Patent Application
20250057829
The present inventions relate to inhibitors of transient receptor potential C6 ion channel (TRPC6) for treating patients having focal segmental glomerulosclerosis (FSGS).
Focal segmental glomerulosclerosis (FSGS) is a leading glomerular cause of End Stage Kidney Disease (ESKD) in the United States. FSGS refers to a histologic pattern that is a characteristic of perhaps distinct underlying etiologies sharing a common theme of podocyte injury and depletion. See Rosenberg A Z and Kopp J B, “Focal segmental glomerulosclerosis,” Clin J Am Soc Nephrol 2017; 12(3):502-517.
FSGS is characterized by histologic lesions as opposed to a specific disease. FSGS is a pathophysiological entity which commonly explains the onset of nephrotic syndrome in adult or pediatric patients. Histological abnormalities contain sclerosis in segmental (parts) of focal (some) glomeruli as assessed by microscopic investigation of kidney biopsies.
FSGS is a frequently found histopathologic lesion in adults with nephrotic syndrome within the United States accounting for 35% of all cases and >50% among African Americans. See Haas M et al., “Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997,” Am J Kidney Dis 1997; 30(5):621-631 and Kitiyakara C et al., “Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States,” Am J Kidney Dis 2004; 44(5):815-825.
The classification of FSGS in specific categories is based on various etiologies as defined below:
Primary (idiopathic) FSGS: Frequently presenting with nephrotic syndrome.
Secondary FSGS (sFSGS) or also referred to as adaptive FSGS: Often presenting with non-nephrotic proteinuria and, commonly, with some extent of kidney function impairment. This category is a common adaptive response to hyperfiltration or glomerular hypertrophy and disorders characterized by renal vasodilation and/or kidney mass reduction (e.g. unilateral renal agenesis). Drug- or toxin-induced (e.g. heroin, interferon, pamidronate) and viral-induced (especially HIV) pathologies account for the other causes of sFSGS.
Genetic (familial) FSGS: Presents generally in early childhood with substantial nephrotic syndrome and proteinuria or with less severe proteinuria in adolescence or adulthood.
FSGS classification will depend on a multitude of assessments including clinical history, laboratory testing, kidney biopsy, and in some cases genetic testing. While considerable progress has been achieved with the clinical understanding of FSGS, research is still needed to identify plasma factor(s) believed to be responsible for primary FSGS, to assess the clinical utility of routine genetic testing, and to find more effective and safer therapeutic interventions for FSGS. See Rosenberg A Z and Kopp J B, “Focal segmental glomerulosclerosis,” Clin J Am Soc Nephrol 2017; 12(3):502-517.
A possibly important mechanism related to glomerular dysfunction in proteinuric diseases could be the calcium overload of the podocyte. In subjects with TRPC6 mutations increased podocyte foot process detachment and loss has been observed as a consequence of disruption of the glomerular filtration barrier. Jiang L et al., “Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca2+ and RhoA activation,” Exp Biol Med (Maywood) 2011; 236:184-193 and Tian D et al., “Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels,” Sci Signal 2010; 3(145):ra77. It is hypothesized that increased TRPC6 activity could be a principal mechanism in proteinuric kidney disease driving progression to ESKD. Therefore, the use of a TRPC6 inhibitor, may be a novel treatment option by limiting TRPC6 channel activity in case of pathological Ca2+ entry which should result in preserved podocyte function and reduced podocyte loss.
FSGS is one of the most common forms of acquired glomerular disease leading to ESKD and it is one of the most important causes of acquired chronic kidney disease in children and adults. Kiffel J et al., “Focal segmental glomerulosclerosis and chronic kidney disease in pediatric patients,” Adv Chronic Kidney Dis 2011; 18(5):332-338. Based on a clear biological link between FSGS and gain of function mutations of TRPC6 in this disease and the TRPC6 inhibitory mechanism of action, treatment with an inhibitor of TRPC6 is expected to reduce proteinuria in FSGS thereby reducing disease burden and potential progression.
TRPC6 is expressed in several renal cell types, including podocytes which are key cells for glomerular filtration function of the kidney. Multiple gain of function mutations in TRPC6 have been demonstrated to cause FSGS by elevating intracellular calcium concentration in podocytes and inducing cytoskeletal rearrangements. This has been linked to podocyte apoptosis, foot process detachment and loss of podocytes, leading to disruption of the glomerular filtration barrier. The modulation of TRPC6 activity should therefore have the potential to improve both podocyte function and survival in proteinuric glomerular diseases and specifically in FSGS.
