The study were performed in accordance with ethical principles that have their origin in the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects) and are consistent with ICH GCP applicable regulatory requirements.

Written Informed Consent

Informed consent was conducted in a two-step process. A phone call was placed to all potential participants to explain the study and assess patient interest and initial eligibility. A copy of the ICF was emailed to the participant in conjunction with this initial discussion. If the participant seemed eligible and was interested in participating in the Screening period, then they were asked to start using a Diary to record the daily clinical features and symptoms of their SSc-RP for the next 7 to 10 days. Use of the Diary was considered implied consent for the Screening period, the data from which was used to confirm eligibility and conduct baseline analyses assuming the participant was randomized.

The participants full written informed consent was obtained before randomization, once the Screening period was completed and eligibility confirmed.

The PI ensured that the participant was given full and adequate oral and written information about the nature, purpose, possible risk, and benefit of the study. Participants were notified that they are free to discontinue from the study at any time without prejudice. The participant was given the opportunity to ask questions and allowed time to consider the information provided before voluntarily providing informed consent.

The participants were informed of their rights to privacy but were made aware that the study data as submitted to the Sponsor and possibly to drug regulatory authorities for review and evaluation. They were informed also that the study monitor may inspect their medical records to verify the accuracy and completeness of the study records and results. The acquisition of informed consent was documented in the participant's medical records, as required, and the ICF was signed and personally dated by the participant and by the person who conducted the informed consent discussion.

The Investigator(s) maintained the original, signed ICF. A copy of the signed ICF was given to the participant or legal representative. The date that informed consent was signed was recorded on the eCRF.

Data Protection

The Diary (completed by the participant) and the eCRF (completed by the site) was used to collect all patient data assessments that were used for evaluation of specified analyses. Each user had a username and password to control access to each system. All information generated in this study was considered highly confidential and was not disclosed to any persons not directly concerned with the study without written prior permission from the Sponsor. However, authorized regulatory officials and Sponsor personnel were allowed full access to the records. Only initials and unique patient numbers in eCRFs identified patients. Their full names may, however, were made known to a product regulatory agency or other authorized official if necessary.

Participants were informed that data will be held on file by the Sponsor and that these data may be viewed by staff including the study monitor and by external auditors on behalf of the Sponsor and appropriate regulatory authorities. Participants were also informed that a study report was prepared and may be submitted to regulatory authorities and for publication. However, participants were identified in such reports only by study identification number, gender, and age. All participant data was held in strict confidence.

Results: Patients in the study were administered the Scleroderma Health Assessment Questionnaire (SHAQ) at the time of study entry and during clinic visits following the treatment period. The study is a two-part, parallel arm design, prospective, double-blind, randomized study conducted in Australia (Flinders Medical Center). 27 patients were randomized into the first phase of the study, following which a DSMB meeting was held, which reviewed data on the primary study endpoint and key Raynaud's secondary endpoints. Data on the SHAQ was not available for the DSMB to review. The mITT population, in which any data was available post treatment was 24 patients was the analysis population for this first part of the study. The second part (i.e., part B) of the study will randomize 36 patients in a double blind, randomized, prospective, placebo controlled, crossover study. In the first part (i.e., Part A) of the study for which data is presented, patients were randomized into 6 groups, cilnidipine at two doses (10 and 20 mg) alone and in combination with tadalafil 5 mg, tadalafil 5 mg alone, and placebo. The DSMB found both doses of cilnidipine to be effective at reducing Raynaud's endpoints and increased effect with 20 mg compared to 10 mg of cilnidipine. The DSMB recommended that the study proceed into its double blind prospective cross overpowered second phase and compare cilnidipine 20 mg alone to placebo. Data from the SHAQ analysis suggests the following and is first presented in summary format and then data tables are provided.

- a. Cilnidipine treatment may reduce patient-reported SSc disease disability compared to placebo
- b. Cilnidipine treatment may reduce patient-reported SSc disease alternative disability compared to placebo
- c. Cilnidipine treatment may reduce patient-reported SSc disease pain*compared to placebo
- d. Cilnidipine treatment may reduce patient-reported SSc disease severity compared to placebo
- e. Cilnidipine treatment may reduce patient-reported SSc disease skin ulcer severity rating compared to placebo
- f. Cilnidipine treatment may reduce patient-reported SSc disease breathing difficulty compared to placebo
- g. Cilnidipine treatment, in combination with tadalafil (a known—P glycoprotein P inhibitor that increases brain passage and central concentrations of cilnidipine (cilnidipine when given orally is 98% protein bound, largely by PGP)) may further reduce patient-reported SSc disease pain compared to placebo. SSc disease pain comprises not only pain from Raynaud's but joint pain, headache, odynophagia, back pain, pain from skin ulceration, and neuropathic pain).

TABLE E

Table E includes results of the Scleroderma

Health Assessment Questionnaire.

Pooled Cilnidipine
Placebo

Statistics
(N = 7)
(N = 4)

Baseline

n
7
4

Mean (SD)
2.700
(2.3424)
2.000
(1.7963)

Median
2.900
1.300

Q1, Q3
0.400,
3.400
0.800,
3.200

Min, Max
0.00,
7.10
0.80,
4.60

In-Clinic Visit (Day 12)

n
7
4

Mean (SD)
1.486
(1.7743)
2.700
(1.9511)

Median
1.200
2.950

Q1, Q3
0.200,
1.900
1.400,
4.000

Min, Max
0.00,
5.20
0.10,
4.80

Change from Baseline

n
7
4

Mean (SD)
−1.214
(0.7946)
0.700
(1.3089)

Median
−1.500
0.550

Q1, Q3
−1.800,
−0.400
−0.250,
1.650

Min, Max
−1.90,
0.20
−0.70,
2.40

Percent Change from Baseline

n
6
4

Mean (SD)
−59.80
(25.642)
66.71
(165.704)

Median
−55.86
27.17

Q1, Q3
−76.19,
−44.12
−41.58,
175.00

Min, Max
−100.0,
−26.8
−87.5,
300.0

Table E shows that in the pooled cilnidipine patients who received either 10 mg or 20 mg of cilnidipine (n=7), there was a mean 6000 decrease in patient reported disease severity on the SHAQ, versus an increase in severity in 4 placebo treated patients.

Table F shows a summary table comparing 20 mg of cilnidipine to placebo treated patients on the SHAQ parameters in the mITT population. Table F shows substantial benefits in the SHAQ for 20 mg treated and pooled cilnidipine patients versus placebo patients on most of the parameters measured.

TABLE F

Pooled
Cilnidipine

Cilnidipine
20 mg
Placebo

PARAMETER
(n = 7)
(n = 3)
(n = 4)

% change in
−31%
−53%
+7%

Pain

% change in
−25%
−50%
−16%

Standard

Disability Index

% change in
−13%
−42%
−13%

Alternative

Disability Index

% improvement
41% (median)
67% (median)
−7% (worsening)

in Breathing

% improvement
19%
35%
−4% (worsening)

in VAS Digital

Ulcers

% change VAS
−17%
−49%
−42%

Raynauds

% change
−60% (i.e.,
−63% (i.e.,
67% (i.e.,

overall SSc
improvement)
improvement)
worsening)

Disease Severity

Pain on the SHAQ outcome measure on the first line in table F is a composite of all pain experienced in patients with SSc, comprising joint pain, back pain, headache, odynophagia, skin ulcer related discomfort, Raynaud's, and neuropathic pain. Aisa Pharma believes, based on the biologic attributes and actions of cilnidipine that differ from most dihydropyridine calcium channel antagonists that cilnidipine might have direct analgesic effects in certain pain conditions and in fact has been designated to receive evaluation through the NPH-NINDS Preclinical Pain Screening Platform Program to investigate the drug in multiple in vitro and in vivo preclinical models of pain that are validated and predictive of effects in man.

Analysis of data that may support an increased analgesic effect of cilnidipine on Raynaud's pain, when given in combination with tadalafil, which increases brain concentrations of cilnidipine by competitively inhibiting the protein (p-glycoprotein p) which is largely responsible for 9800 protein binding of cilnidipine in plasma when the drug is given orally, inhibiting transmission across the blood-brain barrier. Given the small numbers of patients in the first part of the study, baseline pain differences vary amongst the groups, but a trend towards an increased reduction of Raynaud's VAS pain is seen in both the 10 mg cilnidipine (*) and 20 mg cilnidipine (†) groups.

Table G shows data that supports an increased analgesic effect of cilnidipine on Raynaud's pain.

Percent Change

Baseline

from Baseline

Average
Average
Change From
(red = reduction,

Group
Pain Score
Pain Score
Baseline
black = increase)

(N = 24)
[Mean (SD)]
[Mean (SD)]
[Mean (SD)]
[Mean (SD)]

Cilnidipine
1.76
(0.885)
1.28
(1.993)
−0.47
(2.025)
−26.89
(89.725)*

20 mg, mean

(SD) (n = 3)

Cilnidipine
2.35
(1.758)
2.82
(2.268)
0.47
(0.558)
11.76
(27.478)†

10 mg, mean

(SD) (n = 4)

Tadalafil
5.47
(3.586)
5.84
(4.768)
0.37
(2.219)
17.20
(64.838)

5 mg, (n = 4)

Cilnidipine
5.23
(1.445)
2.26
(2.208)
−2.97
(1.399)
−61.84
(34.512)*

10 mg +

Tadalafil

5 mg, (n = 5)

Cilnidipine
4.16
(2.427)
3.39
(3.692)
−0.77
(2.677)
−24.00
(54.180)†

20 mg +

Tadalafil

5 mg, (n = 4)

Placebo, mean
2.31
(1.623)
1.68
(0.828)
−0.63
(1.346)
−3.92
(67.665)

(SD) (n = 4)

Tables H—O show listings for each parameter on the SHAQ assessment in the Modified ITT population.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
4

Mean (SD)
0.656
0.250
0.594
0.550
0.781
0.813

(0.7731)
(0.2165)
(0.4719)
(0.4108)
(0.8377)
(0.6654)

Median
0.563
0.375
0.625
0.500
0.750
0.813

Q1, Q3
0.000, 1.313
0.000, 0.375
0.250, 0.938
0.250, 0.500
0.063, 1.500
0.375, 1.250

Min, Max
0.00, 1.50
0.00, 0.38
0.00, 1.13
0.25, 1.25
0.00, 1.63
0.00, 1.63

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
0.656
0.125
0.531
0.391
0.714
0.719

(0.7731)
(0.1250)
(0.4130)
(0.3370)
(0.7786)
(0.7526)

Median
0.563
0.125
0.563
0.250
0.554
0.563

Q1, Q3
0.000, 1.313
0.000, 0.250
0.250, 0.813
0.188, 0.500
0.125, 1.304
0.188, 1.250

Min, Max
0.00, 1.50
0.00, 0.25
0.00, 1.00
0.13, 1.13
0.00, 1.75
0.00, 1.75

Change from Baseline

n
4
3
4
8
4
4

Mean (SD)
0.0
−0.125
−0.063
−0.141
−0.067
−0.094

(0.0000)
(0.1250)
(0.0722)
(0.2449)
(0.3063)
(0.2772)

Median
0.000
−0.125
−0.063
−0.188
0.063
0.000

Q1, Q3
0.000, 0.000
−0.250, 0.000
−0.125, 0.000
−0.313, −0.063
−0.259, 0.125
−0.250, 0.063

Min, Max
0.00, 0.00
−0.25, 0.00
−0.13, 0.00
−0.38, 0.38
−0.52, 0.13
−0.50, 0.13

Percent Change from Baseline

n
2
2
3
8
3
3

Mean (SD)
0.0
−50.00
−9.26
−16.88
23.34
−16.48

(0.000)
(23.570)
(8.486)
(72.896)
(70.153)
(35.421)

Median
0.00
−50.00
−11.11
−37.50
7.69
0.00

Q1, Q3
0.00, 0.00
−66.67, −33.33
−16.67, 0.00
−62.50, −5.00
−37.66, 100.00
−57.14, 7.69

Min, Max
0.0, 0.0
−66.7, −33.3
−16.7, 0.0
−75.0, 150.0
−37.7, 100.0
−57.1, 7.7

TABLE I

Change from baseline and Percent change from baseline-Modified ITT

Population-Part A. Parameter is the alternative disability index.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
4

Mean (SD)
0.500
0.208
0.469
0.425
0.688
0.594

(0.5863)
(0.1909)
(0.5141)
(0.4644)
(0.7672)
(0.4719)

Median
0.438
0.250
0.375
0.250
0.563
0.625

Q1, Q3
0.000, 1.000
0.000, 0.375
0.063, 0.875
0.250, 0.250
0.063, 1.313
0.250, 0.938

Min, Max
0.00, 1.13
0.00, 0.38
0.00, 1.13
0.13, 1.25
0.00, 1.63
0.00, 1.13

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
0.563
0.125
0.375
0.328
0.616
0.531

(0.6575)
(0.1250)
(0.4787)
(0.3532)
(0.6594)
(0.75242)

Median
0.500
0.125
0.250
0.250
0.482
0.438

Q1, Q3
0.000, 1.125
0.000, 0.250
0.000, 0.750
0.125, 0.375
0.125, 1.107
0.188, 0.875

Min, Max
0.00, 1.25
0.00, 0.25
0.00, 1.00
0.00, 1.13
0.00, 1.50
0.00, 1.25

Change from Baseline

n
4
3
4
8
4
4

Mean (SD)
0.063
−0.083
−0.094
−0.031
−0.071
−0.063

(0.2165)
(0.0722)
(0.0625)
(0.1860)
(0.1756)
(0.2165)

Median
0.000
−0.125
−0.125
−0.063
−0.063
0.000

Q1, Q3
−0.063, 0.188
−0.125, 0.000
−0.125, −0.063
−0.125, −0.000
−0.205, 0.063
−0.188, 0.063

Min, Max
−0.13, 0.38
−0.13, 0.00
−0.13, 0.00
−0.25, 0.38
−0.29, 0.13
−0.38, 0.13

Percent Change from Baseline

n
2
2
3
8
3
3

Mean (SD)
15.87
−41.67
−43.70
11.25
21.25
−12.96

(38.161)
(11.785)
(48.956)
(121.941)
(68.998)
(32.553)

Median
15.87
−41.67
−20.00
−5.00
−7.69
0.00

Q1, Q3
−11.11, 42.86
−50.00, −33.33
−100.00, −11.11
−50.00, 0.00
−28.57, 100.00
−50.00, 11.11

Min, Max
−11.1, 42.9
−50.0, −33.3
−100.0, −11.1
−100.0, 300.0
−28.6, 100.0
−50.0, 11.1

TABLE J

Change from baseline and Percent change from baseline-Modified ITT Population-Part A. Visual Analog Scale-Pain.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
3
5
3
4

Mean (SD)
1.975
2.167
5.967
4.320
3.167
3.325

(1.5283)
(1.7010)
(3.4790)
(2.5352)
(1.1240)
(2.2366)

Median
2.150
1.500
7.400
3.200
2.900
3.500

Q1, Q3
0.850, 3.100
0.900, 4.100
2.000, 8.500
3.100, 5.200
2.200, 4.400
1.500, 5.150

Min, Max
0.00, 3.60
0.90, 4.10
2.00, 8.50
1.80, 8.30
2.20, 4.40
0.70, 5.60

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
1.875
1.067
5.300
3.463
2.700
4.100

(1.6641)
(0.9074)
(4.1577)
(1.5250)
(1.7907)
(3.1145)

Median
1.950
0.700
5.850
4.050
2.150
4.450

Q1, Q3
0.500, 3.250
0.400, 2.100
1.900, 8.700
2.600, 4.200
1.650, 3.750
1.600, 6.600

Min, Max
0.00, 3.60
0.40, 2.10
0.30, 9.20
0.50, 5.50
1.20, 5.30
0.30, 7.20

Change from Baseline

n
4
3
3
8
3
4

Mean (SD)
−0.100
−1.100
1.000
−0.438
−0.300
0.775

(0.4243)
(0.7937)
(0.4359)
(1.3362)
(1.3115)
(1.2285)

Median
0.000
−0.800
0.800
−0.550
−0.100
0.500

Q1, Q3
−0.350, 0.150
−2.000, −0.500
0.700, 1.500
−1.200, 0.900
−1.700, 0.900
−0.000, 1.550

Min, Max
−0.70, 0.30
−2.00, −0.50
0.70, 1.50
−2.80, 1.00
−1.70, 0.90
−0.40, 2.50

Percent Change from Baseline

n
3
3
3
8
3
4

Mean (SD)
−9.88
−52.56
31.35
−9.34
−14.24
7.32

(27.711)
(3.454)
(37.825)
(36.544)
(40.419)
(46.946)

Median
0.00
−53.33
10.81
−16.83
−4.55
16.61

Q1, Q3
−41.18, 11.54
−55.56, −48.78
8.24, 75.00
−28.16, 28.13
−58.62, 20.45
−25.00, 39.64

Min, Max
−41.2, 11.5
−55.6, −48.8
8.2, 75.0
−72.2, 31.3
−58.6, 20.5
−57.1, 53.2

TABLE K

Change from baseline and Percent change from baseline-Modified

ITT Population-Part A. Visual Analog Scale-Intestinal Problems.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
3

Mean (SD)
2.975
0.833
3.150
2.020
0.925
1.100

(3.4568)
(0.7638)
(3.7009)
(1.9930)
(0.9069)
(1.5620)

Median
2.550
1.000
2.600
1.100
0.950
0.300

Q1, Q3
0.050, 5.900
0.000, 1.500
0.050, 6.250
0.700, 2.500
0.150, 1.700
0.100, 2.900

Min, Max
0.00, 6.80
0.00, 1.50
0.00, 7.40
0.50, 5.30
0.00, 1.80
0.10, 2.90

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
1.100
1.133
3.025
1.663
1.175
0.450

(1.8221)
(1.0599)
(4.3162)
(1.9227)
(2.2187)
(0.4509)

Median
0.300
1.300
1.450
1.350
0.100
0.300

Q1, Q3
0.000, 2.200
0.000, 2.100
0.050, 6.000
0.350, 1.950
0.000, 2.350
0.150, 0.750

Min, Max
0.00, 3.80
0.00, 2.10
0.00, 9.20
0.00, 6.00
0.00, 4.50
0.10, 1.10

Change from Baseline

n
4
3
4
8
4
3

Mean (SD)
−1.875
0.300
−0.125
−0.538
−0.250
−0.567

(2.1838)
(0.3000)
(1.6800)
(2.1547)
(1.8982)
(1.0970)

Median
−1.550
0.300
0.000
−0.800
−0.150
−0.200

Q1, Q3
−3.700, −0.050
0.000, 0.600
−1.150, 0.900
−2.000, 0.600
−0.950, 1.450
−1.800, 0.300

Min, Max
−4.40, 0.00
0.00, 0.60
−2.30, 1.80
−3.40, 3.50
−1.60, 2.90
−1.80, 0.30

Percent Change from Baseline

n
3
2
3
8
3
3

Mean (SD)
−77.37
35.00
−6.92
−2.66
−2.55
57.09

(29.418)
(7.071)
(35.225)
(99.762)
(159.269)
(210.380)

Median
−88.00
35.00
0.00
−40.00
−88.89
−62.07

Q1, Q3
−100.00, −44.12
30.00, 40.00
−45.10, 24.32
−82.08, 90.00
−100.00, 181.25
−66.67, 300.00

Min, Max
−100.0, −44.1
30.0, 40.0
−45.1, 24.3
−100.0, 142.9
−100.0, 181.3
−66.7, 300.0

TABLE L

Change from baseline and Percent change from baseline-Modified

ITT Population-Part A. Visual Analog Scale-Breathing Problems

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
4

Mean (SD)
1.875
1.133
3.800
1.220
1.025
0.525

(3.7500)
(0.9018)
(3.0144)
(0.9550)
(1.4930)
(0.5852)

Median
0.000
1.200
4.050
1.200
0.450
0.250

Q1, Q3
0.000, 3.750
0.200, 2.000
1.550, 6.050
0.800, 1.500
0.050, 2.000
0.200, 0.850

Min, Max
0.00, 7.50
0.20, 2.00
0.00, 7.10
0.00, 2.60
0.00, 3.20
0.20, 1.40

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
1.575
0.300
4.300
3.188
1.950
0.450

(3.1500)
(0.2646)
(4.8840)
(4.2680)
(3.3131)
(0.3416)

Median
0.000
0.400
4.000
1.300
0.450
0.400

Q1, Q3
0.000, 3.150
0.000, 0.500
0.100, 8.500
0.350, 6.100
0.100, 3.800
0.200, 0.700

Min, Max
0.00, 6.30
0.00, 0.50
0.00, 9.20
0.00, 10.00
0.00, 6.90
0.10, 0.90

Change from Baseline

n
4
3
4
8
4
4

Mean (SD)
−0.300
−0.833
0.500
1.450
0.925
−0.075

(0.6000)
(1.1504)
(2.5599)
(4.1604)
(1.9138)
(0.3500)

Median
0.000
−0.800
1.050
−0.400
0.300
−0.050

Q1, Q3
−0.600, 0.000
−2.000, 0.300
−1.450, 2.450
−0.950, 3.700
−0.300, 2.150
−0.350, 0.200

Min, Max
−1.20, 0.00
−2.00, 0.30
−2.90, 2.80
−1.90, 8.80
−0.60, 3.70
−0.50, 0.30

Percent Change from Baseline

n
1
3
3
7
3
4

Mean (SD)
−16.00
−5.56
−2.66
108.64
213.54
24.40

(135.742)
(79.815)
(303.929)
(347.990)
(97.190)

Median
−16.00
−66.67
29.58
−26.67
115.63
7.14

Q1, Q3
−16.00, −16.00
−100.00, 150.00
−93.55, 56.00
−73.08, 284.62
−75.00, 600.00
−51.19, 100.00

Min, Max
−16.0, −16.0
−100.0, 150.0
−93.5, 56.0
−100.0, 733.3
−75.00, 600.0
−66.7, 150.0

TABLE M

Change from baseline and Percent change from baseline-Modified ITT Population-Part A. Visual Analog Scale-Raynaud's.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
4

Mean (SD)
1.600
2.300
5.775
3.640
2.325
3.250

(1.9270)
(1.3115)
(4.0252)
(2.9057)
(3.9911)
(2.3274)

Median
1.000
2.500
6.400
2.400
0.500
2.550

Q1, Q3
0.450, 2.750
0.900, 3.500
3.350, 8.200
1.400, 5.000
0.200, 4.450
1.750, 4.750

Min, Max
0.00, 4.40
0.90, 3.50
0.30, 10.00
1.30, 8.10
0.00, 8.30
1.30, 6.60

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
1.925
1.033
4.950
3.400
1.500
2.750

(1.9207)
(0.4041)
(3.7749)
(2.0626)
(2.4752)
(3.6538)

Median
1.700
1.100
5.200
3.400
0.400
1.500

Q1, Q3
0.400, 3.450
0.600, 1.400
2.200, 7.700
2.050, 4.450
0.150, 2.850
0.150, 5.350

Min, Max
0.00, 4.30
0.60, 1.40
0.20, 9.20
0.40, 7.00
0.00, 5.20
0.10, 7.90

Change from Baseline

n
4
3
4
8
4
4

Mean (SD)
0.325
−1.267
−0.825
−0.750
−0.825
−0.500

(1.0468)
(1.0599)
(0.9674)
(1.8150)
(1.5262)
(1.4306)

Median
0.350
−1.100
−0.500
−0.500
−0.150
−0.650

Q1, Q3
−0.500, 1.150
−2.400, −0.300
−1.500, −0.150
−1.600, 0.150
−1.700, 0.050
−1.600, 0.600

Min, Max
−0.90, 1.50
−2.40, −0.30
−2.20, −0.10
−4.10, 2.00
−3.10, 0.10
−2.00, 1.30

Percent Change from Baseline

n
3
3
4
8
3
4

Mean (SD)
11.36
−48.63
−19.71
−16.67
−20.78
−41.74

(118.770)
(18.070)
(16.460)
(36.309)
(40.151)
(58.354)

Median
−2.27
−44.00
−20.67
−11.00
−37.35
−47.18

Q1, Q3
−100.00, −136.36
−68.57, −33.33
−33.85, −5.56
−47.31, 6.25
−50.00, 25.00
−91.61, 8.12

Min, Max
−100.0, 136.4
−68.6, −33.3
−34.4, −3.1
−69.2, 40.0
−50.00, 25.0
−92.3, 19.7

TABLE N

Change from baseline and Percent change from baseline-Modified ITT Population-Part A. Finger Ulcers.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
3

Mean (SD)
0.700
1.800
2.075
0.620
2.125
3.133

(0.8718)
(2.8618)
(4.0836)
(0.8319)
(4.1836)
(4.0612)

Median
0.500
0.300
0.050
0.200
0.050
1.200

Q1, Q3
0.000, 1.400
0.000, 5.100
0.000, 4.150
0.100, 0.800
0.000, 4.250
0.400, 7.800

Min, Max
0.00, 1.80
0.00, 5.10
0.00, 8.20
0.00, 2.00
0.00, 8.40
0.40, 7.80

In Clinic Visit (Day 12)

n
4
3
4
8
3
4

Mean (SD)
0.275
0.867
2.325
0.863
1.867
2.275

(0.5500)
(0.9609)
(4.5836)
(1.1070)
(3.2332)
(3.8922)

Median
0.000
0.700
0.050
0.450
0.000
0.450

Q1, Q3
0.000, 0.550
0.000, 1.900
0.000, 4.650
0.000, 1.500
0.000, 5.600
0.150, 4.400

Min, Max
0.00, 1.10
0.00, 1.90
0.00, 9.20
0.00, 3.00
0.00, 5.60
0.10, 8.10

Change from Baseline

n
4
3
4
8
3
3

Mean (SD)
−0.425
−0.933
0.250
−0.275
−0.967
−0.167

(0.5058)
(1.9732)
(0.5000)
(0.8795)
(1.5885)
(0.8083)

Median
−0.350
0.000
0.000
−0.050
−0.100
0.300

Q1, Q3
−0.850, 0.000
−3.200, 0.400
0.000, 0.500
−0.550, 0.000
−2.800, 0.000
−1.100, 0.300

Min, Max
−1.00, 0.00
−3.20, 0.40
0.00, 1.00
−2.00, 1.00
−2.80, 0.00
−1.10, 0.30

Percent Change from Baseline

n
2
2
2
7
2
3

Mean (SD)
−69.44
35.29
6.10
−30.36
−66.67
−4.27

(43.212)
(138.648)
(8.623)
(55.835)
(47.140)
(83.629)

Median
−69.44
35.29
6.10
−12.50
−66.67
3.85

Q1, Q3
−100.00, −38.89
−62.75, 133.33
0.00, 12.20
−100.00, 0.00
−100.00, −33.33
−91.67, 75.00

Min, Max
−100.0, −38.9
−62.7, 133.3
0.0, 12.2
−100.0, 50.0
−100.0, −33.3
−91.7, 75.0

TABLE O

Change from baseline and Percent change from baseline-Modified ITT Population-Part A. Overall Change in Severity.

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 4)
(N = 3)
(N = 4)
5 mg (N = 5)
5 mg (N = 4)
(N = 4)

Baseline

n
4
3
4
5
4
4

Mean (SD)
2.725
2.667
4.975
3.300
3.600
2.000

(3.2877)
(0.4933)
(3.3837)
(2.3152)
(3.2321)
(1.7963)

Median
1.900
2.900
6.000
1.900
2.550
1.300

Q1, Q3
0.200, 5.250
2.100, 3.000
2.800, 7.150
1.900, 4.700
1.250, 5.950
0.800, 3.200

Min, Max
0.00, 7.10
2.10, 3.00
0.10, 7.80
1.30, 6.70
1.20, 8.10
0.80, 4.60

In Clinic Visit (Day 12)

n
4
3
4
8
4
4

Mean (SD)
1.825
1.033
5.600
2.975
2.750
2.700

(2.4061)
(0.4726)
(4.2528)
(1.8367)
(3.0957)
(1.9511)

Median
1.050
1.200
6.550
3.300
1.500
2.950

Q1, Q3
0.100, 3.550
0.500, 1.400
2.200, 9.000
1.150, 4.050
0.800, 4.700
1.400, 4.000

Min, Max
0.00, 5.20
0.50, 1.40
0.20, 9.10
0.80, 6.00
0.70, 7.30
0.10, 4.80

Change from Baseline

n
4
3
4
8
4
4

Mean (SD)
−0.900
−1.633,
0.625,
−0.850
−0.850
0.700

(0.9695)
(0.1528
(1.5903)
(1.4948)
(0.5916)
(1.3089)

Median
−0.950
−1.600
0.700
−0.700
−0.650
0.550

Q1, Q3
−1.700, −0.100
−1.800, −1.500
−0.600, 1.850
−1.500, −0.450
−1.250, −0.450
−0.250, 1.650

Min, Max
−1.90, 0.20
−1.80, −1.50
−1.30, 2.40
−3.40, 1.90
−1.70, −0.40
−0.70, 2.40

Percent Change from Baseline

n
3
3
4
8
4
4

Mean (SD)
−56.96
−62.64
32.49
−16.48
−31.76
66.71

(38.271)
(12.445)
(51.568)
(52.198)
(15.773)
(165.704)

Median
−44.12
−60.00
26.790
−18.99
−36.22
27.17

Q1, Q3
−100.00, −26.76
−76.19, −51.72
−3.48, 68.46
−49.16, −11.61
−43.20, −20.32
−41.58, 175.00

Min, Max
−100.0, −26.8
−76.2, −51.7
−23.6, 100.0
−72.3, 100.0
−44.7, −9.9
−87.5, 300.0

Table P shows the SHAQ parameter differences between Pooled cilnidipine (n) and placebo (n). Results with a (*) show a favorable treatment effect for cilnidipine.

Pooled

cilnidipine
Placebo

SHAQ PARAMETER
(n)
(n)

% Δ from baseline, standard disability mean,
−25, −16.7
(4)*
−16.5, 0
(3)

median

% Δ from baseline, alternative disability
−12.9, −22.2
(4)*
−13, 0
(3)

mean, median

% Δ from baseline, VAS Pain mean, median
−31.2, −45
(6)*
7.3, 16.6
(3)

% Δ from baseline, Intestinal Problems mean,
−32.4, −44.1
(5)*
57, −62
(3)

median

% Δ from baseline, VAS Breathing mean,
−8.2, −41.3
(4)*
24.4, 7.1
(4)

median

% Δ from baseline, VAS Raynaud's mean,
−18.6, −38.7
(6)
−41.8, −47.2
(4)

median

% Δ from baseline, VAS Finger Ulcers mean,
−17.1, −50.9
(4)*
−4.3, 3.9
(3)

median

% Δ from baseline, VAS Overall Disease
−59.8, −55.9
(6)*
66.7, 27
(4)

Severity mean, median

Table Q shows difference for pooled cilnidipine patients compared to placebo on the SHAQ rating of overall disease severity is significant (p=0.01).

Scleroderma health assessment questionnaire (SHAQ)

Wilcoxon
T test

Parameter
20 mg
placebo
p value
p value

VAS-Pain
−1.1
(0.79)
0.78
(1.23)
0.200
0.136

VAS- Breathing
−0.83
(1.15)
−0.075
(0.35)
0.943
0.540

problems

Change

VAS- Raynaud's
−1.27
(1.06)
−0.5
(1.43)
0.686
0.436

Change

VAS- overall
−1.63
(0.15)
0.7
(1.31)
0.029
0.0115

disease severity

Change

Other results

Cilnidipine

Placebo
(20 mg)
Rirash 2017

Parameter
(n = 4)
**(n-3)
metanalysis^†

Mean weekly
16.7
12.7
16.4 (n = 117

attacks at

for 2°RP)

baseline

Mean %
18.9*
43
24% (n = 117

reduction of

for 2°RP)

weekly attacks

at baseline

Mean severity
3.3
3.7
Unknown

at baseline

Mean %
−16.2
35.5
10.2(n = 138

reduction in

for 2°RP)

severity

Mean duration
164.2
19.4
Unknown

of attack at

baseline

Mean %
12.3
20.0
6(n = 138)

reduction in

duration

Mean pain level
2.3
2.3
Unknown

at baseline

Mean %
−3.9
−11.8
Ns

reduction in pain

Mean RCS at
2.6
3.5
Unknown

baseline

Mean %
5.1
27.9
9(n = 192)

reduction in

RCS

^†Rirash, F. et. al.; Cochrane Syst Rev. 2017 Dec. 13; 12 (12)

Table R shows additional results.

Cilnidipine
Placebo

Parameter
20 mg (n = 3)
(n = 4)

Standard disability Index
50% improvement
11% improvement

Alternative disability index
42% improvement
13% improvement

VAS- PAIN
53% improvement*
23% worse**

VAS - Breathing problems
75% improvement*
24% improvement

VAS - Raynaud's
55% improvement
16% improvemnt

VAS Overall Disease Severity
63% improvement
35% worse

*Baseline was 2.17 on a 0-10 VAS

**Baseline was 3.3 on a 0-10 VAS

**Baseline was 1.13 on a 0-10 VAS

TABLE S

provides a summary of data:

Grade 1 Adverse

Safety
No treatment D/Cs
Events (AEs) only
Efficacy Seen

Dose
20 mg dose superior to
Worst AE in tadalafil
20 mg dose group

response seen
all groups > Part B
monotherapy group
shows best overall

response

Tadalafil 10
17% Adverse effects in
Study conduct good
Attacks reduced

mg helps
any Profervia dose

43%_vs 23% with

standard calcium

channel blockers

Table T shows a dose response comparison between cilnidipine 10 mg and 20 mg

Pooled

Cilnidipine
Cilnidipine
Placebo

PARAMETER
(n = 7)
20 mg (n = 3)
(n = 4)

Weekly attack
−41%
−43%
−19%

frequency

If baseline

RCS <3.5
−27%
−42%
−18%

Duration
20%
−20%
−12%

Severity
−16%
−36%
16%

Daily RCS
12% (n = 3)
−28%
−5%

Change

Average
−27%
12%
4%

Raynaud's Pain

Safety
1AE (in combo with
1AE (HA−mild; 1
1AE (Increase in

T); no withdrawals
withdrawal (n = 8)
GERD)

(n = 9)

Subgroup attack
<10 baseline −55%
<10 baseline −29%
<10 baseline 43%

frequency
(n = 2)
(n = 2)
(n = 1)

>10 baseline −28%
>10 baseline −50%
>10 baseline −39%

(n = 2)
(n = 2)
(n = 2)

Subgroup
<3.5 baseline −27%
<3.5 baseline −42%
<3.5 baseline −18%

Baseline RCS
(n = 3)
(n = 1)
(n = 3)

3.5-7.5
>3.5-7.5
3.5-7.5

baseline −86%
baseline −43%
baseline −32%

(n = 1)
(n = 2)
(n = 3)

This evaluation study demonstrated successful implementation of the study processes, as indicated by the absence of Serious Adverse Events (SAEs), unblinding, or treatment discontinuations due to drug-related effects. Furthermore, only Grade 1 Adverse Events (AEs) were reported for patients treated with cilnidipine. Both cilnidipine doses, 10 mg and 20 mg, were well tolerated when administered alone or in combination with tadalafil. Notably, the 20 mg dose exhibited a greater overall effect compared to the 10 mg dose. The addition of tadalafil to cilnidipine demonstrated a more pronounced effect with the 10 mg dose compared to the 20 mg dose of cilnidipine alone. In comparison to an imputed historical comparator encompassing all Calcium Channel Blocker (CCB) trials for Systemic Sclerosis-Related Raynaud's Phenomenon (SSc-RP), cilnidipine exhibited improved safety with a lower incidence of Adverse Events (17% AE versus 430% AE, p=0.024′7). Cilnidipine demonstrated an improvement in the overall severity of Systemic Sclerosis (SSc) as measured by the Scleroderma Health Assessment Questionnaire (SHAQ) when compared to the placebo group (p=0.01). Specifically, in the group receiving cilnidipine 20 mg (n=3), there was an improvement in the SHAQ scales of disability, pain, skin ulcers, Raynaud's phenomenon, and breathing difficulty compared to the placebo group (n=4). Furthermore, the addition of tadalafil, which enhances the brain concentration of cilnidipine by inhibiting plasma proteins that bind the drug, resulted in improved pain relief related to all causes of SSc when compared to cilnidipine alone.

Comments on Foregoing Results:

In this study, cilnidipine demonstrated good tolerability among patients, with an overall adverse event rate of 17% observed in all patients who received any dose of cilnidipine (n=17). Importantly, only mild (Grade 1) adverse events occurred, and no treatment discontinuations due to intolerance were reported. A dose response was evident between cilnidipine 10 mg and 20 mg, with the higher dose showing a greater effect. Regarding the primary endpoint, cilnidipine 20 mg led to a significant reduction of 43% in weekly attack frequency, compared to 19% in patients treated with placebo. This reduction surpasses the clinically meaningful threshold of 25%. Comparatively, in this study, cilnidipine appeared to be safer and more effective than a large published meta-analysis of Calcium Channel Blocker (CCB) use in Raynaud's (both primary and secondary). Moreover, cilnidipine 20 mg exhibited a more substantial impact on alleviating the underlying burdens and manifestations of systemic sclerosis (SSc) when compared to placebo. In summary, cilnidipine holds promise as a well-tolerated and effective treatment option for patients with secondary Raynaud's primarily due to SSc.

Tables A1-A7, B1-B16, C1-C17, and D1-D15 show additional listings for each parameter on the SHAQ assessment in the Modified ITT population

TABLE A1

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline. Modified ITT Population - Part A. Parameter: Standard Disability Index.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
24

Mean (SD)
0.482
(0.6013)
0.653
(0.6020)
0.597
(0.5582)
0.554
(0.6687)
0.620
(0.5656)

Median
0.375
0.500
0.500
0.375
0.500

Q1, Q3
0.000,
1.125
0.250,
1.250
0.250,
1.125
0.000,
1.375
0.063,
1.125

Min, Max
0.00,
1.50
0.00,
1.63
0.00,
1.50
0.00,
1.63
0.00,
1.63

In-Clinic Visit

(Day 12)

n
7
9
9
7
24

Mean (SD)
0.429
(0.6202)
0.602
(0.5580)
0.576
(0.5500)
0.462
(0.6384)
0.559
(0.5615)

Median
0.125
0.375
0.375
0.250
0.375

Q1, Q3
0.000,
1.125
0.250,
0.857
0.188,
1.125
0.000,
0.857
0.063,
0.929

Min, Max
0.00,
1.50
0.00,
1.75
0.00,
1.50
0.00,
1.75
0.00,
1.75

Change from

Baseline

n
7
9
9
7
24

Mean (SD)
−0.054
(0.0983)
−0.051
(0.2612)
−0.021
(0.1822)
−0.092
(0.2304)
−0.061
(0.1929)

Median
0.000
0.000
0.000
0.000
0.000

Q1, Q3
−0.125,
0.000
−0.125,
0.125
−0.125,
0.000
−0.250,
0.125
−0.125,
0.000

Min, Max
−0.25,
0.00
−0.52,
0.38
−0.31,
0.38
−0.52,
0.13
−0.52,
0.38

Percent Change

from Baseline

n
4
8
7
5
18

Mean (SD)
−25.00
(31.914)
15.32
(72.439)
7.50
(66.755)
−5.99
(64.911)
−3.04
(52.984)

Median
−16.67
−5.00
0.00
−33.33
−5.00

Q1, Q3
−50.00,
0.00
−31.33,
53.85
−25.00,
0.00
−37.66,
7.69
−33.33,
0.00

Min, Max
−66.7,
0.0
−62.5,
150.0
−62.5,
150.0
−66.7,
100.0
−66.7,
150.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE A2

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Pain.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
8
9
6
22

Mean (SD)
2.057
(1.4639)
3.888
(2.0952)
3.278
(2.3700)
2.667
(1.4010)
3.486
(2.3598)

Median
1.700
3.150
3.100
2.550
3.000

Q1, Q3
0.900,
3.600
2.550,
4.800
1.800,
3.600
1.500,
4.100
1.800,
4.700

Min, Max
0.00,
4.10
1.80,
8.30
0.00,
8.30
0.90,
4.40
0.00,
8.50

In-Clinic Visit

(Day 12)

n
7
9
9
7
24

Mean (SD)
1.529
(1.3586)
3.011
(1.7567)
2.644
(1.8352)
2.000
(1.6248)
3.142
(2.6160)

Median
1.000
2.400
2.900
2.100
2.650

Q1, Q3
0.400,
2.900
2.100,
4.100
1.000,
3.800
0.700,
2.200
0.850,
4.700

Min, Max
0.00,
3.60
0.50,
5.50
0.00,
5.50
0.40,
5.30
0.00,
9.20

Change from

Baseline

n
7
8
9
6
22

Mean (SD)
−0.529
(0.7653)
−0.775
(1.2245)
−0.633
(1.0344)
−0.700
(1.0640)
−0.173
(1.2036)

Median
−0.500
−0.900
−0.700
−0.650
−0.050

Q1, Q3
−0.800,
0.000
−1.500,
0.250
−1.100,
0.000
−1.700,
−0.100
−0.800,
0.600

Min, Max
−2.00,
0.30
−2.80,
0.90
−2.80,
0.60
−2.00,
0.90
−2.80,
2.50

Percent Change

from Baseline

n
6
8
8
6
21

Mean (SD)
−31.22
(29.297)
−21.71
(33.315)
−20.07
(29.925)
−33.40
(33.147)
−11.32
(39.764)

Median
−44.98
−21.87
−21.87
−51.06
−4.55

Q1, Q3
−53.33,
0.00
−46.18,
7.10
−37.46,
5.77
−55.56,
−4.55
−48.78,
11.54

Min, Max
−55.6,
11.5
−72.2,
20.5
−72.2,
18.8
−58.6,
20.5
−72.2,
75.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE A3

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent Change

from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Intestinal Problems

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
23

Mean (SD)
2.057
(2.7349)
1.533
(1.6210)
2.444
(2.5923)
0.886
(0.7798)
1.917
(2.3492)

Median
1.000
1.100
1.100
1.000
1.000

Q1, Q3
0.000,
5.000
0.500,
1.800
0.500,
5.000
0.000,
1.600
0.100,
2.900

Min, Max
0.00,
6.80
0.00,
5.30
0.00,
6.80
0.00,
1.80
0.00,
7.40

In-Clinic Visit

(Day 12)

n
7
9
9
7
24

Mean (SD)
1.114
(1.4265)
1.250
(1.5116)
1.217
(1.3005)
1.157
(1.6841)
1.373
(2.1050)

Median
0.600
0.700
0.700
0.200
0.500

Q1, Q3
0.000,
2.100
0.000,
1.900
0.000,
1.900
0.000,
2.100
0.000,
2.000

Min, Max
0.00,
3.80
0.00,
4.50
0.00,
3.80
0.00,
4.50
0.00,
9.20

Change from

Baseline

n
7
9
9
7
23

Mean (SD)
−0.943
(1.9407)
−0.283
(1.7396)
−1.228
(1.8933)
0.271
(1.3537)
−0.493
(1.6522)

Median
0.000
−0.250
−0.250
0.000
0.000

Q1, Q3
−3.000,
0.300
−1.100,
0.200
−3.000,
0.000
−0.300,
0.600
−1.600,
0.300

Min, Max
−4.40,
0.60
−3.40,
2.90
−4.40,
1.00
−1.60,
2.90
−4.40,
2.90

Percent Change

from Baseline

n
5
8
8
5
19

Mean (SD)
−32.42
(65.065)
0.13
(111.468)
−27.93
(84.240)
12.47
(114.537)
−0.56
(108.034)

Median
−44.12
−37.08
−54.13
30.00
−44.12

Q1, Q3
−88.00,
30.00
−94.44,
91.43
−94.00,
15.00
−88.89,
40.00
−88.00,
40.00

Min, Max
−100.0,
40.0
−100.0,
181.3
−100.0,
142.9
−100.0,
181.3
−100.0,
300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE A4

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent Change

from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Breathing Problems.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
24

Mean (SD)
1.557
(2.7312)
1.133
(1.1413)
1.511
(2.4184)
1.071 (1.1786)
1.600
(2.1811)

Median
0.200
0.800
0.800
0.800
0.800

Q1, Q3
0.000, 2.000
0.100, 1.500
0.000, 1.500
0.100, 2.000
0.050, 2.300

Min, Max
0.00, 7.50
0.00, 3.20
0.00, 7.50
0.00, 3.20
0.00, 7.50

In-Clinic Visit

(Day 12)

n
7
8
8
7
23

Mean (SD)
1.029
(2.3343)
1.563
(2.4721)
1.375
(2.3524)
1.243 (2.5079)
1.683
(2.8918)

Median
0.000
0.450
0.000
0.400
0.300

Q1, Q3
0.000, 0.500
0.000, 2.350
0.000, 2.350
0.000, 0.700
0.000, 1.100

Min, Max
0.00, 6.30
0.00, 6.90
0.00, 6.30
0.00, 6.90
0.00, 9.20

Change from

Baseline

n
7
8
8
7
23

Mean (SD)
−0.529
(0.8381)
0.438
(1.4481)
−0.175
(0.6541)
0.171 (1.7764)
0.065
(1.4034)

Median
0.000
0.000
0.000
0.000
0.000

Q1, Q3
−1.200, 0.000
−0.500, 0.800
−0.600, 0.000
−0.800, 0.600
−0.600, 0.300

Min, Max
−2.00, 0.30
−0.80, 3.70
−1.20, 1.00
−2.00, 3.70
−2.90, 3.70

Percent Change

from Baseline

n
4
6
4
6
17

Mean (SD)
−8.17
(110.956)
92.07
(260.892)
−26.05
(56.955)
103.99 (264.972)
35.85
(167.709)

Median
−41.33
5.90
−21.33
24.48
−16.00

Q1, Q3
−83.33, 67.00
−75.00, 115.63
−63.33, 11.23
−75.00, 150.00
−66.67, 56.00

Min, Max
−100.0, 150.0
−100.0, 600.0
−100.0, 38.5
−100.0, 600.0
−100.0, 600.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE A5

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Raynaud's

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
24

Mean (SD)
1.900
(1.6031)
3.056
(3.2673)
2.733
(2.6019)
2.314
(2.9220)
3.204
(2.9799)

Median
1.100
1.400
1.400
0.900
2.300

Q1, Q3
0.900, 3.500
0.600, 5.000
1.100, 4.400
0.400, 3.500
0.900, 5.700

Min, Max
0.00, 4.40
0.00, 8.30
0.00, 8.10
0.00, 8.30
0.00, 10.00

In-Clinic Visit

(Day 12)

n
7
9
9
7
24

Mean (SD)
1.543
(1.4581)
2.131
(2.0552)
2.319
(1.7585)
1.300
(1.7833)
2.532
(2.6476)