In one embodiment (Embodiment One), the invention relates to methods for reducing the level of proteinuria and/or preserving renal function in a patient having focal segmental glomerulosclerosis (FSGS), comprising administering to the patient in need thereof a pharmaceutically effective amount of a compound of formula (I),
In another embodiment, (Embodiment Two), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Three), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Four), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Five), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Six), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Seven), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Eight), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Nine), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Ten), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Eleven), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Twelve), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Thirteen), the invention relates to the method according to Embodiment One, wherein
In another embodiment, (Embodiment Fourteen), the invention relates to the method according to Embodiment One, wherein
As noted above, the invention relates to methods for treating an FSGS patient, comprising administering to the patient a pharmaceutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
The method of the invention also relates to a compound of formula (I) as defined above, and the pharmaceutically acceptable salts therefore, for use in the treatment of a patient with FSGS.
As used herein, the term “compound of the invention” or “compounds of the invention” refers to any compound embraced by the compound of formula (I) as defined above and in Table 1 below, and the pharmaceutically acceptable salts thereof.
In one embodiment, invention relates to methods for reducing the level of proteinuria in an FSGS patient, comprising administering to the patient a pharmaceutically effective amount of a compound of the invention.
In another embodiment, the invention relates to methods for reducing the level of proteinuria in an FSGS patient, wherein the method provides at least 25% reduction in 24-hour urine protein-creatinine ratio (UPCR) relative to baseline at week 12 in the patient.
In another embodiment, invention relates to methods for preserving renal function in an FSGS patient, comprising administering to the patient a pharmaceutically effective amount of a compound of the invention.
In another embodiment, the invention relates to methods for preserving renal function in an FSGS patient, wherein the method preserves the estimated glomerular filtration rate (eGFR) in the patient. In another embodiment, the eGFR is based on serum cystatin C values.
In another embodiment, invention relates to methods for reducing the level of proteinuria and preserving renal function in an FSGS patient, comprising administering to the patient a pharmaceutically effective amount of a compound of the invention.
In one embodiment, the invention relates to a compound of the invention for use in the treatment of a patient with FSGS.
In another embodiment, invention relates to a compound of the invention for use in reducing the level of proteinuria in an FSGS patient.
In another embodiment, the invention relates to a compound of the invention for use in reducing the level of proteinuria in an FSGS patient, wherein the method provides at least 25% reduction in 24-hour urine protein-creatinine ratio (UPCR) relative to baseline at week 12 in the patient.
In another embodiment, invention relates to a compound of the invention for use in preserving renal function in an FSGS patient. In another embodiment, the preservation of renal function is an improvement in the eGFR of the patient from visit 2 (before first dose) to week 12 and/or 13 using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula based on serum cystatin C for efficacy analysis.
In another embodiment, invention relates to a compound of the invention for use in reducing the level of proteinuria and preserving renal function in an FSGS patient, comprising administering to the patient a pharmaceutically effective amount of a compound of the invention.
Table 1 shows specific compounds of the invention which may be used according to the methods of the invention.
In one embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is selected from any one of the compounds 1 to 95 depicted in Table 1 above, and the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is selected from any one of the compounds 6, 16, 17, 33, 34, 40, 41, 44, 54, 57, 80, 83 and 88 depicted in Table 1; and the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is selected from any one of the compounds 29, 31, 49, 56, 66, 85, 87, and 90 depicted in Table 1; and the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is selected from the group consisting of:
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is selected from the group consisting of:
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone (compound 17 depicted in Table 1); and the pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to any of the methods described herein, wherein the compound of the invention is 6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine (compound 90 depicted in Table 1); and the pharmaceutically acceptable salts thereof.
The terms “treatment” and “treating” comprise therapeutic treatment of patients having already developed one of the conditions described herein, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
The TRPC6 inhibitors of the invention may be prepared according to the methods described in WO2019081637.
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-3-alkyl” means an aryl group, which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
In case a compound is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.
The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, formates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, trifluoroacetates, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like (also see Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19) or with cations from ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.
The term halogen generally denotes fluorine, chlorine, bromine and iodine.