Median
1.100
1.400
2.600
0.600
1.400

Q1, Q3
0.600, 2.600
0.400, 4.000
0.800, 4.000
0.300, 1.400
0.350, 4.250

Min, Max
0.00, 4.30
0.00, 5.20
0.00, 4.68
0.00, 5.20
0.00, 9.20

Change from

Baseline

n
7
9
9
7
24

Mean (SD)
−0.357
(1.2830)
−0.925
(1.5742)
−0.414
(1.5805)
−1.014
(1.2628)
−0.672
(1.3209)

Median
−0.300
−0.300
−0.100
−0.300
−0.300

Q1, Q3
−1.100, 0.800
−0.900, 0.000
−0.900, 0.300
−2.400, 0.000
−1.150, 0.000

Min, Max
−2.40, 1.50
−4.10, 0.30
−4.10, 1.50
−3.10, 0.10
−4.10, 1.50

Percent Change

from Baseline

n
6
8
8
6
22

Mean (SD)
−18.64
(82.784)
−22.02
(34.211)
−9.97
(71.072)
−34.71
(31.752)
−24.26
(51.187)

Median
−38.67
−21.92
−4.39
−40.67
−33.33

Q1, Q3
−68.57, −2.27
−50.31, 6.25
−59.92, 6.25
−50.00, −33.33
−50.62, −2.27

Min, Max
−100.0, 136.4
−69.2, 25.0
−100.0, 136.4
−68.6, 25.0
−100.0, 136.4

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE A6

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent Change

from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Finger Ulcers

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
23

Mean (SD)
1.171
(1.8590)
1.289
(2.7457)
0.656
(0.7955)
1.986
(3.3928)
1.630
(2.8135)

Median
0.300
0.100
0.200
0.100
0.200

Q1, Q3
0.000, 1.800
0.000, 0.800
0.000, 1.000
0.000, 5.100
0.000, 1.800

Min, Max
0.00, 5.10
0.00, 8.40
0.00, 2.00
0.00, 8.40
0.00, 8.40

In-Clinic Visit

(Day 12)

n
7
8
9
6
23

Mean (SD)
0.529
(0.7477)
1.000
(1.9324)
0.389
(0.5732)
1.367
(2.2024)
1.309
(2.6186)

Median
0.000
0.100
0.000
0.350
0.100

Q1, Q3
0.000, 1.100
0.000, 1.100
0.000, 0.700
0.000, 1.900
0.000, 1.100

Min, Max
0.00, 1.90
0.00, 5.60
0.00, 1.50
0.00, 5.60
0.00, 9.20

Change from

Baseline

n
7
8
9
6
22

Mean (SD)
−0.643
(1.2246)
−0.450
(0.9636)
−0.267
(0.3742)
−0.950
(1.6022)
−0.345
(0.9704)

Median
0.000
−0.100
−0.100
−0.050
0.000

Q1, Q3
−1.000, 0.000
−0.300, 0.000
−0.500, 0.000
−2.800, 0.000
−0.500, 0.000

Min, Max
−3.20, 0.40
−2.80, 0.00
−1.00, 0.00
−3.20, 0.40
−3.20, 1.00

Percent Change

from Baseline

n
4
6
6
4
15

Mean (SD)
−17.08
(103.378)
−45.14
(43.971)
−46.06
(43.731)
−15.69
(103.024)
−22.65
(66.341)

Median
−50.82
−29.17
−31.94
−48.04
−25.00

Q1, Q3
−81.37, 47.22
−100.00, −12.50
−100.00, −12.50
−81.37, 50.00
−91.67, 3.85

Min, Max
−100.0, 133.3
−100.0, 0.0
−100.0, 0.0
−100.0, 133.3
−100.0, 133.3

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE A7

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent Change

from Baseline. Modified ITT Population - Part A. Parameter: Visual Analogue Scale - Overall Disease Severity

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 7)
(N = 9)
(N = 9)
(N = 7)
(N = 24)

Baseline

n
7
9
9
7
24

Mean (SD)
2.700
(2.3424)
3.433
(2.5734)
3.044
(2.6125)
3.200
(2.3566)
3.238
(2.5580)

Median
2.900
1.900
1.900
2.900
2.500

Q1, Q3
0.400, 3.400
1.300, 4.700
1.300, 4.700
1.300, 3.800
1.250, 5.100

Min, Max
0.00, 7.10
1.20, 8.10
0.00, 7.10
1.20, 8.10
0.00, 8.10

In-Clinic Visit

(Day 12)

n
7
9
9
7
24

Mean (SD)
1.486
(1.7743)
2.850
(2.4310)
2.439
(2.1948)
2.014
(2.3892)
2.885
(2.7599)

Median
1.200
2.100
1.900
1.200
2.000

Q1, Q3
0.200, 1.900
0.900, 3.800
0.800, 3.800
0.700, 2.100
0.750, 4.500

Min, Max
0.00, 5.20
0.70, 7.30
0.00, 6.00
0.50, 7.30
0.00, 9.10

Change from

Baseline

n
7
9
9
7
24

Mean (SD)
−1.214
(0.7946)
−0.583
(1.0607)
−0.606
(1.1663)
−1.186
(0.5984)
−0.352
(1.3096)

Median
−1.500
−0.700
−0.700
−1.500
−0.600

Q1, Q3
−1.800, −0.400
−1.100, −0.400
−1.500, −0.300
−1.700, −0.500
−1.500, 0.200

Min, Max
−1.90, 0.20
−1.70, 1.90
−1.90, 1.90
−1.80, −0.40
−1.90, 2.40

Percent Change

from Baseline

n
6
9
8
7
23

Mean (SD)
−59.80
(25.642)
−17.06
(46.620)
−24.68
(57.343)
−44.99
(21.176)
−5.02
(84.354)

Median
−55.86
−30.77
−30.93
−44.74
−26.76

Q1, Q3
−76.19, −44.12
−41.67, −10.45
−51.01, −16.76
−60.00, −30.77
−51.72, 16.67

Min, Max
−100.0, −26.8
−57.9, 100.0
−100.0, 100.0
−76.2, −9.9
−100.0, 300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE B1

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from

Baseline and Percent Change from Baseline Modified ITT Population - Part A-Parameter: Standard Disability Index

Cilnidipine
Cilnidipine

Cilnidipine
Cilnidipine
Tadalafil
10 mg +
20 mg +

10 mg
20 mg
5 mg
Tadalafil
Tadalafil
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
5 mg (N = 4)
5 mg (N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
4

Mean (SD)
0.875
0.250
0.594
0.375
0.781
0.813

(0.7806)
(0.2165)
(0.4719)
(0.1443)
(0.8377)
(0.6654)

Median
1.125
0.375
0.625
0.375
0.750
0.813

Q1, Q3
0.000, 1.500
0.000, 0.375
0.250, 0.938
0.250, 0.500
0.063, 1.500
0.375, 1.250

Min, Max
0.00, 1.50
0.00, 0.38
0.00, 1.13
0.25, 0.50
0.00, 1.63
0.00, 1.63

In-Clinic Visit (Day 12)

n
3
3
4
4
4
4

Mean (SD)
0.875
0.125
0.531
0.359
0.714
0.719

(0.7806)
(0.1250)
(0.4130)
(0.1935)
(0.7786)
(0.7526)

Median
1.125
0.125
0.563
0.313
0.554
0.563

Q1, Q3
0.000, 1.500
0.000, 0.250
0.250, 0.813
0.219, 0.500
0.125, 1.304
0.188, 1.250

Min, Max
0.00, 1.50
0.00, 0.25
0.00, 1.00
0.19, 0.63
0.00, 1.75
0.00, 1.75

Change from Baseline

n
3
3
4
4
4
4

Mean (SD)
0.000
−0.125
−0.063
−0.016
−0.067
−0.094

(0.0000)
(0.1250)
(0.0722)
(0.2904)
(0.3063)
(0.2772)

Median
0.000
−0.125
−0.063
−0.063
0.063
0.000

Q1, Q3
0.000, 0.000
−0.250, 0.000
−0.125, 0.000
−0.219, 0.188
−0.259, 0.125
−0.250, 0.063

Min, Max
0.00, 0.00
−0.25, 0.00
−0.13, 0.00
−0.31, 0.38
−0.52, 0.13
−0.50, 0.13

p-value vs
0.5472
0.8505
0.8397
0.7106
0.9011

Placebo

Percent Change from Baseline

n
2
2
3
4
3
3

Mean (SD)
0.00
−50.00
−9.26
15.63
23.34
−16.48

(0.000)
(23.570)
(8.486)
(93.193)
(70.153)
(35.421)

Median
0.00
−50.00
−11.11
−12.50
7.69
0.00

Q1, Q3
0.00, 0.00
−66.67, −33.33
−16.67, 0.00
−43.75, 75.00
−37.66, 100.00
−57.14, 7.69

Min, Max
0.0, 0.0
−66.7, −33.3
−16.7, 0.0
−62.5, 150.0
−37.7, 100.0
−57.1, 7.7

p-value vs
0.5048
0.2951
0.7609
0.5620
0.4455

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS,

TABLE B2

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline. Modified ITT Population - Part A-Parameter: Alternative Disability Index

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
4

Mean (SD)
0.667
(0.5907)
0.208
(0.1909)
0.469
(0.5141)
0.219
(0.0625)
0.688
(0.7672)
0.594
(0.4719)

Median
0.875
0.250
0.375
0.250
0.563
0.625

Q1, Q3
0.000,
1.125
0.000,
0.375
0.063,
0.875
0.188,
0.250
0.063,
1.313
0.250,
0.938

Min, Max
0.00,
1.13
0.00,
0.38
0.00,
1.13
0.13,
0.25
0.00,
1.63
0.00,
1.13

In-Clinic Visit

(Day 12)

n
3
3
4
4
4
4

Mean (SD)
0.750
(0.6614)
0.125
(0.1250)
0.375
(0.4787)
0.234
(0.2065)
0.616
(0.6594)
0.531
(0.5242)

Median
1.000
0.125
0.250
0.219
0.482
0.438

Q1, Q3
0.000,
1.250
0.000,
0.250
0.000,
0.750
0.094,
0.375
0.125,
1.107
0.188,
0.875

Min, Max
0.00,
1.25
0.00,
0.25
0.00,
1.00
0.00,
0.50
0.00,
1.50
0.00,
1.25

Change from

Baseline

n
3
3
4
4
4
4

Mean (SD)
0.083
(0.2602)
−0.083
(0.0722)
−0.094
(0.0625)
0.016
(0.2621)
−0.071
(0.1756)
−0.063
(0.2165)

Median
0.000
−0.125
−0.125
−0.031
−0.063
0.000

Q1, Q3
−0.125,
0.375
−0.125,
0.000
−0.125,
−0.063
−0.156,
0.188
−0.205,
0.063
−0.188,
0.063

Min, Max
−0.13,
0.38
−0.13,
0.00
−0.13,
0.00
−0.25,
0.38
−0.29,
0.13
−0.38,
0.13

p-value vs
0.4759
0.8666
0.7971
0.6625
0.9511

Placebo

Percent Change

from Baseline

n
2
2
3
4
3
3

Mean (SD)
15.87
(38.161)
−41.67
(11.785)
−43.70
(48.956)
43.75
(176.039)
21.25
(68.998)
−12.96
(32.553)

Median
15.87
−41.67
−20.00
−12.50
−7.69
0.00

Q1, Q3
−11.11,
42.86
−50.00,
−33.33
−100.00,
−11.11
−62.50,
150.00
−28.57,
100.00
−50.00,
11.11

Min, Max
−11.1,
42.9
−50.0,
−33.3
−100.0,
−11.1
−100.0,
300.0
−28.6,
100.0
−50.0,
11.1

p-value vs
0.4741
0.2678
0.4234
0.5699
0.4967

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B3

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline Modified ITT Population - Part A-Parameter: Visual Analogue Scale - Pain

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
3
4
3
4

Mean (SD)
2.067
(1.8583)
2.167
(1.7010)
5.967
(3.4790)
3.325
(1.4033)
3.167
(1.1240)
3.325
(2.2366)

Median
2.600
1.500
7.400
3.150
2.900
3.500

Q1, Q3
0.000,
3.600
0.900,
4.100
2.000,
8.500
2.450,
4.200
2.200,
4.400
1.500,
5.150

Min, Max
0.00,
3.60
0.90,
4.10
2.00,
8.50
1.80,
5.20
2.20,
4.40
0.70,
5.60

In-Clinic Visit

(Day 12)

n
3
3
4
4
4
4

Mean (SD)
2.167
(1.9088)
1.067
(0.9074)
5.300
(4.1577)
2.700
(1.6432)
2.700
(1.7907)
4.100
(3.1145)

Median
2.900
0.700
5.850
3.100
2.150
4.450

Q1, Q3
0.000,
3.600
0.400,
2.100
1.900,
8.700
1.450,
3.950
1.650,
3.750
1.600,
6.600

Min, Max
0.00,
3.60
0.40,
2.10
0.30,
9.20
0.50,
4.10
1.20,
5.30
0.30,
7.20

Change from

Baseline

n
3
3
3
4
3
4

Mean (SD)
0.100
(0.1732)
−1.100
(0.7937)
1.000
(0.4359)
−0.625
(0.8539)
−0.300
(1.3115)
0.775
(1.2285)

Median
0.000
−0.800
0.800
−0.900
−0.100
0.500

Q1, Q3
0.000,
0.300
−2.000,
−0.500
0.700,
1.500
−1.200,
−0.050
−1.700,
0.900
0.000,
1.550

Min, Max
0.00,
0.30
−2.00,
−0.50
0.70,
1.50
−1.30,
0.60
−1.70,
0.90
−0.40,
2.50

p-value vs
0.3539
0.0585
0.7520
0.1164
0.3285

Placebo

Percent Change

from Baseline

n
2
3
3
4
3
4

Mean (SD)
5.77
(8.159)
−52.56
(3.454)
31.35
(37.825)
−24.30
(37.250)
−14.24
(40.419)
7.32
(46.946)

Median
5.77
−53.33
10.81
−21.87
−4.55
16.61

Q1, Q3
0.00,
11.54
−55.56,
−48.78
8.24,
75.00
−47.40,
−1.20
−58.62,
20.45
−25.00,
39.64

Min, Max
0.0,
11.5
−55.6,
−48.8
8.2,
75.0
−72.2,
18.8
−58.6,
20.5
−57.1,
53.2

p-value vs
0.9525
0.0834
0.4879
0.3339
0.5447

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B4

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline Modified ITT Population - Part A-Parameter: Visual Analogue Scale - Intestinal Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
3

Mean (SD)
3.933
(3.5233)
0.833
(0.7638)
3.150
(3.7009)
1.200
(0.9018)
0.925
(0.9069)
1.100
(1.5620)

Median
5.000
1.000
2.600
0.900
0.950
0.300

Q1, Q3
0.000,
6.800
0.000,
1.500
0.050,
6.250
0.600,
1.800
0.150,
1.700
0.100,
2.900

Min, Max
0.00,
6.80
0.00,
1.50
0.00,
7.40
0.50,
2.50
0.00,
1.80
0.10,
2.90

In-Clinic Visit

(Day 12)

n
3
3
4
4
4
4

Mean (SD)
1.467
(2.0429)
1.133
(1.0599)
3.025
(4.3162)
1.163
(1.0061)
1.175
(2.2187)
0.450
(0.4509)

Median
0.600
1.300
1.450
1.200
0.100
0.300

Q1, Q3
0.000,
3.800
0.000,
2.100
0.050,
6.000
0.350,
1.975
0.000,
2.350
0.150,
0.750

Min, Max
0.00,
3.80
0.00,
2.10
0.00,
9.20
0.00,
2.25
0.00,
4.50
0.10,
1.10

Change from

Baseline

n
3
3
4
4
4
3

Mean (SD)
−2.467
(2.2480)
0.300
(0.3000)
−0.125
(1.6800)
−0.038
(0.8769)
0.250
(1.8982)
−0.567
(1.0970)

Median
−3.000
0.300
0.000
−0.025
−0.150
−0.200

Q1, Q3
−4.400,
0.000
0.000,
0.600
−1.150,
0.900
−0.675,
0.600
−0.950,
1.450
−1.800,
0.300

Min, Max
−4.40,
0.00
0.00,
0.60
−2.30,
1.80
−1.10,
1.00
−1.60,
2.90
−1.80,
0.30

p-value vs
0.2826
0.3030
0.6921
0.5318
0.5073

Placebo

Percent Change

from Baseline

n
2
2
3
4
3
3

Mean (SD)
−66.06
(31.030)
35.00
(7.071)
−6.92
(35.225)
18.21
(101.294)
−2.55
(159.269)
57.09
(210.380)

Median
−66.06
35.00
0.00
15.00
−88.89
−62.07

Q1, Q3
−88.00,
−44.12
30.00,
40.00
−45.10,
24.32
−55.00,
91.43
−100.00,
181.25
−66.67,
300.00

Min, Max
−88.0,
−44.1
30.0,
40.0
45.1,
24.3
−100.0,
142.9
−100.0,
181.3
−66.7,
300.0

p-value vs
0.4181
0.8725
0.6526
0.7889
0.7168

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B5

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline Modified ITT Population - Part A-Parameter: Visual Analogue Scale - Breathing Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
4

Mean (SD)
2.500
(4.3301)
1.133
(0.9018)
3.800
(3.0144)
1.525
(0.7719)
1.025
(1.4930)
0.525
(0.5852)

Median
0.000
1.200
4.050
1.350
0.450
0.250

Q1, Q3
0.000,
7.500
0.200,
2.000
1.550,
6.050
1.000,
2.050
0.050,
2.000
0.200,
0.850

Min, Max
0.00,
7.50
0.20,
2.00
0.00,
7.10
0.80,
2.60
0.00,
3.20
0.20,
1.40

In-Clinic Visit

(Day 12)

n
3
3
4
3
4
4

Mean (SD)
2.100
(3.6373)
0.300
(0.2646)
4.300
(4.8840)
1.567
(1.8448)
1.950
(3.3131)
0.450
(0.3416)

Median
0.000
0.400
4.000
1.100
0.450
0.400

Q1, Q3
0.000,
6.300
0.000,
0.500
0.100,
8.500
0.000,
3.600
0.100,
3.800
0.200,
0.700

Min, Max
0.00,
6.30
0.00,
0.50
0.00,
9.20
0.00,
3.60
0.00,
6.90
0.10,
0.90

Change from

Baseline

n
3
3
4
3
4
4

Mean (SD)
−0.400
(0.6928)
−0.833
(1.1504)
0.500
(2.5599)
−0.067
(0.9452)
0.925
(1.9138)
−0.075
(0.3500)

Median
0.000
−0.800
1.050
−0.400
0.300
−0.050

Q1, Q3
−1.200,
0.000
−2.000,
0.300
−1.450,
2.450
−0.800,
1.000
−0.300,
2.150
−0.350,
0.200

Min, Max
−1.20,
0.00
−2.00,
0.30
−2.90,
2.80
−0.80,
1.00
−0.60,
3.70
−0.50,
0.30

p-value vs
0.5147
0.3723
0.6854
0.9895
0.3753

Placebo

Percent Change

from Baseline

n
1
3
3
3
3
4

Mean (SD)
−16.00
−5.56
(135.742)
−2.66
(79.815)
−29.40
(69.271)
213.54
(347.990)
24.40
(97.190)

Median
−16.00
−66.67
29.58
−26.67
115.63
7.14

Q1, Q3
−16.00,
−16.00
−100.00,
150.00
−93.55,
56.00
−100.00,
38.46
−75.00,
600.00
−51.19,
100.00

Min, Max
−16.0,
−16.0
−100.0,
150.0
−93.5,
56.0
−100.0,
38.5
−75.0,
600.0
−66.7,
150.0

p-value vs

0.7638
0.7032
0.4316
0.4479

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B6

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline Modified ITT Population - Part A- Parameter: Visual Analogue Scale - Raynaud's

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
4

Mean (SD)
2.133
(1.9655)
2.300
(1.3115)
5.775
(4.0252)
2.525
(1.7231)
2.325
(3.9911)
3.250
(2.3274)

Median
1.100
2.500
6.400
1.900
0.500
2.550

Q1, Q3
0.900,
4.400
0.900,
3.500
3.350,
8.200
1.350,
3.700
0.200,
4.450
1.750,
4.750

Min, Max
0.90,
4.40
0.90,
3.50
0.30,
10.00
1.30,
5.00
0.00,
8.30
1.30,
6.60

In-Clinic Visit

(Day 12)

n
3
3
4
4
4
4

Mean (SD)
2.300
(2.1656)
1.033
(0.4041)
4.950
(3.7749)
2.294
(1.8458)
1.500
(2.4752)
2.750
(3.6538)

Median
2.600
1.100
5.200
2.050
0.400
1.500

Q1, Q3
0.000,
4.300
0.600,
1.400
2.200,
7.700
0.900,
3.688
0.150,
2.850
0.150,
5.350

Min, Max
0.00,
4.30
0.60,
1.40
0.20,
9.20
0.40,
4.68
0.00,
5.20
0.10,
7.90

Change from

Baseline

n
3
3
4
4
4
4

Mean (SD)
0.167
(1.2220)
−1.267
(1.0599)
−0.825
(0.9674)
−0.231
(0.5137)
−0.825
(1.5262)
−0.500
(1.4306)

Median
−0.100
−1.100
−0.500
−0.163
−0.150
−0.650

Q1, Q3
−0.900,
1.500
−2.400,
−0.300
−1.500,
−0.150
−0.612,
0.150
−1.700,
0.050
−1.600,
0.600

Min, Max
−0.90,
1.50
−2.40,
−0.30
−2.20,
−0.10
−0.90,
0.30
−3.10,
0.10
−2.00,
1.30

p-value vs
0.5374
0.4525
0.7213
0.7426
0.7666

Placebo

Percent Change

from Baseline

n
3
3
4
4
3
4

Mean (SD)
11.36
(118.770)
−48.63
(18.070)
−19.71
(16.460)
−15.81
(36.478)
−20.78
(40.151)
−41.74
(58.354)

Median
−2.27
−44.00
−20.67
−3.25
−37.35
−47.18

Q1, Q3
−100.00,
136.36
−68.57,
−33.33
−33.85,
−5.56
−37.87,
6.25
−50.00,
25.00
−91.61,
8.12

Min, Max
−100.0,
136.4
−68.6,
−33.3
−34.4,
−3.1
−69.2,
12.5
−50.0,
25.0
−92.3,
19.7

p-value vs
0.5321
0.8356
0.5133
0.4848
0.5981

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B7

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline Modified ITT Population - Part A -Parameter: Visual Analogue Scale - Finger Ulcers.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
3

Mean (SD)
0.933
(0.9018)
1.800
(2.8618)
2.075
(4.0836)
0.775
(0.8732)
2.125
(4.1836)
3.133
(4.0612)

Median
1.000
0.300
0.050
0.500
0.050
1.200

Q1, Q3
0.000,
1.800
0.000,
5.100
0.000,
4.150
0.150,
1.400
0.000,
4.250
0.400,
7.800

Min, Max
0.00,
1.80
0.00,
5.10
0.00,
8.20
0.10,
2.00
0.00,
8.40
0.40,
7.80

In-Clinic Visit

(Day 12)

n
3
3
4
4
3
4

Mean (SD)
0.367
(0.6351)
0.867
(0.9609)
2.325
(4.5836)
0.600
(0.6683)
1.867
(3.2332)
2.275
(3.8922)

Median
0.000
0.700
0.050
0.450
0.000
0.450

Q1, Q3
0.000,
1.100
0.000,
1.900
0.000,
4.650
0.100,
1.100
0.000,
5.600
0.150,
4.400

Min, Max
0.00,
1.10
0.00,
1.90
0.00,
9.20
0.00,
1.50
0.00,
5.60
0.10,
8.10

Change from

Baseline

n
3
3
4
4
3
3

Mean (SD)
−0.567
(0.5132)
−0.933
(1.9732)
0.250
(0.5000)
−0.175
(0.2217)
−0.967
(1.5885)
−0.167
(0.8083)

Median
−0.700
0.000
0.000
−0.100
−0.100
0.300

Q1, Q3
−1.000,
0.000
−3.200,
0.400
0.000,
0.500
−0.300,
−0.050
−2.800,
0.000
−1.100,
0.300

Min, Max
−1.00,
0.00
−3.20,
0.40
0.00,
1.00
−0.50,
0.00
−2.80,
0.00
−1.10,
0.30

p-value vs
0.5161
0.5828
0.4864
0.9876
0.4941

Placebo

Percent Change

from Baseline

n
2
2
2
4
2
3

Mean (SD)
−69.44
(43.212)
35.29
(138.648)
6.10
(8.623)
−34.38
(44.925)
−66.67
(47.140)
−4.27
(83.629)

Median
−69.44
35.29
6.10
−18.75
−66.67
3.85

Q1, Q3
−100.00,
−38.89
−62.75,
133.33
0.00,
12.20
−62.50,
−6.25
−100.00,
−33.33
−91.67,
75.00

Min, Max
−100.0,
−38.9
−62.7,
133.3
0.0,
12.2
−100.0,
0.0
−100.0,
−33.3
−91.7,
75.0

p-value vs
0.3376
0.7618
0.8505
0.6131
0.3656

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B8

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with Diagnosis of SSc) - Change from Baseline and

Percent Change from Baseline Modified ITT Population - Part A Parameter: Visual Analogue Scale - Overall Disease Severity

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 3)
(N = 3)
(N = 4)
(N = 4)
(N = 4)
(N = 4)

Baseline

n
3
3
4
4
4
4

Mean (SD)
3.500
(3.5511)
2.667
(0.4933)
4.975
(3.3837)
2.450
(1.5264)
3.600
(3.2321)
2.000
(1.7963)

Median
3.400
2.900
6.000
1.900
2.550
1.300

Q1, Q3
0.000,
7.100
2.100,
3.000
2.800,
7.150
1.600,
3.300
1.250,
5.950
0.800,
3.200

Min, Max
0.00,
7.10
2.10,
3.00
0.10,
7.80
1.30,
4.70
1.20,
8.10
0.80,
4.60

In-Clinic Visit

(Day 12)

n
3
3
4
4
4
4

Mean (SD)
2.433
(2.5423)
1.033
(0.4726)
5.600
(4.2528)
2.163
(1.4919)
2.750
(3.0957)
2.700
(1.9511)

Median
1.900
1.200
6.550
2.025
1.500
2.950

Q1, Q3
0.200,
5.200
0.500,
1.400
2.200,
9.000
0.900,
3.425
0.800,
4.700
1.400,
4.000

Min, Max
0.20,
5.20
0.50,
1.40
0.20,
9.10
0.80,
3.80
0.70,
7.30
0.10,
4.80

Change from

Baseline

n
3
3
4
4
4
4

Mean (SD)
−1.067
(1.1150)
−1.633
(0.1528)
0.625
(1.5903)
−0.288
(1.5601)
−0.850
(0.5916)
0.700
(1.3089)

Median
−1.500
−1.600
0.700
−0.700
−0.650
0.550

Q1, Q3
−1.900,
0.200
−1.800,
−1.500
−0.600,
1.850
−1.375,
0.800
−1.250,
−0.450
−0.250,
1.650

Min, Max
−1.90,
0.20
−1.80,
−1.50
−1.30,
2.40
−1.65,
1.90
−1.70,
−0.40
−0.70,
2.40

p-value vs
0.1143
0.0364
0.9444
0.3707
0.0942

Placebo

Percent Change

from Baseline

n
2
3
4
4
4
4

Mean (SD)
−35.44
(12.273)
−62.64
(12.445)
32.49
(51.568)
−4.02
(70.834)
−31.76
(15.773)
66.71
(165.704)

Median
−35.44
−60.00
26.79
−29.09
−36.22
27.17

Q1, Q3
−44.12,
−26.76
−76.19,
−51.72
−3.48,
68.46
−46.50,
38.46
−43.20,
−20.32
−41.58,
175.00

Min, Max
−44.1,
−26.8
−76.2,
−51.7
−23.6,
100.0
−57.9,
100.0
−44.7,
−9.9
−87.5,
300.0

p-value vs
0.3059
0.2164
0.7157
0.4757
0.3206

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B9

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

Modified ITT Population - Part A - Parameter: Standard Disability Index.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
22

Mean (SD)
0.563
(0.6162)
0.571
(0.5816)
0.619
(0.5597)

Median
0.375
0.375
0.500

Q1, Q3
0.000, 1.125
0.125, 1.125
0.125, 1.125

Min, Max
0.00, 1.50
0.00, 1.63
0.00, 1.63

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
0.500
(0.6471)
0.521
(0.5739)
0.559
(0.5614)

Median
0.188
0.250
0.375

Q1, Q3
0.000, 1.125
0.125, 0.857
0.125, 0.857

Min, Max
0.00, 1.50
0.00, 1.75
0.00, 1.75

Change from Baseline

n
6
14
22

Mean (SD)
−0.063
(0.1046)
−0.050
(0.2141)
−0.060
(0.2009)

Median
0.000
0.000
0.000

Q1, Q3
−0.125, 0.000
−0.125, 0.000
−0.125, 0.000

Min, Max
−0.25, 0.00
−0.52, 0.38
−0.52, 0.38

p-value vs Placebo
0.8411
0.7865

Percent Change

from Baseline

n
4
11
17

Mean (SD)
−25.00
(31.914)
2.96
(66.309)
−2.63
(54.585)

Median
−16.67
0.00
0.00

Q1, Q3
−50.00, 0.00
−37.66, 7.69
−33.33, 0.00

Min, Max
−66.7, 0.0
−66.7, 150.0
−66.7, 150.0

p-value vs Placebo
0.7586
0.5202

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B10

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

Modified ITT Population - Part A- Parameter: Alternative Disability Index

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
22

Mean (SD)
0.438
(0.4660)
0.446
(0.5041)
0.477
(0.4797)

Median
0.313
0.250
0.250

Q1, Q3
0.000, 0.875
0.125, 0.875
0.125, 0.875

Min, Max
0.00, 1.13
0.00, 1.63
0.00, 1.63

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
0.438
(0.5463)
0.430
(0.4974)
0.439
(0.4771)

Median
0.188
0.250
0.250

Q1, Q3
0.000, 1.000
0.000, 0.714
0.000, 0.714

Min, Max
0.00, 1.25
0.00, 1.50
0.00, 1.50

Change from Baseline

n
6
14
22

Mean (SD)
0.000
(0.1936)
−0.016
(0.1969)
−0.039
(0.1797)

Median
−0.063
−0.031
−0.031

Q1, Q3
−0.125, 0.000
−0.125, 0.000
−0.125, 0.000

Min, Max
−0.13, 0.38
−0.29, 0.38
−0.38, 0.38

p-value vs Placebo
0.6574
0.7164

Percent Change

from Baseline

n
4
11
17

Mean (SD)
−12.90
(40.439)
17.01
(106.718)
1.01
(90.209)

Median
−22.22
−11.11
−11.11

Q1, Q3
−41.67, 15.87
−33.33, 42.86
−33.33, 0.00

Min, Max
−50.0, 42.9
−100.0, 300.0
−100.0, 300.0

p-value vs Placebo
0.9982
0.4376

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B11

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

Modified ITT Population - Part A- Parameter: Visual Analogue Scale - Pain.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
13
20

Mean (SD)
2.117
(1.5943)
2.731
(1.4545)
3.335
(2.1779)

Median
2.050
2.900
3.000

Q1, Q3
0.900, 3.600
1.800, 3.600
1.900, 4.550

Min, Max
0.00, 4.10
0.00, 5.20
0.00, 8.50

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
1.617
(1.4662)
2.236
(1.5809)
3.132
(2.6480)

Median
1.400
2.150
2.650

Q1, Q3
0.400, 2.900
0.700, 3.600
0.700, 4.100

Min, Max
0.00, 3.60
0.00, 5.30
0.00, 9.20

Change from Baseline

n
6
13
20

Mean (SD)
−0.500
(0.8343)
−0.492
(0.8798)
−0.015
(1.0941)

Median
−0.250
−0.500
0.000

Q1, Q3
−0.800, 0.000
−1.100, 0.000
−0.750, 0.650

Min, Max
−2.00, 0.30
−2.00, 0.90
−2.00, 2.50

p-value vs Placebo
0.1309
0.1277

Percent Change

from Baseline

n
5
12
19

Mean (SD)
−29.23
(32.298)
−23.84
(33.064)
−8.56
(40.883)

Median
−48.78
−21.87
0.00

Q1, Q3
−53.33, 0.00
−54.44, 5.77
−53.33, 18.75

Min, Max
−55.6, 11.5
−72.2, 20.5
−72.2, 75.0

p-value vs Placebo
0.2406
0.2856

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B12

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline Modified

ITT Population - Part A-Parameter: Visual Analogue Scale - Intestinal Problems.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
21

Mean (SD)
2.383
(2.8428)
1.629
(1.9894)
1.843
(2.3082)

Median
1.250
1.050
1.000

Q1, Q3
0.000, 5.000
0.300, 1.800
0.100, 2.500

Min, Max
0.00, 6.80
0.00, 6.80
0.00, 7.40

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
1.300
(1.4670)
1.225
(1.4839)
1.411
(2.1791)

Median
0.950
0.650
0.500

Q1, Q3
0.000, 2.100
0.000, 2.100
0.000, 2.100

Min, Max
0.00, 3.80
0.00, 4.50
0.00, 9.20

Change from Baseline

n
6
14
21

Mean (SD)
−1.083
(2.0865)
−0.404
(1.7520)
−0.374
(1.5992)

Median
0.000
0.000
0.000

Q1, Q3
−3.000, 0.300
−1.100, 0.300
−1.100, 0.300

Min, Max
−4.40, 0.60
−4.40, 2.90
−4.40, 2.90

p-value vs Placebo
0.6417
0.8449

Percent Change

from Baseline

n
4
11
17

Mean (SD)
−15.53
(61.171)
0.28
(97.494)
9.03
(110.280)

Median
−7.06
−10.00
−10.00

Q1, Q3
−66.06, 35.00
−88.89, 40.00
−66.67, 40.00

Min, Max
−88.0, 40.0
−100.0, 181.3
−100.0, 300.0

p-value vs Placebo
0.6148
0.6897

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B13

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

Patients with Diagnosis of SSc) - Change from Baseline and

Percent Change from Baseline Modified ITT Population - Part

A- Parameter: Visual Analogue Scale - Breathing Problems.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
22

Mean (SD)
1.817
(2.8958)
1.507
(1.9983)
1.745
(2.2236)

Median
0.700
1.000
1.000

Q1, Q3
0.000, 2.000
0.100, 2.000
0.200, 2.600

Min, Max
0.00, 7.50
0.00, 7.50
0.00, 7.50

In-Clinic Visit (Day 12)

n
6
13
21

Mean (SD)
1.200
(2.5084)
1.515
(2.4589)
1.843
(2.9814)

Median
0.200
0.400
0.400

Q1, Q3
0.000, 0.500
0.000, 1.100
0.000, 1.100

Min, Max
0.00, 6.30
0.00, 6.90
0.00, 9.20

Change from Baseline

n
6
13
21

Mean (SD)
−0.617
(0.8819)
−0.015
(1.3656)
0.071
(1.4718)

Median
−0.400
0.000
0.000

Q1, Q3
−1.200, 0.000
−0.800, 0.300
−0.600, 0.300

Min, Max
−2.00, 0.30
−2.00, 3.70
−2.90, 3.70

p-value vs Placebo
0.2181
0.8883

Percent Change

from Baseline

n
4
10
17

Mean (SD)
−8.17
(110.956)
51.98
(211.179)
35.85
(167.709)

Median
−41.33
−21.33
−16.00

Q1, Q3
−83.33, 67.00
−75.00, 115.63
−66.67, 56.00

Min, Max
−100.0, 150.0
−100.0, 600.0
−100.0, 600.0

p-value vs Placebo
0.6745
0.7446

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B14

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline Modified

ITT Population - Part A - Parameter: Visual Analogue Scale - Raynaud's.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
22

Mean (SD)
2.217
(1.4972)
2.336
(2.2893)
3.127
(2.8441)

Median
1.800
1.350
2.300

Q1, Q3
0.900, 3.500
0.900, 3.500
0.900, 5.000

Min, Max
0.90, 4.40
0.00, 8.30
0.00, 10.00

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
1.667
(1.5565)
1.798
(1.8008)
2.544
(2.7261)

Median
1.250
1.250
1.400

Q1, Q3
0.600, 2.600
0.400, 2.700
0.300, 4.300

Min, Max
0.00, 4.30
0.00, 5.20
0.00, 9.20

Change from Baseline

n
6
14
22

Mean (SD)
−0.550
(1.2896)
−0.538
(1.1368)
−0.583
(1.1135)

Median
−0.600
−0.300
−0.300

Q1, Q3
−1.100, −0.100
−0.900, 0.000
−1.100, 0.000

Min, Max
−2.40, 1.50
−3.10, 1.50
−3.10, 1.50

p-value vs Placebo
0.9569
0.9637

Percent Change

from Baseline

n
6
13
21

Mean (SD)
−18.64
(82.784)
−18.26
(58.826)
−23.01
(52.103)

Median
−38.67
−33.33
−33.33

Q1, Q3
−68.57, −2.27
−50.00, 0.00
−50.00, −2.27

Min, Max
−100.0, 136.4
−100.0, 136.4
−100.0, 136.4

p-value vs Placebo
0.6190
0.5135

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B15

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline Modified

ITT Population - Part A Parameter: Visual Analogue Scale - Finger Ulcers.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
21

Mean (SD)
1.367
(1.9562)
1.414
(2.4432)
1.786
(2.9011)

Median
0.650
0.250
0.300

Q1, Q3
0.000, 1.800
0.000, 1.800
0.000, 1.800

Min, Max
0.00, 5.10
0.00, 8.40
0.00, 8.40

In-Clinic Visit (Day 12)

n
6
13
21

Mean (SD)
0.617
(0.7782)
0.900
(1.5524)
1.433
(2.7121)

Median
0.350
0.200
0.200

Q1, Q3
0.000, 1.100
0.000, 1.100
0.000, 1.100

Min, Max
0.00, 1.90
0.00, 5.60
0.00, 9.20

Change from Baseline

n
6
13
20

Mean (SD)
−0.750
(1.3050)
−0.623
(1.1167)
−0.380
(1.0134)

Median
−0.350
−0.100
0.000

Q1, Q3
−1.000, 0.000
−0.700, 0.000
−0.600, 0.000

Min, Max
−3.20, 0.40
−3.20, 0.40
−3.20, 1.00

p-value vs Placebo
0.4401
0.4607

Percent Change

from Baseline

n
4
10
15

Mean (SD)
−17.08
(103.378)
−33.91
(69.617)
−22.65
(66.341)

Median
−50.82
−36.11
−25.00

Q1, Q3
−81.37, 47.22
−100.00, −12.50
−91.67, 3.85

Min, Max
−100.0, 133.3
−100.0, 133.3
−100.0, 133.3

p-value vs Placebo
0.8636
0.6168

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE B16

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline and Percent

Change from Baseline Modified ITT Population - Part A - Parameter:

Visual Analogue Scale - Overall Disease Severity.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 6)
(N = 14)
(N = 22)

Baseline

n
6
14
22

Mean (SD)
3.083
(2.3129)
3.050
(2.2826)
3.209
(2.4923)

Median
2.950
2.500
2.500

Q1, Q3
2.100, 3.400
1.300, 3.800
1.300, 4.700

Min, Max
0.00, 7.10
0.00, 8.10
0.00, 8.10

In-Clinic Visit (Day 12)

n
6
14
22

Mean (SD)
1.733
(1.8063)
2.146
(2.0423)
2.875
(2.7356)

Median
1.300
1.300
2.000

Q1, Q3
0.500, 1.900
0.800, 3.050
0.800, 4.200

Min, Max
0.20, 5.20
0.20, 7.30
0.10, 9.10

Change from Baseline

n
6
14
22

Mean (SD)
−1.350
(0.7765)
−0.904
(1.0412)
−0.334
(1.3683)

Median
−1.550
−1.300
−0.600

Q1, Q3
−1.800, −1.500
−1.650, −0.400
−1.500, 0.200

Min, Max
−1.90, 0.20
−1.90, 1.90
−1.90, 2.40

p-value vs Placebo
0.0426
0.0847

Percent Change

from Baseline

n
5
13
21

Mean (SD)
−51.76
(18.358)
−30.92
(43.026)
−0.24
(85.737)

Median
−51.72
−41.67
−26.76

Q1, Q3
−60.00, −44.12
−51.72, −26.76
−44.74, 16.67

Min, Max
−76.2, −26.8
−76.2, 100.0
−87.5, 300.0

p-value vs Placebo
0.2483
0.3247

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, ax = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS,

TABLE C1

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and

Percent Change from Baseline PP Population - Part A -Parameter: Standard Disability Index.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
0.656
(0.7731)
0.344
(0.2577)
0.550
(0.4202)
0.550
(0.4108)
0.781
(0.8377)
0.813
(0.6654)

Median
0.563
0.375
0.500
0.500
0.750
0.813

Q1, Q3
0.000,
1.313
0.188,
0.500
0.375,
0.750
0.250,
0.500
0.063,
1.500
0.375,
1.250

Min, Max
0.00,
1.50
0.00,
0.63
0.00,
1.13
0.25,
1.25
0.00,
1.63
0.00,
1.63

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
0.656
(0.7731)
0.281
(0.3287)
0.531
(0.4130)
0.513
(0.3812)
0.714
(0.7786)
0.719
(0.7526)

Median
0.563
0.188
0.563
0.375
0.554
0.563

Q1, Q3
0.000,
1.313
0.063,
0.500
0.250,
0.813
0.250,
0.625
0.125,
1.304
0.188,
1.250

Min, Max
0.00,
1.50
0.00,
0.75
0.00,
1.00
0.19,
1.13
0.00,
1.75
0.00,
1.75

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.000
(0.0000)
−0.063
(0.1614)
−0.063
(0.0722)
−0.038
(0.2562)
−0.067
(0.3063)
−0.094
(0.2772)

Median
0.000
−0.063
−0.063
−0.125
0.063
0.000

Q1, Q3
0.000,
0.000
−0.188,
0.063
−0.125,
0.000
−0.125,
0.000
−0.259,
0.125
−0.250,
0.063

Min, Max
0.00,
0.00
−0.25,
0.13
−0.13,
0.00
−0.31,
0.38
−0.52,
0.13
−0.50,
0.13

Percent Change

from Baseline

n
2
3
3
5
3
3

Mean (SD)
0.00
(0.000)
−26.67
(43.716)
−9.26
(8.486)
10.50
(81.517)
23.34
(70.153)
−16.48
(35.421)

Median
0.00
−33.33
−11.11
−10.00
7.69
0.00

Q1, Q3
0.00,
0.00
−66.67,
20.00
−16.67,
0.00
−25.00,
0.00
−37.66,
100.00
−57.14,
7.69

Min, Max
0.0,
0.0
−66.7,
20.0
−16.7,
0.0
−62.5,
150.0
−37.7,
100.0
−57.1,
7.7

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE C2

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Alternative Disability Index.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
0.500
(0.5863)
0.219
(0.1573)
0.450
(0.4472)
0.425
(0.4644)
0.688
(0.7672)
0.594
(0.4719)

Median
0.438
0.250
0.375
0.250
0.563
0.625

Q1, Q3
0.000,
1.000
0.125,
0.313
0.125,
0.625
0.250,
0.250
0.063,
1.313
0.250,
0.938

Min, Max
0.00,
1.13
0.00,
0.38
0.00,
1.13
0.13,
1.25
0.00,
1.63
0.00,
1.13

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
0.563
(0.6575)
0.219
(0.2135)
0.375
(0.4787)
0.413
(0.4366)
0.616
(0.6594)
0.531
(0.5242)

Median
0.500
0.188
0.250
0.250
0.482
0.438

Q1, Q3
0.000,
1.125
0.063,
0.375
0.000,
0.750
0.188,
0.500
0.125,
1.107
0.188,
0.875

Min, Max
0.00,
1.25
0.00,
0.50
0.00,
1.00
0.00,
1.13
0.00,
1.50
0.00,
1.25

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.063
(0.2165)
0.000
(0.1768)
−0.094
(0.0625)
−0.013
(0.2355)
−0.071
(0.1756)
−0.063
(0.2165)

Median
0.000
−0.063
−0.125
−0.063
−0.063
0.000

Q1, Q3
−0.063,
0.188
−0.125,
0.125
−0.125,
−0.063
−0.125,
0.000
−0.205,
0.063
−0.188,
0.063

Min, Max
−0.13,
0.38
−0.13,
0.25
−0.13,
0.00
−0.25,
0.38
−0.29,
0.13
−0.38,
0.13

Percent Change

from Baseline

n
2
3
3
5
3
3

Mean (SD)
15.87
(38.161)
5.56
(82.215)
−43.70
(48.956)
33.00
(154.337)
21.25
(68.998)
−12.96
(32.553)

Median
15.87
−33.33
−20.00
−10.00
−7.69
0.00

Q1, Q3
−11.11,
42.86
−50.00,
100.00
−100.00,
−11.11
−25.00,
0.00
−28.57,
100.00
−50.00,
11.11

Min, Max
−11.1,
42.9
−50.0,
100.0
−100.0,
−11.1
−100.0,
300.0
−28.6,
100.0
−50.0,
11.1

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE C3

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Visual Analogue Scale - Pain.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
4
5
3
4

Mean (SD)
1.975
(1.5283)
2.525
(1.5628)
4.625
(3.9076)
4.320
(2.5352)
3.167
(1.1240)
3.325
(2.2366)

Median
2.150
2.550
4.700
3.200
2.900
3.500

Q1, Q3
0.850,
3.100
1.200,
3.850
1.300,
7.950
3.100,
5.200
2.200,
4.400
1.500,
5.150

Min, Max
0.00,
3.60
0.90,
4.10
0.60,
8.50
1.80,
8.30
2.20,
4.40
0.70,
5.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.875
(1.6641)
1.875
(1.7783)
5.300
(4.1577)
3.260
(1.8955)
2.700
(1.7907)
4.100
(3.1145)

Median
1.950
1.400
5.850
3.800
2.150
4.450

Q1, Q3
0.500,
3.250
0.550,
3.200
1.900,
8.700
2.400,
4.100
1.650,
3.750
1.600,
6.600

Min, Max
0.00,
3.60
0.40,
4.30
0.30,
9.20
0.50,
5.50
1.20,
5.30
0.30,
7.20

Change from

Baseline

n
4
4
3
5
3
4

Mean (SD)
−0.100
(0.4243)
−0.650
(1.1091)
1.000
(0.4359)
−1.060
(1.2219)
−0.300
(1.3115)
0.775
(1.2285)

Median
0.000
−0.650
0.800
−1.100
−0.100
0.500

Q1, Q3
−0.350,
0.150
−1.400,
0.100
0.700,
1.500
−1.300,
−0.700
−1.700,
0.900
0.000,
1.550

Min, Max
−0.70,
0.30
−2.00,
0.70
0.70,
1.50
−2.80,
0.60
−1.70,
0.90
−0.40,
2.50

Percent Change

from Baseline

n
3
4
3
5
3
4

Mean (SD)
−9.88
(27.711)
−34.56
(36.111)
31.35
(37.825)
−26.19
(32.534)
−14.24
(40.419)
7.32
(46.946)