The term “C1-n alkyl”, wherein n is an integer selected from the group consisting of 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5 alkyl embraces the radicals H3C, H3C CH2, H3C CH2CH2, H3CCH(CH3), H3CCH2CH2CH2, H3CCH2CH(CH3), H3CCH(CH3)CH2, H3CC(CH3)2, H3CCH2CH2CH2CH2, H3CCH2CH2CH(CH3), H3CCH2CH(CH3)CH2, H3CCH(CH3)CH2CH2, H3CCH2C(CH3)2, H3CC(CH3)2CH2, H3CCH(CH3)CH(CH3) and H3CCH2CH(CH2CH3).
The term “C3-n cycloalkyl”, wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example, the term C3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
By the term “halo” added to an “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such an alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC—, HF2C—, F3C—. Analogously, the term “halo” added to an aryl group (e.g., phenyl) means that one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine.
The term “carbocyclyl” as used either alone or in combination with another radical, means a mono bi or tricyclic ring structure consisting of 3 to 9 carbon atoms and optionally a heteroatom selected from the group consisting of N, O, and S. The term “carbocyclyl” refers to fully saturated ring systems and encompasses fused, bridged and spirocyclic systems.
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
Some of the compounds in Table 1 can exist in more than one tautomeric form. The invention includes methods for using all such tautomers.
In addition, within the scope of the invention is the use of prodrugs of the TRPC6 inhibitors within the methods of treatment of the invention. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention.
Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
For all compounds disclosed herein above in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defined by the structure.
Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable to the particular dosage form selected. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous.
The compounds of this invention may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. In one embodiment, for example, multiple compounds of the present invention can be administered. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compounds of the invention may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of the invention (w/w) or a combination thereof. The optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds of the present invention and the conventional therapeutics or other adjuvants may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regimen.
As mentioned above, dosage forms of the compounds of this invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable to the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements for the compounds of the present invention may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.
The compounds of the invention may be used alone or in combination of one or more additional therapeutic agents. Nonlimiting examples of additional therapeutic agents may include:
The use of the compounds of the invention to treat FSGS may be shown in the below-described clinical trial.
Applicant found a higher proportion of patients treated with TRPC6 inhibition with Compound 17 show a proteinuria reduction of more than 25% vs their baseline level as compared to patients treated with placebo.
This multicenter, randomized, double-blind, parallel group study will assess 3 doses of a TRPC6 inhibitor of the invention compared to placebo administered orally once daily for 12 weeks in patients with primary or TRPC6 monogenic FSGS.
After completion of all the screening procedures, eligible patients will be randomized into one of the 4 treatment groups stratified by use of corticosteroids and treated for 12 weeks. It is planned to randomize approximately 15 patients in each treatment group. At the end of the treatment period, there will be a follow-up visit at day 7 after end of treatment. A 2nd follow-up visit will be scheduled via telephone, 30 days from end of treatment. Eye exams will be completed at the 2nd follow-up visit. A schematic illustration of the trial design is presented in
A randomized, double-blind, placebo-controlled design is selected for this study. It is standard in studies at this early stage of development to use placebo as a control group in order to evaluate efficacy, safety and tolerability. The conduct of this short duration proof of clinical principal study will be on top of an array of established standard of care modalities including conservative management and steroid-based immunosuppression regimens.
Most FSGS studies on glomerular diseases have used different metrics of proteinuria including UPCR. UPCR will be measured from 24-hour urine in this study.
UPCR reduction ratio (follow-up vs. baseline) for Cyclosporine A (CSA) and mycophenolate mofetil/dexamethasone (MMF/DEX) in a study with adults and children with steroid resistant FSGS was analyzed. Gipson D S, et al., “Clinical trial of focal segmental glomerulosclerosis in children and young adults,” Kidney Int 2011; 80(8):868-878. At week 8, there were approximately 65% and 50% reduction of UPCR for CSA and MMF/DEX, respectively. A 12-week treatment to identify a reduction in UPCR should therefore be sufficient to demonstrate efficacy in the study. In addition, efficacy will further be assessed in this study by the evaluation of UACR and 24-hour proteinuria as secondary endpoints.
This study will randomize approximately 60 patients with primary FSGS or with TRPC6 mutations causing FSGS. It is planned to conduct the study in approximately 55 sites in multiple countries. A sufficient number of patients will be screened to meet the randomization goal.