Median
0.00
−51.06
10.81
−22.58
−4.55
16.61

Q1, Q3
−41.18,
11.54
−54.44,
−14.67
8.24,
75.00
−33.73,
−21.15
−58.62,
20.45
−25.00,
39.64

Min, Max
−41.2,
11.5
−55.6,
19.4
8.2,
75.0
−72.2,
18.8
−58.6,
20.5
−57.1,
53.2

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE C4

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A -Parameter: Visual Analogue Scale - Intestinal Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
3

Mean (SD)
2.975
(3.4568)
0.700
(0.6782)
2.700
(3.3593)
2.020
(1.9930)
0.925
(0.9069)
1.100
(1.5620)

Median
2.550
0.650
0.900
1.100
0.950
0.300

Q1, Q3
0.050,
5.900
0.150,
1.250
0.100,
5.100
0.700,
2.500
0.150,
1.700
0.100,
2.900

Min, Max
0.00,
6.80
0.00,
1.50
0.00,
7.40
0.50,
5.30
0.00,
1.80
0.10,
2.90

In-Clinic

Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.100
(1.8221)
0.850
(1.0344)
3.025
(4.3162)
1.310
(0.9317)
1.175
(2.2187)
0.450
(0.4509)

Median
0.300
0.650
1.450
1.700
0.100
0.300

Q1, Q3
0.000,
2.200
0.000,
1.700
0.050,
6.000
0.700,
1.900
0.000,
2.350
0.150,
0.750

Min, Max
0.00,
3.80
0.00,
2.10
0.00,
9.20
0.00,
2.25
0.00,
4.50
0.10,
1.10

Change from

Baseline

n
4
4
4
5
4
3

Mean (SD)
−1.875
(2.1838)
0.150
(0.3873)
−0.125
(1.6800)
−0.710
(1.6846)
0.250
(1.8982)
−0.567
(1.0970)

Median
−1.550
0.150
0.000
−0.250
−0.150
−0.200

Q1, Q3
−3.700,
−0.050
−0.150,
0.450
−1.150,
0.900
−1.100,
0.200
−0.950,
1.450
−1.800,
0.300

Min, Max
−4.40,
0.00
−0.30,
0.60
−2.30,
1.80
−3.40,
1.00
−1.60,
2.90
−1.80,
0.30

Percent

Change from

Baseline

n
3
3
3
5
3
3

Mean (SD)
−77.37
(29.418)
−10.00
(78.102)
−6.92
(35.225)
1.74
(95.142)
−2.55
(159.269)
57.09
(210.380)

Median
−88.00
30.00
0.00
−10.00
−88.89
−62.07

Q1, Q3
−100.00,
−44.12
−100.00,
40.00
−45.10,
24.32
−64.15,
40.00
−100.00,
181.25
−66.67,
300.00

Min, Max
−100.0,
−44.1
−100.0,
40.0
−45.1,
24.3
−100.0,
142.9
−100.0,
181.3
−66.7,
300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE C5

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change

from Baseline and Percent Change from Baseline PP Population -

Part A -Parameter: Visual Analogue Scale - Breathing Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
1.875
1.325
3.240
1.220
1.025
0.525

(3.7500)
(0.8302)
(2.8953)
(0.9550)
(1.4930)
(0.5852)

Median
0.000
1.550
3.100
1.200
0.450
0.250

Q1, Q3
0.000,
0.700,
1.000,
0.800,
0.050,
0.200,

3.750
1.950
5.000
1.500
2.000
0.850

Min, Max
0.00,
0.20,
0.00,
0.00,
0.00,
0.20,

7.50
2.00
7.10
2.60
3.20
1.40

In-Clinic Visit

(Day 12)

n
4
4
4
4
4
4

Mean (SD)
1.575
0.850
4.300
1.175
1.950
0.450

(3.1500)
(1.1210)
(4.8840)
(1.6978)
(3.3131)
(0.3416)

Median
0.000
0.450
4.000
0.550
0.450
0.400

Q1, Q3
0.000,
0.200,
0.100,
0.000,
0.100,
0.200,

3.150
1.500
8.500
2.350
3.800
0.700

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.10,

6.30
2.50
9.20
3.60
6.90
0.90

Change from

Baseline

n
4
4
4
4
4
4

Mean (SD)
−0.300
−0.475
0.500
−0.050
0.925
−0.075

(0.6000)
(1.1815)
(2.5599)
(0.7724)
(1.9138)
(0.3500)

Median
0.000
−0.250
1.050
−0.200
0.300
−0.050

Q1, Q3
−0.600,
−1.400,
−1.450,
−0.600,
−0.300,
−0.350,

0.000
0.450
2.450
0.500
2.150
0.200

Min, Max
−1.20,
−2.00,
−2.90,
−0.80,
−0.60,
−0.50,

0.00
0.60
2.80
1.00
3.70
0.30

Percent Change

from Baseline

n
1
4
3
3
3
4

Mean (SD)
−16.00
3.73
−2.66
−29.40
213.54
24.40

(112.377)
(79.815)
(69.271)
(347.990)
(97.190)

Median
−16.00
−17.54
29.58
−26.67
115.63
7.14

Q1, Q3
−16.00,
−83.33,
−93.55,
−100.00,
−75.00,
−51.19,

−16.00
90.79
56.00
38.46
600.00
100.00

Min, Max
−16.0,
−100.0,
−93.5,
−100.0,
−75.0,
−66.7,

−16.0
150.0
56.0
38.5
600.0
150.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ S.SAS.

TABLE C6

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change

from Baseline and Percent Change from Baseline PP Population -

Part A -Parameter:Visual Analogue Scale - Raynaud's.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
1.600
3.075
4.860
3.640
2.325
3.250

(1.9270)
(1.8839)
(4.0420)
(2.9057)
(3.9911)
(2.3274)

Median
1.000
3.000
6.400
2.400
0.500
2.550

Q1, Q3
0.450,
1.700,
1.200,
1.400,
0.200,
1.750,

2.750
4.450
6.400
5.000
4.450
4.750

Min, Max
0.00,
0.90,
0.30,
1.30,
0.00,
1.30,

4.40
5.40
10.00
8.10
8.30
6.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.925
1.875
4.950
2.635
1.500
2.750

(1.9207)
(1.7154)
(3.7749)
(1.7713)
(2.4752)
(3.6538)

Median
1.700
1.250
5.200
2.700
0.400
1.500

Q1, Q3
0.400,
0.850,
2.200,
1.400,
0.150,
0.150,

3.450
2.900
7.700
4.000
2.850
5.350

Min, Max
0.00,
0.60,
0.20,
0.40,
0.00,
0.10,

4.30
4.40
9.20
4.68
5.20
7.90

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.325
−1.200
−0.825
−1.005
−0.825
−0.500

(1.0468)
(0.8756)
(0.9674)
(1.7864)
(1.5262)
(1.4306)

Median
0.350
−1.050
−0.500
−0.325
−0.150
−0.650

Q1, Q3
−0.500,
−1.750,
−1.500,
−0.900,
−1.700,
−1.600,

1.150
−0.650
−0.150
0.000
0.050
0.600

Min, Max
−0.90,
−2.40,
−2.20,
−4.10,
−3.10,
−2.00,

1.50
−0.30
−0.10
0.30
0.10
1.30

Percent Change

from Baseline

n
3
4
4
5
3
4

Mean (SD)
11.36
−41.11
−19.71
−22.77
−20.78
−41.74

(118.770)
(21.082)
(16.460)
(35.218)
(40.151)
(58.354)

Median
−2.27
−38.67
−20.67
−6.50
−37.35
−47.18

Q1, Q3
−100.00,
−56.29,
−33.85,
−50.62,
−50.00,
−91.61,

136.36
−25.93
−5.56
0.00
25.00
8.12

Min, Max
−100.0,
−68.6,
−34.4,
−69.2,
−50.0,
−92.3,

136.4
−18.5
−3.1
12.5
25.0
19.7

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C7

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change

from Baseline and Percent Change from Baseline PP Population -

Part A -Parameter: Visual Analogue Scale - Finger Ulcers.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
3
5
5
4
3

Mean (SD)
0.700
1.800
1.700
0.620
2.125
3.133

(0.8718)
(2.8618)
(3.6346)
(0.8319)
(4.1836)
(4.0612)

Median
0.500
0.300
0.100
0.200
0.050
1.200

Q1, Q3
0.000,
0.000,
0.000,
0.100,
0.000,
0.400,

1.400
5.100
0.200
0.800
4.250
7.800

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.40,

1.80
5.10
8.20
2.00
8.40
7.80

In-Clinic Visit

(Day 12)

n
4
4
4
5
3
4

Mean (SD)
0.275
0.650
2.325
0.480
1.867
2.275

(0.5500)
(0.8963)
(4.5836)
(0.6380)
(3.2332)
(3.8922)

Median
0.000
0.350
0.050
0.200
0.000
0.450

Q1, Q3
0.000,
0.000,
0.000,
0.000,
0.000,
0.150,

0.550
1.300
4.650
0.700
5.600
4.400

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.10,

1.10
1.90
9.20
1.50
5.60
8.10

Change from

Baseline

n
4
3
4
5
3
3

Mean (SD)
−0.425
−0.933
0.250
−0.140
−0.967
−0.167

(0.5058)
(1.9732)
(0.5000)
(0.2074)
(1.5885)
(0.8083)

Median
−0.350
0.000
0.000
−0.100
−0.100
0.300

Q1, Q3
−0.850,
−3.200,
0.000,
−0.100,
−2.800,
−1.100,

0.000
0.400
0.500
0.000
0.000
0.300

Min, Max
−1.00,
−3.20,
0.00,
−0.50,
−2.80,
−1.10,

0.00
0.40
1.00
0.00
0.00
0.30

Percent Change

from Baseline

n
2
2
2
4
2
3

Mean (SD)
−69.44
35.29
6.10
−34.38
−66.67
−4.27

(43.212)
(138.648)
(8.623)
(44.925)
(47.140)
(83.629)

Median
−69.44
35.29
6.10
−18.75
−66.67
3.85

Q1, Q3
−100.00,
−62.75,
0.00,
−62.50,
−100.00,
−91.67,

−38.89
133.33
12.20
−6.25
−33.33
75.00

Min, Max
−100.0,
−62.7,
0.0,
−100.0,
−100.0,
−91.7,

−38.9
133.3
12.2
0.0
−33.3
75.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C8

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change

from Baseline and Percent Change from Baseline PP Population -

Part A -Parameter: Visual Analogue Scale - Overall Disease Severity.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
2.725
3.125
4.100
3.300
3.600
2.000

(3.2877)
(1.0012)
(3.5235)
(2.3152)
(3.2321)
(1.7963)

Median
1.900
2.950
5.500
1.900
2.550
1.300

Q1, Q3
0.200,
2.500,
0.600,
1.900,
1.250,
0.800,

5.250
3.750
6.500
4.700
5.950
3.200

Min, Max
0.00,
2.10,
0.10,
1.30,
1.20,
0.80,

7.10
4.50
7.80
6.70
8.10
4.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.825
1.125
5.600
2.930
2.750
2.700

(2.4061)
(0.4272)
(4.2528)
(2.1481)
(3.0957)
(1.9511)

Median
1.050
1.300
6.550
3.050
1.500
2.950

Q1, Q3
0.100,
0.850,
2.200,
1.000,
0.800,
1.400,

3.550
1.400
9.000
3.800
4.700
4.000

Min, Max
0.00,
0.50,
0.20,
0.80,
0.70,
0.10,

5.20
1.40
9.10
6.00
7.30
4.80

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
−0.900
−2.000
0.625
−0.370
−0.850
0.700

(0.9695)
(0.7439)
(1.5903)
(1.3636)
(0.5916)
(1.3089)

Median
−0.950
−1.700
0.700
−0.700
−0.650
0.550

Q1, Q3
−1.700,
−2.450,
−0.600,
−1.100,
−1.250,
−0.250,

−0.100
−1.550
1.850
−0.300
−0.450
1.650

Min, Max
−1.90,
−3.10,
−1.30,
−1.65,
−1.70,
−0.70,

0.20
−1.50
2.40
1.90
−0.40
2.40

Percent Change

from Baseline

n
3
4
4
5
4
4

Mean (SD)
−56.96
−64.20
32.49
−5.31
−31.76
66.71

(38.271)
(10.631)
(51.568)
(61.411)
(15.773)
(165.704)

Median
−44.12
−64.44
26.79
−23.08
−36.22
27.17

Q1, Q3
−100.00,
−72.54,
−3.48,
−35.11,
−43.20,
−41.58,

−26.76
−55.86
68.46
−10.45
−20.32
175.00

Min, Max
−100.0,
−76.2,
−23.6,
−57.9,
−44.7,
−87.5,

−26.8
−51.7
100.0
100.0
−9.9
300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C9

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and

Percent Change from Baseline PP Population - Part A - Parameter: Standard Disability Index.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
0.500
(0.5590)
0.653
(0.6020)
0.597
(0.5582)
0.563
(0.6196)
0.611
(0.5447)

Median
0.375
0.500
0.500
0.375
0.500

Q1, Q3
0.000,
0.875
0.250,
1.250
0.250,
1.125
0.063,
1.000
0.125,
1.125

Min, Max
0.00,
1.50
0.00,
1.63
0.00,
1.50
0.00,
1.63
0.00,
1.63

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
0.469
(0.5853)
0.602
(0.5580)
0.576
(0.5500)
0.498
(0.5998)
0.567
(0.5510)

Median
0.188
0.375
0.375
0.250
0.375

Q1, Q3
0.000,
0.938
0.250,
0.857
0.188,
1.125
0.063,
0.804
0.125,
0.857

Min, Max
0.00,
1.50
0.00,
1.75
0.00,
1.50
0.00,
1.75
0.00,
1.75

Change from

Baseline

n
8
9
9
8
25

Mean (SD)
−0.031
(0.1108)
−0.051
(0.2612)
−0.021
(0.1822)
−0.065
(0.2267)
−0.053
(0.1924)

Median
0.000
0.000
0.000
0.000
0.000

Q1, Q3
−0.063,
0.000
−0.125,
0.125
−0.125,
0.000
−0.188,
0.125
−0.125,
0.000

Min, Max
−0.25,
0.13
−0.52,
0.38
−0.31,
0.38
−0.52,
0.13
−0.52,
0.38

Percent Change

from Baseline

n
5
8
7
6
19

Mean (SD)
−16.00
(34.189)
15.32
(72.439)
7.50
(66.755)
−1.66
(59.020)
−1.83
(51.762)

Median
0.00
−5.00
0.00
−12.82
0.00

Q1, Q3
−33.33,
0.00
−31.33,
53.85
−25.00,
0.00
−37.66,
20.00
−33.33,
7.69

Min, Max
−66.7,
20.0
−62.5,
150.0
−62.5,
150.0
−66.7,
100.0
−66.7,
150.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C10

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and

Percent Change from Baseline PP Population - Part A -Parameter: Standard Disability Index.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
0.500
(0.5590)
0.653
(0.6020)
0.597
(0.5582)
0.563
(0.6196)
0.611
(0.5447)

Median
0.375
0.500
0.500
0.375
0.500

Q1, Q3
0.000,
0.875
0.250,
1.250
0.250,
1.125
0.063,
1.000
0.125,
1.125

Min, Max
0.00,
1.50
0.00,
1.63
0.00,
1.50
0.00,
1.63
0.00,
1.63

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
0.469
(0.5853)
0.602
(0.5580)
0.576
(0.5500)
0.498
(0.5998)
0.567
(0.5510)

Median
0.188
0.375
0.375
0.250
0.375

Q1, Q3
0.000,
0.938
0.250,
0.857
0.188,
1.125
0.063,
0.804
0.125,
0.857

Min, Max
0.00,
1.50
0.00,
1.75
0.00,
1.50
0.00,
1.75
0.00,
1.75

Change from

Baseline

n
8
9
9
8
25

Mean (SD)
−0.031
(0.1108)
−0.051
(0.2612)
−0.021
(0.1822)
−0.065
(0.2267)
−0.053
(0.1924)

Median
0.000
0.000
0.000
0.000
0.000

Q1, Q3
−0.063,
0.000
−0.125,
0.125
−0.125,
0.000
−0.188,
0.125
−0.125,
0.000

Min, Max
−0.25,
0.13
−0.52,
0.38
−0.31,
0.38
−0.52,
0.13
−0.52,
0.38

Percent Change

from Baseline

n
5
8
7
6
19

Mean (SD)
−16.00
(34.189)
15.32
(72.439)
7.50
(66.755)
−1.66
(59.020)
−1.83
(51.762)

Median
0.00
−5.00
0.00
−12.82
0.00

Q1, Q3
−33.33,
0.00
−31.33,
53.85
−25.00,
0.00
−37.66,
20.00
−33.33,
7.69

Min, Max
−66.7,
20.0
−62.5,
150.0
−62.5,
150.0
−66.7,
100.0
−66.7,
150.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C11

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Alternative Disability Index.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
0.359
(0.4249)
0.542
(0.5896)
0.458
(0.4881)
0.453
(0.5706)
0.476
(0.4783)

Median
0.250
0.250
0.250
0.250
0.250

Q1, Q3
0.000,
0.625
0.125,
1.000
0.125,
0.875
0.063,
0.688
0.125,
0.875

Min, Max
0.00,
1.13
0.00,
1.63
0.00,
1.25
0.00,
1.63
0.00,
1.63

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
0.391
(0.4884)
0.503
(0.5195)
0.479
(0.5135)
0.417
(0.5010)
0.451
(0.4762)

Median
0.188
0.250
0.250
0.250
0.250

Q1, Q3
0.000,
0.750
0.188,
0.714
0.000,
1.000
0.063,
0.607
0.000,
0.714

Min, Max
0.00,
1.25
0.00,
1.50
0.00,
1.25
0.00,
1.50
0.00,
1.50

Change from

Baseline

n
8
9
9
8
25

Mean (SD)
0.031
(0.1860)
−0.039
(0.2006)
0.021
(0.2165)
−0.036
(0.1675)
−0.029
(0.1789)

Median
0.000
−0.063
0.000
−0.063
0.000

Q1, Q3
−0.125,
0.125
−0.125,
0.000
−0.125,
0.000
−0.125,
0.063
−0.125,
0.000

Min, Max
−0.13,
0.38
−0.29,
0.38
−0.25,
0.38
−0.29,
0.25
−0.38,
0.38

Percent Change

from Baseline

n
5
8
7
6
19

Mean (SD)
9.68
(61.446)
28.59
(122.510)
28.11
(127.250)
13.40
(68.424)
5.64
(88.102)

Median
−11.11
−8.85
−10.00
−18.13
−11.11

Q1, Q3
−33.33,
42.86
−26.79,
50.00
−25.00,
42.86
−33.33,
100.00
−33.33,
11.11

Min, Max
−50.0,
100.0
−100.0,
300.0
−100.0,
300.0
−50.0,
100.0
−100.0,
300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C12

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Visual Analogue Scale - Pain.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
8
9
7
24

Mean (SD)
2.250
(1.4609)
3.888
(2.0952)
3.278
(2.3700)
2.800
(1.3266)
3.371
(2.3310)

Median
2.150
3.150
3.100
2.900
3.000

Q1, Q3
1.200,
3.600
2.550,
4.800
1.800,
3.600
1.500,
4.100
1.750,
4.550

Min, Max
0.00,
4.10
1.80,
8.30
0.00,
8.30
0.90,
4.40
0.00,
8.50

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
1.875
(1.5944)
3.011
(1.7567)
2.644
(1.8352)
2.288
(1.7100)
3.188
(2.5714)

Median
1.550
2.400
2.900
2.100
2.900

Q1, Q3
0.550,
3.250
2.100,
4.100
1.000,
3.800
0.950,
3.250
1.000,
4.300

Min, Max
0.00,
4.30
0.50,
5.50
0.00,
5.50
0.40,
5.30
0.00,
9.20

Change from

Baseline

n
8
8
9
7
23

Mean (SD)
−0.375
(0.8311)
−0.775
(1.2245)
−0.633
(1.0344)
−0.500
(1.1060)
−0.135
(1.1900)

Median
−0.250
−0.900
−0.700
−0.500
0.000

Q1, Q3
−0.750,
0.150
−1.500,
0.250
−1.100,
0.000
−1.700,
0.700
−0.800,
0.700

Min, Max
−2.00,
0.70
−2.80,
0.90
−2.80,
0.60
−2.00,
0.90
−2.80,
2.50

Percent Change

from Baseline

n
7
8
8
7
22

Mean (SD)
−23.98
(32.893)
−21.71
(33.315)
−20.07
(29.925)
−25.85
(36.256)
−9.92
(39.356)

Median
−41.18
−21.87
−21.87
−48.78
−2.27

Q1, Q3
−53.33,
11.54
−46.18,
7.10
−37.46,
5.77
−55.56,
19.44
−48.78,
18.75

Min, Max
−55.6,
19.4
−72.2,
20.5
−72.2,
18.8
−58.6,
20.5
−72.2,
75.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C13

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Visual Analogue Scale - Intestinal Problems.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
25

Mean (SD)
1.838
(2.6071)
1.533
(1.6210)
2.444
(2.5923)
0.813
(0.7511)
1.812
(2.2802)

Median
0.650
1.100
1.100
0.650
0.900

Q1, Q3
0.050,
3.250
0.500,
1.800
0.500,
5.000
0.150,
1.550
0.100,
2.500

Min, Max
0.00,
6.80
0.00,
5.30
0.00,
6.80
0.00,
1.80
0.00,
7.40

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
0.975
(1.3781)
1.250
(1.5116)
1.217
(1.3005)
1.013
(1.6120)
1.318
(2.0789)

Median
0.300
0.700
0.700
0.100
0.400

Q1, Q3
0.000,
1.700
0.000,
1.900
0.000,
1.900
0.000,
1.700
0.000,
1.900

Min, Max
0.00,
3.80
0.00,
4.50
0.00,
3.80
0.00,
4.50
0.00,
9.20

Change from

Baseline

n
8
9
9
8
24

Mean (SD)
−0.863
(1.8110)
−0.283
(1.7396)
−1.228
(1.8933)
0.200
(1.2694)
−0.485
(1.6163)

Median
−0.050
−0.250
−0.250
0.000
−0.050

Q1, Q3
−1.650,
0.150
−1.100,
0.200
−3.000,
0.000
−0.300,
0.450
−1.350,
0.250

Min, Max
−4.40,
0.60
−3.40,
2.90
−4.40,
1.00
−1.60,
2.90
−4.40,
2.90

Percent Change

from Baseline

n
6
8
8
6
20

Mean (SD)
−43.69
(64.404)
0.13
(111.468)
−27.93
(84.240)
−6.27
(112.265)
−5.53
(107.478)

Median
−66.06
−37.08
−54.13
−29.44
−44.61

Q1, Q3
−100.00,
30.00
−94.44,
91.43
−94.00,
15.00
−100.00,
40.00
−88.44,
35.00

Min, Max
−100.0,
40.0
−100.0,
181.3
−100.0,
142.9
−100.0,
181.3
−100.0,
300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C14

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A - Parameter: Visual Analogue Scale - Breathing Problems.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
1.600
(2.5315)
1.133
(1.1413)
1.511
(2.4184)
1.175
(1.1298)
1.588
(2.0963)

Median
0.700
0.800
0.800
1.000
0.900

Q1, Q3
0.000,
1.950
0.100,
1.500
0.000,
1.500
0.150,
1.950
0.100,
2.000

Min, Max
0.00,
7.50
0.00,
3.20
0.00,
7.50
0.00,
3.20
0.00,
7.50

In-Clinic Visit

(Day 12)

n
8
8
8
8
24

Mean (SD)
1.213
(2.2229)
1.563
(2.4721)
1.375
(2.3524)
1.400
(2.3640)
1.717
(2.8331)

Median
0.200
0.450
0.000
0.450
0.350

Q1, Q3
0.000,
1.500
0.000,
2.350
0.000,
2.350
0.100,
1.600
0.000,
1.800

Min, Max
0.00,
6.30
0.00,
6.90
0.00,
6.30
0.00,
6.90
0.00,
9.20

Change from

Baseline

n
8
8
8
8
24

Mean (SD)
−0.388
(0.8725)
0.438
(1.4481)
−0.175
(0.6541)
0.225
(1.6516)
0.088
(1.3769)

Median
0.000
0.000
0.000
0.150
0.000

Q1, Q3
−1.000,
0.150
−0.500,
0.800
−0.600,
0.000
−0.700,
0.600
−0.550,
0.450

Min, Max
−2.00,
0.60
−0.80,
3.70
−1.20,
1.00
−2.00,
3.70
−2.90,
3.70

Percent Change

from Baseline

n
5
6
4
7
18

Mean (SD)
−0.22
(97.721)
92.07
(260.892)
−26.05
(56.955)
93.65
(243.429)
35.61
(162.705)

Median
−16.00
5.90
−21.33
31.58
6.79

Q1, Q3
−66.67,
31.58
−75.00,
115.63
−63.33,
11.23
−75.00,
150.00
−66.67,
56.00

Min, Max
−100.0,
150.0
−100.0,
600.0
−100.0,
38.5
−100.0,
600.0
−100.0,
600.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C15

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A- Parameter: Visual Analogue Scale - Raynaud's.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
A11

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
2.338
(1.9324)
3.056
(3.2673)
2.733
(2.6019)
2.700
(2.9169)
3.212
(2.9194)

Median
1.800
1.400
1.400
1.700
2.300

Q1, Q3
0.900,
3.950
0.600,
5.000
1.100,
4.400
0.500,
4.450
0.900,
5.400

Min, Max
0.00,
5.40
0.00,
8.30
0.00,
8.10
0.00,
8.30
0.00,
10.00

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
1.900
(1.6861)
2.131
(2.0552)
2.319
(1.7585)
1.688
(1.9817)
2.607
(2.6186)

Median
1.250
1.400
2.600
0.850
1.400

Q1, Q3
0.700,
3.450
0.400,
4.000
0.800,
4.000
0.400,
2.900
0.400,
4.300

Min, Max
0.00,
4.40
0.00,
5.20
0.00,
4.68
0.00,
5.20
0.00,
9.20

Change from

Baseline

n
8
9
9
8
25

Mean (SD)
−0.438
(1.2094)
−0.925
(1.5742)
−0.414
(1.5805)
−1.013
(1.1692)
−0.685
(1.2948)

Median
−0.600
−0.300
−0.100
−0.650
−0.300

Q1, Q3
−1.050,
0.350
−0.900,
0.000
−0.900,
0.300
−1.750,
−
−1.100,
0.000

0.150

Min, Max
−2.40,
1.50
−4.10,
0.30
−4.10,
1.50
−3.10,
0.10
−4.10,
1.50

Percent Change

from Baseline

n
7
8
8
7
23

Mean (SD)
−18.62
(75.571)
−22.02
(34.211)
−9.97
(71.072)
−32.40
(29.624)
−24.01
(50.024)

Median
−33.33
−21.92
−4.39
−37.35
−33.33

Q1, Q3
−68.57,
−2.27
−50.31,
6.25
−59.92,
6.25
−50.00,
−18.52
−50.62,
−2.27

Min, Max
−100.0,
136.4
−69.2,
25.0
−100.0,
136.4
−68.6,
25.0
−100.0,
136.4

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C16

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent

Change from Baseline PP Population - Part A- Parameter: Visual Analogue Scale - Finger Ulcers.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
7
9
9
7
24

Mean (SD)
1.171
(1.8590)
1.289
(2.7457)
0.656
(0.7955)
1.986
(3.3928)
1.571
(2.7671)

Median
0.300
0.100
0.200
0.100
0.200

Q1, Q3
0.000,
1.800
0.000,
0.800
0.000,
1.000
0.000,
5.100
0.000,
1.500

Min, Max
0.00,
5.10
0.00,
8.40
0.00,
2.00
0.00,
8.40
0.00,
8.40

In-Clinic Visit

(Day 12)

n
8
8
9
7
24

Mean (SD)
0.463
(0.7170)
1.000
(1.9324)
0.389
(0.5732)
1.171
(2.0758)
1.254
(2.5750)

Median
0.000
0.100
0.000
0.000
0.100

Q1, Q3
0.000,
0.900
0.000,
1.100
0.000,
0.700
0.000,
1.900
0.000,
0.900

Min, Max
0.00,
1.90
0.00,
5.60
0.00,
1.50
0.00,
5.60
0.00,
9.20

Change from

Baseline

n
7
8
9
6
22

Mean (SD)
−0.643
(1.2246)
−0.450
(0.9636)
−0.267
(0.3742)
−0.950
(1.6022)
−0.345
(0.9704)

Median
0.000
−0.100
−0.100
−0.050
0.000

Q1, Q3
−1.000,
0.000
−0.300,
0.000
−0.500,
0.000
−2.800,
0.000
−0.500,
0.000

Min, Max
−3.20,
0.40
−2.80,
0.00
−1.00,
0.00
−3.20,
0.40
−3.20,
1.00

Percent Change

from Baseline

n
4
6
6
4
15

Mean (SD)
−17.08
(103.378)
−45.14
(43.971)
−46.06
(43.731)
−15.69
(103.024)
−22.65
(66.341)

Median
−50.82
−29.17
−31.94
−48.04
−25.00

Q1, Q3
−81.37,
47.22
−100.00,
−12.50
−100.00,
−12.50
−81.37,
50.00
−91.67,
3.85

Min, Max
−100.0,
133.3
−100.0,
0.0
−100.0,
0.0
−100.0,
133.3
−100.0,
133.3

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ_S.SAS.

TABLE C17

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire - Change from Baseline and Percent Change

from Baseline PP Population - Part A -Parameter: Visual Analogue Scale - Overall Disease Severity.

Pooled
Pooled

Cilnidipine
Cilnidipine

10 mg and
20 mg and

Cilnidipine
Cilnidipine

Pooled
10 mg +
20 mg +

Pooled
Cilnidipine +
Tadalafil
Tadalafil
All

Cilnidipine
Tadalafil
5 mg
5 mg
Participants

Statistics
(N = 8)
(N = 9)
(N = 9)
(N = 8)
(N = 26)

Baseline

n
8
9
9
8
26

Mean (SD)
2.925 (2.2601)
3.433 (2.5734)
3.044 (2.6125)
3.363 (2.2296)
3.185 (2.5217)

Median
2.950
1.900
1.900
2.950
2.500

Q1, Q3
1.250, 3.950
1.300, 4.700
1.300, 4.700
1.700, 4.150
1.200, 4.700

Min, Max
0.00, 7.10
1.20, 8.10
0.00, 7.10
1.20, 8.10
0.00, 8.10

In-Clinic Visit

(Day 12)

n
8
9
9
8
25

Mean (SD)
1.475 (1.6430)
2.850 (2.4310)
2.439 (2.1948)
1.938 (2.2226)
2.826 (2.7180)

Median
1.300
2.100
1.900
1.300
1.900

Q1, Q3
0.350, 1.650
0.900, 3.800
0.800, 3.800
0.800, 1.750
0.800, 4.200

Min, Max
0.00, 5.20
0.70, 7.30
0.00, 6.00
0.50, 7.30
0.00, 9.10

Change from

Baseline

n
8
9
9
8
25

Mean (SD)
−1.450 (0.9928)
−0.583 (1.0607)
−0.606 (1.1663)
−1.425 (0.8746)
−0.462 (1.3949)

Median
−1.550
−0.700
−0.700
−1.550
−0.700

Q1, Q3
−1.850, −0.950
−1.100, −0.400
−1.500, −0.300
−1.750, −0.650
−1.500, 0.200

Min, Max
−3.10, 0.20
−1.70, 1.90
−1.90, 1.90
−3.10, −0.40
−3.10, 2.40

Percent Change

from Baseline

n
7
9
8
8
24

Mean (SD)
−61.10 (23.658)
−17.06 (46.620)
−24.68 (57.343)
−47.98 (21.347)
−7.69 (83.524)

Median
−60.00
−30.77
−30.93
−48.23
−28.76

Q1, Q3
−76.19, −44.12
−41.67, −10.45
−51.01, −16.76
−64.44, −36.22
−54.81, 10.51

Min, Max
−100.0, −26.8
−57.9, 100.0
−100.0, 100.0
−76.2, −9.9
−100.0, 300.0

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ_S.SAS.

TABLE D1

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

PP Population - Part A -Parameter: Standard Disability Index.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
0.656
0.344
0.550
0.550
0.781
0.813

(0.7731)
(0.2577)
(0.4202)
(0.4108)
(0.8377)
(0.6654)

Median
0.563
0.375
0.500
0.500
0.750
0.813

Q1, Q3
0.000,
0.188,
0.375,
0.250,
0.063,
0.375,

1.313
0.500
0.750
0.500
1.500
1.250

Min, Max
0.00,
0.00,
0.00,
0.25,
0.00,
0.00,

1.50
0.63
1.13
1.25
1.63
1.63

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
0.656
0.281
0.531
0.513
0.714
0.719

(0.7731)
(0.3287)
(0.4130)
(0.3812)
(0.7786)
(0.7526)

Median
0.563
0.188
0.563
0.375
0.554
0.563

Q1, Q3
0.000,
0.063,
0.250,
0.250,
0.125,
0.188,

1.313
0.500
0.813
0.625
1.304
1.250

Min, Max
0.00,
0.00,
0.00,
0.19,
0.00,
0.00,

1.50
0.75
1.00
1.13
1.75
1.75

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.000
−0.063
−0.063
−0.038
−0.067
−0.094

(0.0000)
(0.1614)
(0.0722)
(0.2562)
(0.3063)
(0.2772)

Median
0.000
−0.063
−0.063
−0.125
0.063
0.000

Q1, Q3
0.000,
−0.188,
−0.125,
−0.125,
−0.259,
−0.250,

0.000
0.063
0.000
0.000
0.125
0.063

Min, Max
0.00,
−0.25,
−0.13,
−0.31,
−0.52,
−0.50,

0.00
0.13
0.00
0.38
0.13
0.13

p-value vs
0.5472
0.8534
0.8397
0.7645
0.9011

Placebo

Percent Change

from Baseline

n
2
3
3
5
3
3

Mean (SD)
0.00
−26.67
−9.26
10.50
23.34
−16.48

(0.000)
(43.716)
(8.486)
(81.517)
(70.153)
(35.421)

Median
0.00
−33.33
−11.11
−10.00
7.69
0.00

Q1, Q3
0.00,
−66.67,
−16.67,
−25.00,
−37.66,
−57.14,

0.00
20.00
0.00
0.00
100.00
7.69

Min, Max
0.0,
−66.7,
−16.7,
−62.5,
−37.7,
−57.1,

0.0
20.0
0.0
150.0
100.0
7.7

p-value vs
0.5048
0.7702
0.7609
0.5434
0.4455

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D2

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

PP Population - Part A- Parameter: Alternative Disability Index.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
0.500
0.219
0.450
0.425
0.688
0.594

(0.5863)
(0.1573)
(0.4472)
(0.4644)
(0.7672)
(0.4719)

Median
0.438
0.250
0.375
0.250
0.563
0.625

Q1, Q3
0.000,
0.125,
0.125,
0.250,
0.063,
0.250,

1.000
0.313
0.625
0.250
1.313
0.938

Min, Max
0.00,
0.00,
0.00,
0.13,
0.00,
0.00,

1.13
0.38
1.13
1.25
1.63
1.13

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
0.563
0.219
0.375
0.413
0.616
0.531

(0.6575)
(0.2135)
(0.4787)
(0.4366)
(0.6594)
(0.5242)

Median
0.500
0.188
0.250
0.250
0.482
0.438

Q1, Q3
0.000,
0.063,
0.000,
0.188,
0.125,
0.188,

1.125
0.375
0.750
0.500
1.107
0.875

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.00,

1.25
0.50
1.00
1.13
1.50
1.25

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.063
0.000
−0.094
−0.013
−0.071
−0.063

(0.2165)
(0.1768)
(0.0625)
(0.2355)
(0.1756)
(0.2165)

Median
0.000
−0.063
−0.125
−0.063
−0.063
0.000

Q1, Q3
−0.063,
−0.125,
−0.125,
−0.125,
−0.205,
−0.188,

0.188
0.125
−0.063
0.000
0.063
0.063

Min, Max
−0.13,
−0.13,
−0.13,
−0.25,
−0.29,
−0.38,

0.38
0.25
0.00
0.38
0.13
0.13

p-value vs
0.4454
0.6710
0.7971
0.7506
0.9511

Placebo

Percent Change

from Baseline

n
2
3
3
5
3
3

Mean (SD)
15.87
5.56
−43.70
33.00
21.25
−12.96

(38.161)
(82.215)
(48.956)
(154.337)
(68.998)
(32.553)

Median
15.87
−33.33
−20.00
−10.00
−7.69
0.00

Q1, Q3
−11.11,
−50.00,
−100.00,
−25.00,
−28.57,
−50.00,

42.86
100.00
−11.11
0.00
100.00
11.11

Min, Max
−11.1,
−50.0,
−100.0,
−100.0,
−28.6,
−50.0,

42.9
100.0
−11.1
300.0
100.0
11.1

p-value vs
0.4741
0.7441
0.4234
0.5514
0.4967

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D3

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

PP Population - Part A-Parameter: Visual Analogue Scale - Pain.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
4
5
3
4

Mean (SD)
1.975
2.525
4.625
4.320
3.167
3.325

(1.5283)
(1.5628)
(3.9076)
(2.5352)
(1.1240)
(2.2366)

Median
2.150
2.550
4.700
3.200
2.900
3.500

Q1, Q3
0.850,
1.200,
1.300,
3.100,
2.200,
1.500,

3.100
3.850
7.950
5.200
4.400
5.150

Min, Max
0.00,
0.90,
0.60,
1.80,
2.20,
0.70,

3.60
4.10
8.50
8.30
4.40
5.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.875
1.875
5.300
3.260
2.700
4.100

(1.6641)
(1.7783)
(4.1577)
(1.8955)
(1.7907)
(3.1145)

Median
1.950
1.400
5.850
3.800
2.150
4.450

Q1, Q3
0.500,
0.550,
1.900,
2.400,
1.650,
1.600,

3.250
3.200
8.700
4.100
3.750
6.600

Min, Max
0.00,
0.40,
0.30,
0.50,
1.20,
0.30,

3.60
4.30
9.20
5.50
5.30
7.20

Change from

Baseline

n
4
4
3
5
3
4

Mean (SD)
−0.100
−0.650
1.000
−1.060
−0.300
0.775

(0.4243)
(1.1091)
(0.4359)
(1.2219)
(1.3115)
(1.2285)

Median
0.000
−0.650
0.800
−1.100
−0.100
0.500

Q1, Q3
−0.350,
−1.400,
0.700,
−1.300,
−1.700,
0.000,

0.150
0.100
1.500
−0.700
0.900
1.550

Min, Max
−0.70,
−2.00,
0.70,
−2.80,
−1.70,
−0.40,

0.30
0.70
1.50
0.60
0.90
2.50

p-value vs
0.2546
0.1364
0.7520
0.0634
0.3285

Placebo

Percent Change

from Baseline

n
3
4
3
5
3
4

Mean (SD)
−9.88
−34.56
31.35
−26.19
−14.24
7.32

(27.711)
(36.111)
(37.825)
(32.534)
(40.419)
(46.946)

Median
0.00
−51.06
10.81
−22.58
−4.55
16.61

Q1, Q3
−41.18,
−54.44,
8.24,
−33.73,
−58.62,
−25.00,

11.54
−14.67
75.00
−21.15
20.45
39.64

Min, Max
−41.2,
−55.6,
8.2,
−72.2,
−58.6,
−57.1,

11.5
19.4
75.0
18.8
20.5
53.2

p-value vs
0.5720
0.2102
0.4879
0.2775
0.5447

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D4

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline PP

Population - Part A -Parameter: Visual Analogue Scale - Intestinal Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
3

Mean (SD)
2.975
0.700
2.700
2.020
0.925
1.100

(3.4568)
(0.6782)
(3.3593)
(1.9930)
(0.9069)
(1.5620)

Median
2.550
0.650
0.900
1.100
0.950
0.300

Q1, Q3
0.050,
0.150,
0.100,
0.700,
0.150,
0.100,

5.900
1.250
5.100
2.500
1.700
2.900

Min, Max
0.00,
0.00,
0.00,
0.50,
0.00,
0.10,

6.80
1.50
7.40
5.30
1.80
2.90

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.100
0.850
3.025
1.310
1.175
0.450

(1.8221)
(1.0344)
(4.3162)
(0.9317)
(2.2187)
(0.4509)

Median
0.300
0.650
1.450
1.700
0.100
0.300

Q1, Q3
0.000,
0.000,
0.050,
0.700,
0.000,
0.150,

2.200
1.700
6.000
1.900
2.350
0.750

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.10,

3.80
2.10
9.20
2.25
4.50
1.10

Change from

Baseline

n
4
4
4
5
4
3

Mean (SD)
−1.875
0.150
−0.125
−0.710
0.250
−0.567

(2.1838)
(0.3873)
(1.6800)
(1.6846)
(1.8982)
(1.0970)

Median
−1.550
0.150
0.000
−0.250
−0.150
−0.200

Q1, Q3
−3.700,
−0.150,
−1.150,
−1.100,
−0.950,
−1.800,

−0.050
0.450
0.900
0.200
1.450
0.300

Min, Max
−4.40,
−0.30,
−2.30,
−3.40,
−1.60,
−1.80,

0.00
0.60
1.80
1.00
2.90
0.30

p-value vs
0.3516
0.3766
0.6921
0.8891
0.5073

Placebo

Percent Change

from Baseline

n
3
3
3
5
3
3

Mean (SD)
−77.37
−10.00
−6.92
1.74
−2.55
57.09

(29.418)
(78.102)
(35.225)
(95.142)
(159.269)
(210.380)

Median
−88.00
30.00
0.00
−10.00
−88.89
−62.07

Q1, Q3
−100.00,
−100.00,
−45.10,
−64.15,
−100.00,
−66.67,

−44.12
40.00
24.32
40.00
181.25
300.00

Min, Max
−100.0,
−100.0,
−45.1,
−100.0,
−100.0,
−66.7,

−44.1
40.0
24.3
142.9
181.3
300.0

p-value vs
0.3836
0.6462
0.6526
0.7014
0.7168

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D5

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline PP

Population - Part A -Parameter: Visual Analogue Scale - Breathing Problems.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
1.875
1.325
3.240
1.220
1.025
0.525

(3.7500)
(0.8302)
(2.8953)
(0.9550)
(1.4930)
(0.5852)

Median
0.000
1.550
3.100
1.200
0.450
0.250

Q1, Q3
0.000,
0.700,
1.000,
0.800,
0.050,
0.200,

3.750
1.950
5.000
1.500
2.000
0.850

Min, Max
0.00,
0.20,
0.00,
0.00,
0.00,
0.20,

7.50
2.00
7.10
2.60
3.20
1.40

In-Clinic Visit

(Day 12)

n
4
4
4
4
4
4

Mean (SD)
1.575
0.850
4.300
1.175
1.950
0.450

(3.1500)
(1.1210)
(4.8840)
(1.6978)
(3.3131)
(0.3416)

Median
0.000
0.450
4.000
0.550
0.450
0.400

Q1, Q3
0.000,
0.200,
0.100,
0.000,
0.100,
0.200,

3.150
1.500
8.500
2.350
3.800
0.700

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.10,

6.30
2.50
9.20
3.60
6.90
0.90

Change from

Baseline

n
4
4
4
4
4
4

Mean (SD)
−0.300
−0.475
0.500
−0.050
0.925
−0.075

(0.6000)
(1.1815)
(2.5599)
(0.7724)
(1.9138)
(0.3500)

Median
0.000
−0.250
1.050
−0.200
0.300
−0.050

Q1, Q3
−0.600,
−1.400,
−1.450,
−0.600,
−0.300,
−0.350,

0.000
0.450
2.450
0.500
2.150
0.200

Min, Max
−1.20,
−2.00,
−2.90,
−0.80,
−0.60,
−0.50,

0.00
0.60
2.80
1.00
3.70
0.30

p-value vs
0.5466
0.5561
0.6854
0.9557
0.3753

Placebo

Percent Change

from Baseline

n
1
4
3
3
3
4

Mean (SD)
−16.00
3.73
−2.66
−29.40
213.54
24.40

(112.377)
(79.815)
(69.271)
(347.990)
(97.190)

Median
−16.00
−17.54
29.58
−26.67
115.63
7.14

Q1, Q3
−16.00,
−83.33,
−93.55,
−100.00,
−75.00,
−51.19,

−16.00
90.79
56.00
38.46
600.00
100.00

Min, Max
−16.0,
−100.0,
−93.5,
−100.0,
−75.0,
−66.7,

−16.0
150.0
56.0
38.5
600.0
150.0

p-value vs

0.7903
0.7032
0.4316
0.4479

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D6

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

PP Population - Part A- Parameter: Visual Analogue Scale - Raynaud's.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
1.600
3.075
4.860
3.640
2.325
3.250

(1.9270)
(1.8839)
(4.0420)
(2.9057)
(3.9911)
(2.3274)

Median
1.000
3.000
6.400
2.400
0.500
2.550

Q1, Q3
0.450,
1.700,
1.200,
1.400,
0.200,
1.750,

2.750
4.450
6.400
5.000
4.450
4.750

Min, Max
0.00,
0.90,
0.30,
1.30,
0.00,
1.30,

4.40
5.40
10.00
8.10
8.30
6.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.925
1.875
4.950
2.635
1.500
2.750

(1.9207)
(1.7154)
(3.7749)
(1.7713)
(2.4752)
(3.6538)

Median
1.700
1.250
5.200
2.700
0.400
1.500

Q1, Q3
0.400,
0.850,
2.200,
1.400,
0.150,
0.150,

3.450
2.900
7.700
4.000
2.850
5.350

Min, Max
0.00,
0.60,
0.20,
0.40,
0.00,
0.10,

4.30
4.40
9.20
4.68
5.20
7.90

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
0.325
−1.200
−0.825
−1.005
−0.825
−0.500

(1.0468)
(0.8756)
(0.9674)
(1.7864)
(1.5262)
(1.4306)

Median
0.350
−1.050
−0.500
−0.325
−0.150
−0.650

Q1, Q3
−0.500,
−1.750,
−1.500,
−0.900,
−1.700,
−1.600,

1.150
−0.650
−0.150
0.000
0.050
0.600

Min, Max
−0.90,
−2.40,
−2.20,
−4.10,
−3.10,
−2.00,

1.50
−0.30
−0.10
0.30
0.10
1.30

p-value vs
0.3910
0.4422
0.7213
0.6520
0.7666

Placebo

Percent Change

from Baseline

n
3
4
4
5
3
4

Mean (SD)
11.36
−41.11
−19.71
−22.77
−20.78
−41.74

(118.770)
(21.082)
(16.460)
(35.218)
(40.151)
(58.354)

Median
−2.27
−38.67
−20.67
−6.50
−37.35
−47.18

Q1, Q3
−100.00,
−56.29,
−33.85,
−50.62,
−50.00,
−91.61,

136.36
−25.93
−5.56
0.00
25.00
8.12

Min, Max
−100.0,
−68.6,
−34.4,
−69.2,
−50.0,
−92.3,

136.4
−18.5
−3.1
12.5
25.0
19.7

p-value vs
0.5321
0.9847
0.5133
0.5934
0.5981

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D7

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients

with Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline

PP Population - Part A -Parameter: Visual Analogue Scale - Finger Ulcers.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
3
5
5
4
3

Mean (SD)
0.700
1.800
1.700
0.620
2.125
3.133

(0.8718)
(2.8618)
(3.6346)
(0.8319)
(4.1836)
(4.0612)

Median
0.500
0.300
0.100
0.200
0.050
1.200

Q1, Q3
0.000,
0.000,
0.000,
0.100,
0.000,
0.400,

1.400
5.100
0.200
0.800
4.250
7.800

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.40,

1.80
5.10
8.20
2.00
8.40
7.80

In-Clinic Visit

(Day 12)

n
4
4
4
5
3
4

Mean (SD)
0.275
0.650
2.325
0.480
1.867
2.275

(0.5500)
(0.8963)
(4.5836)
(0.6380)
(3.2332)
(3.8922)

Median
0.000
0.350
0.050
0.200
0.000
0.450

Q1, Q3
0.000,
0.000,
0.000,
0.000,
0.000,
0.150,

0.550
1.300
4.650
0.700
5.600
4.400

Min, Max
0.00,
0.00,
0.00,
0.00,
0.00,
0.10,

1.10
1.90
9.20
1.50
5.60
8.10

Change from

Baseline

n
4
3
4
5
3
3

Mean (SD)
−0.425
−0.933
0.250
−0.140
−0.967
−0.167

(0.5058)
(1.9732)
(0.5000)
(0.2074)
(1.5885)
(0.8083)

Median
−0.350
0.000
0.000
−0.100
−0.100
0.300

Q1, Q3
−0.850,
−3.200,
0.000,
−0.100,
−2.800,
−1.100,

0.000
0.400
0.500
0.000
0.000
0.300

Min, Max
−1.00,
−3.20,
0.00,
−0.50,
−2.80,
−1.10,

0.00
0.40
1.00
0.00
0.00
0.30

p-value vs
0.6582
0.5828
0.4864
0.9601
0.4941

Placebo

Percent Change

from Baseline

n
2
2
2
4
2
3

Mean (SD)
−69.44
35.29
6.10
−34.38
−66.67
−4.27

(43.212)
(138.648)
(8.623)
(44.925)
(47.140)
(83.629)

Median
−69.44
35.29
6.10
−18.75
−66.67
3.85

Q1, Q3
−100.00,
−62.75,
0.00,
−62.50,
−100.00,
−91.67,

−38.89
133.33
12.20
−6.25
−33.33
75.00

Min, Max
−100.0,
−62.7,
0.0,
−100.0,
−100.0,
−91.7,

−38.9
133.3
12.2
0.0
−33.3
75.0

p-value vs
0.3376
0.7618
0.8505
0.6131
0.3656

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D8

Sensitivity Analysis: Scleroderma Health Assessment

Questionnaire (Patients with Diagnosis of SSc) - Change

from Baseline and Percent Change from Baseline PP Population -

Part A -Parameter: Visual Analogue Scale - Overall Disease Severity.