Study sites in selected countries will have the option of integrating a decentralized clinical trial (DCT) model where the study visits are conducted outside of a dedicated healthcare or research facility. This would allow patients to participate in the trial remotely and complete the study in their own home or residence. The DCT model can bring the clinical trial to patient's homes through telemedicine, a smartphone device, and through the deployment of mobile research nurses (MRN). The MRN will visit the patient's home and complete trial procedures in collaboration with the site principal investigator and study staff.
Sites participating in the DCT model would also continue to enroll patients using the traditional site-based approach where the patient visits the clinic at the specified time points in the protocol. Sites with DCT integration can also allow active ongoing patients in the trial to switch to remote participation. Additional operational guidelines will be provided in a separate DCT operational manual. A copy of the operational manual will be provided in the ISF.
Recruitment of patients for this trial is competitive, i.e. screening for the trial will stop at all sites at the same time once a sufficient number of patients has been screened. Investigators will be notified about screening completion and will then not be allowed to screen additional patients for this trial. Patients already in screening at this time may be allowed to continue to randomization if eligible.
A log of all patients enrolled into the trial (i.e. who have signed informed consent including patients who signed a screening consent or provided verbal consent) will be maintained in the ISF irrespective of whether they have been treated with investigational drug or not. If retrospectively it is found that a patient has been randomized in error (did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be contacted immediately. Based on individual benefit-risk assessment, a decision will be made whether continued trial participation is possible.
The study will include patients with primary FSGS, and patients with monogenic FSGS as a result of TRPC6 mutations.
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole (“withdrawal of consent”) with very different implications (see Discontinuation of Patients from Treatment or Assessments). Every effort should be made to keep the patients in the trial. Measures to control the withdrawal rate include careful patient selection, appropriate explanation of the trial requirements and procedures prior to trial enrollment, as well as the explanation of the consequences of withdrawal. The decision to discontinue trial treatment or withdraw consent to trial participation and the reason must be documented in the patient files and electronic case report forms (eCRF). If applicable, consider the requirements for AE collection reporting (section Assessment of Adverse Events below).
An individual patient will discontinue trial treatment if:
Patient experiences acute kidney injury as per clinical judgement by the investigator and/or according to the modified Kidney Disease: Improving Global Outcomes (KDIGO) definition. See “Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KIDGO clinical practice guideline for acute kidney injury,” Kidney Int Suppl 2012; 2(1):1-138 and adapted for cystatin C as opposed to serum creatinine. Inker L A et al., “CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C,” N Engl J Med 2012; 367(1):20-29 and Levey A S et al., “Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review,” JAMA 2015; 313(8):837-846.
If new efficacy/safety information becomes available, the benefit-risk-assessment will be reviewed and, if needed, paused or discontinued the trial treatment for all patients or take any other appropriate action to guarantee the safety of the trial patients.
If the trial treatment is permanently discontinued, patient should complete the EoT, follow-up (FUP1), and EoS visits as outlined in study procedures in Table 2.
15
X12
X12
X15
X16
X17
X22
Patients may withdraw their consent to trial participation at any time without the need to justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion with the patient and explain the difference between trial treatment discontinuation and withdrawal of consent to trial participation. Investigator should also explain the options for continued follow-up after trial treatment discontinuation.
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons:
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason).
The general description of the investigational test products is shown in Table 3 (TRPCi medicinal product) and Table 4 (placebo).
The proposed dosage of the TRPC6 inhibitor is from 1 to 100 mg.
In one embodiment, the TRPC inhibitor is administered to the patient in an amount of 10 mg, or 12.5 mg, or 15 mg, or 17.5 mg, or 20 mg, or 22.5 mg, or 25 mg, or 27.5 mg, or 30 mg, or 32.5 mg, or 35 mg, or 37.5 mg, or 40 mg, or 42.5 mg, or 45 mg, or 47.5 mg, or 50 mg, or 52.5 mg, or 55 mg, or 57.5 mg, or 60 mg, or 62.5 mg, or 65 mg, or 67.5 mg, or 70 mg, or 72.5 mg, or 75 mg, or 77.5 mg, or 80 mg, or 82.5 mg, or 85 mg, or 87.5 mg, or 90 mg.
In another embodiment, the TRPC inhibitor is administered to the patient in an amount of 20 mg, 40 mg, or 80 mg.
In some embodiments, the proposed dosage may include a low dosage, moderate dosage, and/or a high dosage treatment regimen.