Cilnidipine
Cilnidipine

10 mg +
20 mg +

Cilnidipine
Cilnidipine
Tadalafil
Tadalafil
Tadalafil

10 mg
20 mg
5 mg
5 mg
5 mg
Placebo

Statistics
(N = 4)
(N = 4)
(N = 5)
(N = 5)
(N = 4)
(N = 4)

Baseline

n
4
4
5
5
4
4

Mean (SD)
2.725
3.125
4.100
3.300
3.600
2.000

(3.2877)
(1.0012)
(3.5235)
(2.3152)
(3.2321)
(1.7963)

Median
1.900
2.950
5.500
1.900
2.550
1.300

Q1, Q3
0.200,
2.500,
0.600,
1.900,
1.250,
0.800,

5.250
3.750
6.500
4.700
5.950
3.200

Min, Max
0.00,
2.10,
0.10,
1.30,
1.20,
0.80,

7.10
4.50
7.80
6.70
8.10
4.60

In-Clinic Visit

(Day 12)

n
4
4
4
5
4
4

Mean (SD)
1.825
1.125
5.600
2.930
2.750
2.700

(2.4061)
(0.4272)
(4.2528)
(2.1481)
(3.0957)
(1.9511)

Median
1.050
1.300
6.550
3.050
1.500
2.950

Q1, Q3
0.100,
0.850,
2.200,
1.000,
0.800,
1.400,

3.550
1.400
9.000
3.800
4.700
4.000

Min, Max
0.00,
0.50,
0.20,
0.80,
0.70,
0.10,

5.20
1.40
9.10
6.00
7.30
4.80

Change from

Baseline

n
4
4
4
5
4
4

Mean (SD)
−0.900
−2.000
0.625
−0.370
−0.850
0.700

(0.9695)
(0.7439)
(1.5903)
(1.3636)
(0.5916)
(1.3089)

Median
−0.950
−1.700
0.700
−0.700
−0.650
0.550

Q1, Q3
−1.700,
−2.450,
−0.600,
−1.100,
−1.250,
−0.250,

−0.100
−1.550
1.850
−0.300
−0.450
1.650

Min, Max
−1.90,
−3.10,
−1.30,
−1.65,
−1.70,
−0.70,

0.20
−1.50
2.40
1.90
−0.40
2.40

p-value vs
0.1012
0.0172
0.9444
0.2723
0.0942

Placebo

Percent Change

from Baseline

n
3
4
4
5
4
4

Mean (SD)
−56.96
−64.20
32.49
−5.31
−31.76
66.71

(38.271)
(10.631)
(51.568)
(61.411)
(15.773)
(165.704)

Median
−44.12
−64.44
26.79
−23.08
−36.22
27.17

Q1, Q3
−100.00,
−72.54,
−3.48,
−35.11,
−43.20,
−41.58,

−26.76
−55.86
68.46
−10.45
−20.32
175.00

Min, Max
−100.0,
−76.2,
−23.6,
−57.9,
−44.7,
−87.5,

−26.8
−51.7
100.0
100.0
−9.9
300.0

p-value vs
0.2342
0.2122
0.7157
0.4597
0.3206

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum.

Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics.

Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12.

This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis.

Program: T_SHAQ2_S.SAS

TABLE D9

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline PP Population - Part

A -Parameter: Standard Disability Index.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
26

Mean (SD)
0.500 (0.5590)
0.581 (0.5693)
0.611 (0.5447)

Median
0.375
0.375
0.500

Q1, Q3
0.000, 0.875
0.125, 1.125
0.125, 1.125

Min, Max
0.00, 1.50
0.00, 1.63
0.00, 1.63

In-Clinic

Visit (Day 12)

n
8
17
25

Mean (SD)
0.469 (0.5853)
0.539 (0.5570)
0.567 (0.5510)

Median
0.188
0.250
0.375

Q1, Q3
0.000, 0.938
0.125, 0.857
0.125, 0.857

Min, Max
0.00, 1.50
0.00, 1.75
0.00, 1.75

Change from

Baseline

n
8
17
25

Mean (SD)
−0.031 (0.1108)
−0.041 (0.1990)
−0.053 (0.1924)

Median
0.000
0.000
0.000

Q1, Q3
−0.063, 0.000
−0.125, 0.000
−0.125, 0.000

Min, Max
−0.25, 0.13
−0.52, 0.38
−0.52, 0.38

p-value vs
0.6898
0.7408

Placebo

Percent Change

from Baseline

n
5
13
19

Mean (SD)
−16.00 (34.189)
3.27 (60.845)
−1.83 (51.762)

Median
0.00
0.00
0.00

Q1, Q3
−33.33, 0.00
−33.33, 7.69
−33.33, 7.69

Min, Max
−66.7, 20.0
−66.7, 150.0
−66.7, 150.0

p-value vs
0.9858
0.4882

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

TABLE D10

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline PP Population - Part

A -Parameter: Alternative Disability Index.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
26

Mean (SD)
0.359 (0.4249)
0.456 (0.5115)
0.476 (0.4783)

Median
0.250
0.250
0.250

Q1, Q3
0.000, 0.625
0.125, 0.875
0.125, 0.875

Min, Max
0.00, 1.13
0.00, 1.63
0.00, 1.63

In-Clinic Visit

(Day 12)

n
8
17
25

Mean (SD)
0.391 (0.4884)
0.450 (0.4926)
0.451 (0.4762)

Median
0.188
0.250
0.250

Q1, Q3
0.000, 0.750
0.000, 0.714
0.000, 0.714

Min, Max
0.00, 1.25
0.00, 1.50
0.00, 1.50

Change from

Baseline

n
8
17
25

Mean (SD)
0.031 (0.1860)
−0.006 (0.1912)
−0.029 (0.1789)

Median
0.000
0.000
0.000

Q1, Q3
−0.125, 0.125
−0.125, 0.000
−0.125, 0.000

Min, Max
−0.13, 0.38
−0.29, 0.38
−0.38, 0.38

p-value vs
0.4906
0.6542

Placebo

Percent Change

from Baseline

n
5
13
19

Mean (SD)
9.68 (61.446)
21.32 (100.525)
5.64 (88.102)

Median
−11.11
−10.00
−11.11

Q1, Q3
−33.33, 42.86
−28.57, 42.86
−33.33, 11.11

Min, Max
−50.0, 100.0
−100.0, 300.0
−100.0, 300.0

p-value vs
0.5218
0.3292

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

TABLE D11

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline

and Percent Change from Baseline PP Population - Part

A -Parameter: Visual Analogue Scale - Pain.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
16
24

Mean (SD)
2.250 (1.4609)
3.069 (1.9390)
3.371 (2.3310)

Median
2.150
3.000
3.000

Q1, Q3
1.200, 3.600
1.750, 3.850
1.750, 4.550

Min, Max
0.00, 4.10
0.00, 8.30
0.00, 8.50

In-Clinic Visit

(Day 12)

n
8
17
25

Mean (SD)
1.875 (1.5944)
2.476 (1.7312)
3.188 (2.5714)

Median
1.550
2.200
2.900

Q1, Q3
0.550, 3.250
1.000, 3.800
1.000, 4.300

Min, Max
0.00, 4.30
0.00, 5.50
0.00, 9.20

Change from

Baseline

n
8
16
23

Mean (SD)
−0.375 (0.8311)
−0.575 (1.0318)
−0.135 (1.1900)

Median
−0.250
−0.600
0.000

Q1, Q3
−0.750, 0.150
−1.200, 0.150
−0.800, 0.700

Min, Max
−2.00, 0.70
−2.80, 0.90
−2.80, 2.50

p-value vs
0.1595
0.1105

Placebo

Percent Change

from Baseline

n
7
15
22

Mean (SD)
−23.98 (32.893)
−22.77 (31.937)
−9.92 (39.356)

Median
−41.18
−22.58
−2.27

Q1, Q3
−53.33, 11.54
−53.33, 11.54
−48.78, 18.75

Min, Max
−55.6, 19.4
−72.2, 20.5
−72.2, 75.0

p-value vs
0.2945
0.2968

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

TABLE D12

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire (Patients with

Diagnosis of SSc) - Change from Baseline and Percent Change from Baseline PP

Population - Part A -Parameter: Visual Analogue Scale - Intestinal Problems.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
25

Mean (SD)
1.838 (2.6071)
1.676 (2.0765)
1.812 (2.2802)

Median
0.650
1.000
0.900

Q1, Q3
0.050, 3.250
0.300, 1.800
0.100, 2.500

Min, Max
0.00, 6.80
0.00, 6.80
0.00, 7.40

In-Clinic Visit

(Day 12)

n
8
17
25

Mean (SD)
0.975 (1.3781)
1.121 (1.4119)
1.318 (2.0789)

Median
0.300
0.600
0.400

Q1, Q3
0.000, 1.700
0.000, 1.900
0.000, 1.900

Min, Max
0.00, 3.80
0.00, 4.50
0.00, 9.20

Change from

Baseline

n
8
17
24

Mean (SD)
−0.863 (1.8110)
−0.556 (1.7427)
−0.485 (1.6163)

Median
−0.050
−0.100
−0.050

Q1, Q3
−1.650, 0.150
−1.100, 0.200
−1.350, 0.250

Min, Max
−4.40, 0.60
−4.40, 2.90
−4.40, 2.90

p-value vs Placebo
0.7532
0.9894

Percent Change

from Baseline

n
6
14
20

Mean (SD)
−43.69 (64.404)
−18.65 (93.767)
−5.53 (107.478)

Median
−66.06
−54.13
−44.61

Q1, Q3
−100.00, 30.00
−100.00, 40.00
−88.44, 35.00

Min, Max
−100.0, 40.0
−100.0, 181.3
−100.0, 300.0

p-value vs Placebo
0.4961
0.5992

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

TABLE D13

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline and Percent

Change from Baseline PP Population - Part A -Parameter: Visual

Analogue Scale - Breathing Problems.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
26

Mean (SD)
1.600 (2.5315)
1.353 (1.8742)
1.588 (2.0963)

Median
0.700
0.800
0.900

Q1, Q3
0.000, 1.950
0.000, 1.900
0.100, 2.000

Min, Max
0.00, 7.50
0.00, 7.50
0.00, 7.50

In-Clinic Visit

(Day 12)

n
8
16
24

Mean (SD)
1.213 (2.2229)
1.388 (2.2783)
1.717 (2.8331)

Median
0.200
0.300
0.350

Q1, Q3
0.000, 1.500
0.000, 1.800
0.000, 1.800

Min, Max
0.00, 6.30
0.00, 6.90
0.00, 9.20

Change from

Baseline

n
8
16
24

Mean (SD)
−0.388 (0.8725)
0.025 (1.2310)
0.088 (1.3769)

Median
0.000
0.000
0.000

Q1, Q3
−1.000, 0.150
−0.700, 0.450
−0.550, 0.450

Min, Max
−2.00, 0.60
−2.00, 3.70
−2.90, 3.70

p-value vs
0.3992
0.7809

Placebo

Percent Change

from Baseline

n
5
11
18

Mean (SD)
−0.22 (97.721)
50.12 (200.437)
35.61 (162.705)

Median
−16.00
−16.00
6.79

Q1, Q3
−66.67, 31.58
−75.00, 115.63
−66.67, 56.00

Min, Max
−100.0, 150.0
−100.0, 600.0
−100.0, 600.0

p-value vs
0.7182
0.7462

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

TABLE D14

Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline and Percent

Change from Baseline PP Population - Part A -Parameter: Visual

Analogue Scale - Raynaud's.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
26

Mean (SD)
2.338 (1.9324)
2.718 (2.6660)
3.212 (2.9194)

Median
1.800
1.400
2.300

Q1, Q3
0.900, 3.950
0.900, 4.400
0.900, 5.400

Min, Max
0.00, 5.40
0.00, 8.30
0.00, 10.00

In-Clinic Visit

(Day 12)

n
8
17
25

Mean (SD)
1.900 (1.6861)
2.022 (1.8357)
2.607 (2.6186)

Median
1.250
1.400
1.400

Q1, Q3
0.700, 3.450
0.500, 4.000
0.400, 4.300

Min, Max
0.00, 4.40
0.00, 5.20
0.00, 9.20

Change from

Baseline

n
8
17
25

Mean (SD)
−0.438 (1.2094)
−0.696 (1.3935)
−0.685 (1.2948)

Median
−0.600
−0.300
−0.300

Q1, Q3
−1.050, 0.350
−1.000, 0.000
−1.100, 0.000

Min, Max
−2.40, 1.50
−4.10, 1.50
−4.10, 1.50

p-value vs
0.9430
0.8157

Placebo

Percent Change

from Baseline

n
7
15
23

Mean (SD)
−18.62 (75.571)
−20.44 (55.098)
−24.01 (50.024)

Median
−33.33
−33.33
−33.33

Q1, Q3
−68.57, −2.27
−50.62, 0.00
−50.62, −2.27

Min, Max
−100.0, 136.4
−100.0, 136.4
−100.0, 136.4

p-value vs
0.5869
0.5434

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

D14: Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline and

Percent Change from Baseline PP Population - Part A - Parameter:

Visual Analogue Scale - Finger Ulcers.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
7
16
24

Mean (SD)
1.171 (1.8590)
1.238 (2.3252)
1.571 (2.7671)

Median
0.300
0.150
0.200

Q1, Q3
0.000, 1.800
0.000, 1.400
0.000, 1.500

Min, Max
0.00, 5.10
0.00, 8.40
0.00, 8.40

In-Clinic Visit

(Day 12)

n
8
16
24

Mean (SD)
0.463 (0.7170)
0.731 (1.4351)
1.254 (2.5750)

Median
0.000
0.000
0.100

Q1, Q3
0.000, 0.900
0.000, 0.900
0.000, 0.900

Min, Max
0.00, 1.90
0.00, 5.60
0.00, 9.20

Change from

Baseline

n
7
15
22

Mean (SD)
−0.643 (1.2246)
−0.540 (1.0568)
−0.345 (0.9704)

Median
0.000
−0.100
0.000

Q1, Q3
−1.000, 0.000
−0.700, 0.000
−0.500, 0.000

Min, Max
−3.20, 0.40
−3.20, 0.40
−3.20, 1.00

p-value vs
0.4962
0.5324

Placebo

Percent Change

from Baseline

n
4
10
15

Mean (SD)
−17.08 (103.378)
−33.91 (69.617)
−22.65 (66.341)

Median
−50.82
−36.11
−25.00

Q1, Q3
−81.37, 47.22
−100.00, −12.50
−91.67, 3.85

Min, Max
−100.0, 133.3
−100.0, 133.3
−100.0, 133.3

p-value vs
0.8636
0.6168

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

D15: Sensitivity Analysis: Scleroderma Health Assessment Questionnaire

(Patients with Diagnosis of SSc) - Change from Baseline and

Percent Change from Baseline PP Population - Part A -Parameter:

Visual Analogue Scale - Overall Disease Severity.

Pooled
Any
All

Cilnidipine
Cilnidipine
Participants

Statistics
(N = 8)
(N = 17)
(N = 26)

Baseline

n
8
17
26

Mean (SD)
2.925 (2.2601)
3.194 (2.3695)
3.185 (2.5217)

Median
2.950
2.900
2.500

Q1, Q3
1.250, 3.950
1.300, 4.500
1.200, 4.700

Min, Max
0.00, 7.10
0.00, 8.10
0.00, 8.10

In-Clinic Visit

(Day 12)

n
8
17
25

Mean (SD)
1.475 (1.6430)
2.203 (2.1532)
2.826 (2.7180)

Median
1.300
1.400
1.900

Q1, Q3
0.350, 1.650
0.800, 3.050
0.800, 4.200

Min, Max
0.00, 5.20
0.00, 7.30
0.00, 9.10

Change from

Baseline

n
8
17
25

Mean (SD)
−1.450 (0.9928)
−0.991 (1.0921)
−0.462 (1.3949)

Median
−1.550
−1.100
−0.700

Q1, Q3
−1.850, −0.950
−1.650, −0.400
−1.500, 0.200

Min, Max
−3.10, 0.20
−3.10, 1.90
−3.10, 2.40

p-value vs
0.0356
0.0741

Placebo

Percent Change

from Baseline

n
7
16
24

Mean (SD)
−61.10 (23.658)
−36.33 (43.497)
−7.69 (83.524)

Median
−60.00
−42.89
−28.76

Q1, Q3
−76.19, −44.12
−58.95, −24.92
−54.81, 10.51

Min, Max
−100.0, −26.8
−100.0, 100.0
−100.0, 300.0

p-value vs
0.2206
0.3027

Placebo

SD = standard deviation, Q1 = 25th percentile, Q3 = 75th percentile, Min = minimum, Max = maximum. Where multiple assessments were performed at a specific visit, the average of the reported results is included in the summary statistics. Subject 01-110 (Cilnidipine 10 mg + Tadalafil 5 mg) reported a Visual Analogue Scale - Breathing Problems score of 10 (Very severe limitations) at Day 12. This result is believed to be erroneous considering the other data at Day 12 and was excluded from this analysis. Program: T_SHAQ2_S.SAS

The Phase 2A study investigated cilnidipine at two doses (10 mg and 20 mg), both as a standalone treatment and in combination with tadalafil, for its impact on secondary Raynaud's symptoms, primarily related to Scleroderma. This initial proof-of-concept trial aimed to assess changes in the frequency of Raynaud's attacks in patients who experienced them frequently. To understand cilnidipine's broader effects on Scleroderma symptoms and outcomes, the Scleroderma Health Assessment Questionnaire (SHAQ®), a validated patient-reported outcome tool, was included in the study methodology. The study, which was double-blinded, prospective, and randomized, included a two-week screening phase to ensure participants met all inclusion and exclusion criteria before randomization and treatment. Following this, patients received two weeks of treatment, with daily assessments via cell phone and an in-clinic evaluation at the study's conclusion, where the SHAQ® was administered.

Data from the study suggest that even a short two-week treatment with cilnidipine can positively affect symptoms, disability, and overall severity of Scleroderma, as assessed by the SHAQ®. This outcome is significant considering the brief treatment duration and the comprehensive improvement across almost all 8 domains of the PRO, compared to placebo, in the groups receiving cilnidipine. Although the number of patients was limited (n=17 across all treatment groups receiving cilnidipine), the observed improvements across various domains indicate meaningful potential. Additionally, the data indicate a dose-response relationship, with the 20 mg dose of cilnidipine showing a broader impact on most parameters evaluated.

Regarding the comparison between monotherapy and combination therapy, cilnidipine alone showed promising results across nearly all evaluated aspects of the disease. However, when cilnidipine was used in combination with a small dose of tadalafil, an additional benefit was observed in the management of finger ulcers, suggesting complementary effects of these treatments without suggesting inferiority of one approach over the other.

TABLE A*

Cilnidipine 20
Placebo

Cilnidipine 20 mg
mg + Tadalafil
(n = 4)

SHAQ PARAMETER
(n = 3) mean %
5 mg (n = 4)
mean %

(minus = improvement)
change
mean % change
change

Standard Disability Index
−50%
−9%
−16%

Alternative Disability
−42%
−10%
−13%

Index

Pain
−53%
−14%
+7%

Intestinal Difficulty
−45% (pooled,
−3%
−52%

n = 7)

Breathing Difficulty
−73%
+90%
−14%

Raynaud's Difficulty
−49%
−35%
−42%

Burden of Finger Ulcers
−17%
−34%
−4%

Overall Scleroderma
−63 (p = 0.02
−32%
+67

Disease Severity
vs. placebo)

The findings are based on factual data analysis and outcomes, focusing on cilnidipine's potential in managing Scleroderma symptoms and improving patient-reported outcomes.

Example 5: Phase 2B and Phase 3 Clinical Trial
Introduction

A Phase 2B study in 50 patients with SSc-RP will include a 6-month open label extension period that will include secondary endpoints to evaluate drug effects on overall SSc disease progression, provide a preliminary estimate of the reduction in adverse clinical events in cilnidipine-treated SSc patients, and validate use of a composite adverse clinical events endpoint to be used in a Phase 3 study. Study results for the treatment of SSc-RP can be analyzed and the database locked prior to completion of the open label extension.

If the Phase 2B study is successful a Phase 3 study for the treatment of SSc-RP and SSc itself with cilnidipine were carried out. The overall development plan will obtain a first approval for cilnidipine for the treatment of SSc-RP, followed by a second approval for treatment of SSc itself.

The Phase 2B and Phase 3 trials will evaluate a slightly higher dose (30 mg cilnidipine) than was used in Example 4. The rationale for the higher dose is that the safety is similar between 10 mg and 20 mg of cilnidipine in Example 4 while efficacy is improved at 20 mg. Cilnidipine is well tolerated at doses >20 mg in patients with hypertension (the Centaur Pharma and DMP Pharma cilnidipine package inserts suggest 20 mg bid [twice daily] may be taken safely), and thus 30 mg may further increase efficacy without a safety tradeoff.

The Phase 2B study, as well as the Phase 3 study, will have co-primary endpoints for the SSc-RP indication:

- 1) A reduction in the weekly frequency of RP attacks in SSc patients, with a target efficacy bar of a >25% reduction in the frequency of RP attacks.
- 2) An ASRAP improvement of 20% from baseline, and a significant difference between the cilnidipine group and the placebo group. The Long form 27 Question ASRAP PRO is a validated instrument to assess the severity and the clinical state of RP. The ASRAP has the strongest correlation with the general health and disease burden of patients with SSc-RP and correlates well with instruments that have previously been used to assess disease severity and disability with SSc-RP patients (see FIG. 7).

The plan for the Phase 3 study, which will in its first part employ the same primacy endpoints as in Phase 2B, is to power the study appropriately such that success on either of the two primary endpoints were considered a trial treatment success. A major difference between the Phase 2B and Phase 3 trials is that the extension period after the two Raynaud's treatment periods (and washout between these periods) is open label in the Phase 2B study and not placebo controlled, whereas the Phase 3 trial will remain blinded, and patients will continue on the treatment they were randomized to for treatment period 2 in the study.

The study design for the Phase 3 is shown in FIG. 6. The Phase 2B trial is a prospective, randomized, double blind, placebo controlled, 1:1 randomization (cilnidipine 30 mg or Placebo once daily in the AM) crossover study, followed by a 24-week open label extension study for which patients may separately consent at the end of treatment period 2 during their in-clinic visit. The primary endpoints for the first part of the Phase 2B study is a significant reduction in the weekly frequency of RP attacks, and a meaningful improvement in ASRAP scores. The open label extension period of the Phase 2B study will collect frequent and robust data and determine the feasibility of a composite clinical event endpoint. The study will also assess the impact of therapy on ACR-CRISS scores, wound (tissue) healing (ulcer severity and rating), inflammation and biomarkers of disease activity (cytokine levels and RNA transcripts), endothelial function (ENDO-pat), and the ASRAP and SHAQ. The study will collect skin and blood samples for these analyses at select clinic visits during the extension period.

In addition to the co-primary endpoints for the SSc-RP indication discussed above, the Phase 3 study will also include co-primary endpoints for the SSc indication:

- 1) Meaningful reduction (to be determined) in composite adverse clinical events.
- 2) Improvement by >20% in 3 of 5 of the ACR-CRISS core set measures.

The composite adverse clinical events endpoint has yet to be finalized and were developed in conjunction with input from the FDA during the pre-IND meeting. This endpoint will likely involve the composite occurrence of disease worsening (EUSTAR Analysis, as validated by Becker 2019) measured by the combined incidence of new digital ulcers, pulmonary hypertension, lung fibrosis and CRP elevation, along with the incidence of renal dysfunction (defined as new occurrence or exacerbation of proteinuria and microalbuminuria, elevations in creatinine >10% from baseline, or ≥10% decline in GFR), new hospitalization for disease complication, and/or new clinic visit for Raynaud's or GI symptoms worsening. It is anticipated that the combined clinical endpoint will occur in ˜50% of placebo-treated patients within one year of randomization and that cilnidipine treatment can reduce the frequency of the composite endpoint by ≥20%. This endpoint were tested in the 24-week open label extension study to be conducted at the end of the Phase 2B study and extrapolated for power and sample size calculations for the Phase 3 study.

A schedule of events and assessments for the US phase 2B and Phase 3 clinical trials are provided in Figure. 8. Additionally, blood samples in the US trials were collected for biomarkers and mRNA transcripts at baseline and in all clinic visits.

Assessments in the US Phase 2B open-label extension study were weekly for patient-reported data on an eCRF cell phone-based application, and each 6 weeks during the open label 24-week, extension period for in-clinic visits for four separate in-clinic assessments.

In the Phase 3 extension study, patient reported data will similarly be collected each week, via a cell phone based eCRF and in-clinic assessments were done every 6 weeks as well for approximately 8 to 9 total in-clinic assessments over the 52-week blinded study.

FIG. 8 shows the schedule for assessments. The figure legend for FIG. 8 is as follows:

*The Procedural Period will consist of two Dosing Periods and were 28 (+5) days in duration.

**Each Dosing Period is 12 (+2) days.

***In-clinic visit should be ideally scheduled at 12 days but could be Day 10 to Day 14; this visit represents the last day of the Dosing Period and is required on the morning of the last day of each Dosing Period (following the morning) to return/dispense study drug.

****Washout period is 4 (+1) days.

*****All patients were requested to report symptoms of SSC-RP in their Diary for 7 days following last dose of study medication. Safety monitoring will continue until 28 (+3) days after last dose.

- 1. Initial screening & capacity conducted via phone, to be finalized prior to randomization.
- 2. Patients willing to participate in the Screening phase will consent when they commence data collection in the Diary. Full signed consent were obtained at Randomization (Day 0) visit prior to randomization.
- 3. Blinded study drug (1 tablet) to be taken daily by mouth in the morning.
- 4. Participants were dispensed with 2 weeks worth of study drug to be taken at home for the following Dosing Period; overage from the prior Dosing Period will also be collected.
- 5. Thermography to be conducted on the most severely impacted digits identified at Screening; participants must be indoors for at least 30 mins prior to the test to give the body time to equilibrate.
- 6. Pharmacokinectic blood sample must be collected within 2 to 6 hours of last dose of study drug, additional clinical laboratory tests may be performed at other times if deemed necessary based on the participant's clinical condition.
- 7. Endo-PAT to be conducted after the participant has been supine for 15 minutes; participant must not be having a Raymond's attack at the time of the test. Participants should fast for at least 4 hours, and refrain from caffeine for at least 8 hours prior to the test.

Abbreviations: AE=Adverse event, ASRAP=Assessment of Scleroderma-associated Raymond's Phenomenon, D=Day, EOS=end of study, FU=Follow-up, DP=Dosing Period, IC=In-clinic visit; WP=Washout period, SAE=Serious adverse event, SHAZ=Scleroderma Health Assessment Questionnaire, UCLA SCTC GIT 2.0=University of California at Los Angeles Scleroderma Clinical Trails Consortium Gastrointestinal Tract 2.0, GERD=Gastroesophageal reflux disease, WO=Wash out.

The study population for both the Phase 2B and Phase 3 trials will be patients with SSc-RP and a frequency of attacks that averages at least 1 attack a day over the screening period. The weekly frequency of attacks is defined as the number of attacks in the last 7 consecutive days for which data is available. This forms the basis for the primary endpoint, the reduction in the frequency of Raynaud's attacks.

The study population will be recruited from the clinic populations with SSC-RP of the various investigators. Previous SSc-RP studies demonstrate average patient recruitment rates for studies of this nature and an indication of approximately 1.5 patients per month per site. With 10 sites participating in the Part 2B study, approximately 15 should be recruited monthly and the Phase 2B study should complete enrollment in 4 months.

The Phase 3 study will take longer; with 125 patients and with 16 sites recruiting 24 patients per month, this study should complete initial enrollment in 7-8 months.

Based on the success of the Phase 3 and blinded extension study another study for patients with SSc that fail screening criteria for the SSc-RP studies will be carried out. The study population would be enriched with inflammatory and clinical markers, making this population more likely to have disease progression during the study period (e.g., some levels of elevated CRP, anti Scl-70 antibodies, endothelin-1, VCAM) and thus be able to demonstrate the potential benefit of cilnidipine on disease progression and mitigating adverse clinical outcomes.

Inclusion criteria for the study are similar to study inclusion criteria in Example 4. Participants aged 18-90 years and diagnosed with SSc and severe secondary Raynaud's disease (Raynaud's Condition Score [RCS]≥40 and at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion) and exhibiting regular and frequent RP attacks (averaging at least one attack per day) during the screening period.

Study Exclusion criteria include: baseline hypotension (SBP<95 mm Hg), known allergy to dihydropyridine CCBs, presence of chronic neuropathic pain condition, inability to complete study assessments, cognitive or language difficulties, use of an investigational product in a clinical study within previous 30 days, unstable nitrate doses with changes to dose in last 2 months, recent orthostatic symptoms or fainting spells in last 3 months, severe cardiomyopathy, history of sympathectomy for Raynaud's treatment, pregnant or lactating patients, women or partners of women of childbearing potential who are unable to comply with study recommendations for contraceptive use during study period, history of recreational drug use or alcoholism, cigarette smokers in excess of 2 pack per day.

Patients will be randomized to study treatment or placebo in each of the Phase 2B and Phase 3 trials through stratified randomization based on baseline RCS score and number of weekly attacks to assure an even distribution of patients with mild, moderate, and severe disease. For RCS cut points will be <3.3, <6.6, and >6.6. For number of weekly attacks cut points will be 7-8, 9-13, 14 or more. Randomization will be stratified to ensure an even number of patients within these groups are distributed between treatment and placebo groups. The goal of stratifying the randomization would be to do a subgroup analysis to determine whether baseline severity of disease affects efficacy of cilnidipine. Some medical therapies currently used to treat SSc-RP have diminished efficacy in more severely affected patients. The statistical consultant will develop specific methods to stratify the randomization to accomplish this objective.

The first part of the Phase 2B study will be blinded to sponsor, patients, and investigators (the open label extension period of this study will not be blinded). The research pharmacies will receive a copy of the randomization sequence but also will be blinded. The data management personnel will have a copy of the randomization code and the research pharmacy will also have a secured copy of the randomization code which can be broken if there is an adverse event that investigators believe warrants unblinding for purposes of treating the adverse event. The attribution as to whether or not the adverse event was related to study medication can be done and should be done without unblinding. The Phase 3 study will also be blinded.

The patient reported outcome measures to be utilized in the study as primary (ASRAP) and secondary (SHAQ and UCLA GIT 2.0) measures have each been validated and studied in separate studies (Yu 2022, Steen 2005, Khanna 2010).

Statistical Plan and Data Analysis

Statistical methods will be further outlined in the statistical analysis plan (SAP). Procedures outlined in the SAP will supersede protocol specified statistical methods in the event of divergence.

Primary and secondary efficacy analyses will be based on the Modified Intent-To-Treat (mITT) population. Analyses based on the ITT and PP population will be considered secondary and confirmatory. All safety analyses will be performed on the safety population.

In general, descriptive statistics (e.g., arithmetic mean, SD, median, minimum and maximum) will be calculated for continuous safety data by treatment and protocol specified time point, while frequency summary (e.g., number of observed and percentage of each category) will be applied for categorical safety data by treatment and protocol specified time point.

The sample size for the US Phase 2B study was calculated based on the available data from Part A of Example 4 clinical trial at the time of the protocol specified data review. Assuming a 2-sided 0.05 alpha for the comparison of cilnidipine 30 mg versus placebo, a between-participants standard deviation (SD) of 35, a correlation between the two measurements on the same participant of 0.2, and a 25% dropout rate, it is estimated that a total sample size of 50 participants (25 in each treatment sequence) is needed, in order to obtain complete data from 42 participants (21 in each treatment sequence), for ≥83% power to detect a decrease of 25 in percentage change from baseline in weekly RP attacks in a 2×2 crossover design.

Analysis Populations

Participant inclusion into each population will be determined prior to the final analysis.

Intent-to-Treat (ITT) Population

All participants who are entered into the study and complete screening, sign an informed consent for the study and randomized will be included in the ITT population.

Modified Intent-to-Treat (mITT) Population

All participants who are entered into the study and complete screening, sign an informed consent for the study and randomized and have post-baseline attack data (primary endpoint data) will be included in the mITT population.

Per Protocol Population

All participants who complete the study with all Dosing Periods and meet all eligibility criteria, and without any major/important protocol deviations, will be included in the PP Analysis Population.

Pharmacokinetic Population

All participants who receive any amount of active study drug and have sufficiently evaluable concentration time profile to allow determination of at least one PK parameter will be included in the PK population. An evaluable PK profile will be determined at the discretion of the pharmacokinetics following examination of participants with dosing or protocol deviations that could potentially affect the PK profile. The PK population will be used for the summaries of all PK data.

Safety Population

All randomized participants who received study drug will be included in Safety population and will be classified according to the actual treatment received.

Statistical Methods
Participant Disposition

Participant disposition will be analyzed using counts and percentages. The number and percentage of screened participants, enrolled participants, treated participants, participants discontinued from the study and study treatment, as well as the primary reason for discontinuation will be analyzed and listed.

Demographics, Medical History, and Baseline Characteristics

Demography and baseline characteristics data will be summarized using descriptive statistics. The following demographic variables will be summarized by dose level: race, gender, age, height and weight, concomitant diseases (hypertension, peripheral vascular disease, diabetes, CKD and stage, osteoporosis, history, and type of heart arrhythmia).

In addition, the following baseline characteristics of Raynaud's Disease will be summarized: age of onset, seasonality (months disease is worst), usual number of attacks per day, usual peak severity, baseline RCS assessment, how attacks are usually treated, how long attacks last in general, experience with other treatments both pharmacological and non-pharmacological.

Prior and Concomitant Medication

Prior and concomitant medications will be coded using the most current version of the WHO drug dictionary available at the start of the study. Prior and concomitant medications will be listed by participant and summarized by treatment using anatomical therapeutic chemical (ATC) and preferred name.

Treatment Compliance and Exposure

Treatment compliance and exposure will be summarized and listed by treatment for all participants in the Safety population.

Analysis of Primary Endpoint

Percent change from baseline evaluation for frequency of weekly RP attacks will be the first primary efficacy endpoint. Data collected in the last 7 days of each dosing period will be used for this analysis. Screening assessments will be used as baseline for the analysis of all periods. No multiple comparison adjustment will be used to control alpha for the multiple comparisons. Mixed effects model will be used for analysis of the primary endpoint according to the crossover design. Other efficacy endpoints of continuous variables will be analyzed using similar methodology. For nominal data, Chi-square tests will be applied. Generalized Estimating Equations method will be used, as appropriate, for adjusting for potential confounding factors.

Analysis of Secondary Endpoints

The secondary endpoints of change from baseline evaluation will be compared among treatment groups using a mixed effects model. Kaplan-Meier method will be used to evaluate time to event endpoints. To evaluate the impact of daily ambient temperature on symptomatic Raynaud's attack, logistic regression will be used for temperature versus the occurrence of Raynaud's attack (Yes/No). The effect of temperature on the severity score of Raynaud's attacks and difference of using rescue medication between treatment groups will be evaluated by Chi-square test. The impact of therapy in sympathetic activity will be assessed by mixed model for repeated measures.

Safety Analyses

All safety assessments, including AEs, laboratory evaluations, vital signs, and other safety assessments will be analyzed using the Safety population.

Example 6. Examples of Patient Assessments
Example 6A. Scleroderma Clinical Trials Consortium Damage Index

Item
Score

Musculoskeletal and skin

Joint contracture defined as any degree of contracture with the inability to reduce
2

the joint to the anatomically neutral position in any small joint of the fingers.*

Joint contracture defined as any degree of contracture with the inability to reduce
2

the joint to the anatomically neutral position in the large joints, specifically

elbows and knees.*

Sicca symptoms defined as presence of dry eyes and/or dry mouth requiring treatment
3

on a daily basis, for example, lubricant eye-drops, punctual plugs, saliva replacement.*

Proximal muscle weakness on clinical examination defined as shoulder abduction
3

and/or hip or knee flexion less than 5/5 power (not due to contracture or pain).*

Calcinosis complicated by infection or requiring surgery.
4

Vascular

Digital ulceration defined as loss of epithelialisation, of any degree, of the epidermis,
2

the dermis and/or the subcutaneous tissue, distal to or at the proximal interphalangeal

joint of the hands or feet not thought to be due to trauma and refractory to therapy*

Add 1 point if digital amputation required (surgical or autoamputation).
1

Gastrointestinal

Oesophageal dysmotility defined as distal dysphagia refractory to treatment, with
1

differential diagnoses (eg, oesophageal stricture or malignancy) excluded by endoscopy.

Oesophageal stricture confirmed on testing such as endoscopy or barium swallow.
1

Symptoms of gastro-oesophageal reflux disease (heart burn) refractory to
1

treatment (eg, proton pump inhibitors) and confirmed on endoscopy.*

Gastric antral vascular ectasia confirmed on endoscopy.
2

Pseudo-obstruction with symptoms such as vomiting or constipation, with
3

dilatation of the small and/or large bowel on imaging.

Low body mass index of <18.5 kg/m²or weight loss of >10% in the last 12 months.
2

Respiratory

Moderate to severe interstitial lung disease >20% extent on HRCT of the chest
2

Add 4 points if forced vital capacity <70% on lung function tests (not due to
4

respiratory muscle weakness).*

Dependence on home oxygen.
5

Cardiovascular

Pulmonary arterial hypertension (defined as mean pulmonary arterial pressure >25 mm
2

Hg at rest and pulmonary arterial wedge pressure <15 mm Hg on right heart catheterisation)

Add 5 points if moderate to severe right ventricular dysfunction noted on
5

echocardiography report based on assessment of any measure of RV function by

experienced cardiologist.

Myocardial disease attributable to SSc based on a constellation of clinical
3

features and supportive investigations, for example, syncope secondary to

conduction abnormality, arrhythmia requiring defibrillator, heartblock requiring

permanent pacemaker or ablation, systolic or diastolic dysfunction on TTE.

Presence of moderate to large pericardial effusion equivalent to greater than 1 cm on TTE.*
1

Renal

History of scleroderma renal crisis (SRC), either hypertensive or normotensive, as
3

defined by the International Scleroderma Renal Crisis Study Investigators.45

Add 1 point if history of SRC or other SSc-related kidney disease and persistent renal
1

impairment with estimated glomerular filtration rate <45 mL/min/1.73 m²

Add 2 points if SRC with stage 5 renal impairment and need for renal
2

replacement therapy

TOTAL SCORE
55

Attribution to SSc required for all items. Decision according to investigator

*Item must be present for a minimum of 6 months.

HRCT, high-resolution CT; RV, right ventricular; SSc, systemic sclerosis; TTE, transthoracic echocardiogram.

How to Fill Out Form:

- 1. Based on investigator's history, physical and review of chart
- 2. If * (Item must be present for a minimum of 6 months), to the best of the investigators' knowledge
- 3. Necessary routine testing: pulmonary function tests; weight and height
- 4. Additional tests to be considered based on other information. Decision left to investigator: ECG, echocardiogram, GFR, UGI endoscopy
- 5. Once an item has been scored as present, that item will always maintain that score. Global score can only increase

Example 6B. Scleroderma Clinical Trials Consortium Activity Index

Item
Score

Skin

≥5-point increase in mRSS within 3 months
7

New areas of skin thickening
7

If previous mRSS unavailable:
1

Patient-reported worsening of skin symptoms in past month: Has your skin been

worse in the past month? (yes/no)

Vascular

Digital tip ulcer defined as loss of epithelialisation of any degree of the epidermis, the
3

dermis and/or subcutaneous tissue, distal to or at the PIP joint of the hands of feet

and thought not due to trauma

Add 1 point if Extra score for multiple digital ulcers concurrently present
1

Critical digital ischaemia defined as acute onset (within 7 days) of persistent, painful
9

discolouration of a digit, associated with reduced capillary refill and cool temperature

due to microvascular complications of SSc and not due to atherosclerosis or

thromboembolic disease

Patient-reported worsening of Raynaud's phenomenon in past month: Has your
1

Raynaud's phenomenon (RP) been worse in the past month (yes/no)

Musculoskeletal

Synovitis
6

Tendon friction rub
7

Myositis defined as presence of proximal muscle weakness on examination in
6

combination with elevated CK and/or aldolase with the presence of myositis

demonstrated on either MRI, EMG or muscle biopsy

Respiratory

Change of FVC of ≥−5% over a period of 6-months and, or
8

DLCO of ≥−10%. over a period of 6-months or
7

At least 10% increased extent of ILD on HRCT over a period of 6-months
7

New diagnosis of ILD on HRCT
4

If previous PFT or HRCT results unavailable:
4

Patient-reported worsening of breathlessness in past month: Have you been more

breathless in the past month (yes/no)

Pulmonary arterial hypertension

Presence of pulmonary arterial hypertension detected for first time by right heart catheterisation
3

Renal

Active scleroderma renal crisis with evidence of ongoing active renal crisis indicated
10

by presence of either; poorly controlled hypertension (not due to other aetiology),

rising serum creatinine and/or haemolysis on blood film at the time of clinical assessment

Cardiac

Acute or subacute systolic dysfunction defined as either a new presentation of
5

cardiac failure due to systolic dysfunction, not due to other causes, or cardiogenic shock

Active myocarditis indicated by the presence of acute inflammation on
9

endomyocardial biopsy, acute inflammation on cardiac MRI or the presence of

new-onset symptoms such as dyspnoea, chest pain or palpitations and

new-onset global or regional ventricular dysfunction on TTE, not attributable

to another cause, in combination with elevated troponin

Acute pericarditis, diagnosed clinically on basis of clinical history and examination
6

findings, supportive ECG changes and/or imaging evidence such as a pericardial

effusion with or without concurrent elevated serum troponin

Elevated troponin
8

Elevated BNP/NT-proBNP
8

Gastrointestinal

Patient-reported worsening of gastrointestinal symptoms in past month: Have your
1

gastrointestinal symptoms been worse in the past month (yes/no)

Laboratory findings

Elevated CRP (above upper limit of normal)
6

Constitutional

Decrease in weight by 10%
6

TOTAL SCORE

Abbreviations:

BNP: B-type natriuretic peptide;

CK: creatine kinase;

DLCO: diffuse capacity of the lung for carbon monoxide;

EMG: electromyography;

FVC: forced vital capacity;

HRCT: high resolution computed tomography of the chest;

ILD; interstitial lung disease;

MRI: magnetic resonance imaging;

mRSS: modified Rodnan Skin Score;

NT-proBNP: N terminal pro B-type natriuretic peptide;

PIP: proximal interphalangeal joint;

SCTC: Scleroderma Clinical Trials Consortium;

SSc: systemic sclerosis;

TTE: transthoracic echocardiogram

Required Tests:

- 1. If previous mRSS unavailable:
  - Patient-reported worsening of skin symptoms in past month (yes/no)
- 2. If previous PFT or HRCT results unavailable:
  - Patient-reported worsening of breathlessness in past month (yes/no)
- 3. Patient-reported worsening of gastrointestinal symptoms in past month (yes/no)
- 4. Patient-reported worsening of Raynaud's phenomenon in past month (yes/no)
- 4. CRP
- 5. Weight
- 6. Pulmonary function tests

Other testing based on investigator's assessment.

Attribution to SSc required for all items. Decision according to investigator.

The disclosures of all publications cited herein are expressly incorporated herein by reference, each in its entirety, to the same extent as if each were incorporated by reference individually.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Number	Date	Country
63534982	Aug 2023	US
63528952	Jul 2023	US
63470053	May 2023	US
63453342	Mar 2023	US

TREATMENT OF SCLERODERMA

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