In one embodiment, the amount of the TRPC6 inhibitor in the low dose is from 1 to 30 mg. In another embodiment, the amount of the TRPC6 inhibitor in the low dose is from 5 to 30 mg. In another embodiment, the amount of the TRPC6 inhibitor in the low dose is from 10 to 25 mg. In another embodiment, the amount of the TRPC6 inhibitor in the low dose is from 15 to 25 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the low dose is 10 mg, or 12.5 mg, or 15 mg, or 17.5 mg, or 20 mg, or 22.5 mg, or 25 mg, or 27.5 mg, or 30 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is from 32.5 to 60 mg. In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is from 35 to 45 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 32.5 mg, or 35 mg, or 37.5 mg, or 40 mg, or 42.5 mg, or 45 mg, or 47.5 mg, or 50 mg, or 52.5 mg, or 55 mg, or 57.5 mg, or 60 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the high dose is from 62.5 to 100 mg. In another embodiment, the amount of the TRPC6 inhibitor in the high dose is from 70 to 90 mg. In another embodiment, the amount of the TRPC6 inhibitor in the high dose is from 75 to 85 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the high dose is 62.5 mg, or 65 mg, or 67.5 mg, or 70 mg, or 72.5 mg, or 75 mg, or 77.5 mg, or 80 mg, or 82.5 mg, or 85 mg, or 87.5 mg, or 90 mg, or 92.5 mg, or 95 mg, or 97.5 mg, or 100 mg.
In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 1.25 times the amount in the low dose, and the amount of the TRPC6 inhibitor in the high dose is 2.5 times the amount in the low dose. In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 1.5 times the amount in the low dose, and the amount of the TRPC6 inhibitor in the high dose is 3 times the amount in the low dose. In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 2 times the amount in the low dose, and the amount of the TRPC6 inhibitor in the high dose is 4 times the amount in the low dose. In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 2.25 times the amount in the low dose, and the amount of the TRPC6 inhibitor in the high dose is 4.5 times the amount in the low dose. In another embodiment, the amount of the TRPC6 inhibitor in the moderate dose is 2.5 times the amount in the low dose, and the amount of the TRPC6 inhibitor in the high dose is 5 times the amount in the low dose.
In another embodiment, the low dose, moderate dose, and high dose are 10 mg, 20 mg, and 30 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 15 mg, 30 mg, and 45 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 20 mg, 40 mg, and 60 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 10 mg, 20 mg, and 40 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 20 mg, 40 mg, and 80 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 10 mg, 25 mg, and 50 mg, respectively. In another embodiment, the low dose, moderate dose, and high dose are 20 mg, 50 mg, and 100 mg, respectively.
In one embodiment, the TRPC6 inhibitor is administered to the patient once daily. In another embodiment, TRPC6 inhibitor is administered to the patient twice daily. In another embodiment, TRPC6 inhibitor is administered to the patient thrice daily.
In another embodiment, the TRPC6 inhibitor is administered to the patient in a total daily amount of 20 mg. In another embodiment, the TRPC6 inhibitor is administered to the patient in a total daily amount of 40 mg. In another embodiment, the TRPC6 inhibitor is administered to the patient in a total daily amount of 80 mg.
In one embodiment, the therapeutic dose of the TRPC6 inhibitor of the invention is between 20 and 40 mg. However, in the absence of the possibility to assess target engagement in humans and given the uncertainty of a demonstrable pharmacodynamic effect solely based on in vitro dose estimation, a higher exposure (at multiples of IC90) may be needed to observe a therapeutic response in vivo.
From an efficacy perspective, in this mechanistic study, high doses of TRPC6 inhibitor of the invention (above the anticipated therapeutic dose) are investigated in order to explore whether TRPC6 inhibition induces a clinically meaningful UPCR response in patients with primary or TRPC6 monogenic FSGS. Beyond the establishment of the proof of clinical principle, which is a key objective in this trial, future studies, including a dedicated Phase 2 dose finding trial will enable a thorough investigation of therapeutic doses and the establishment of the minimum effective dose.
After the assessment of all inclusion and exclusion criteria, each eligible patient will be randomized to one of the treatment groups according to the randomization plan in a 1:1:1:1 ratio via Interactive Response Technology (IRT). Randomization will be stratified by use of corticosteroids.
Note that the trial medication number is different from the patient number (the latter is generated during screening via the IRT System). A total of 60 patients will be randomized with approximately 15 patients in each treatment group. Patients randomized by error and did not receive any trial medication may be replaced.
Table 5 shows the trial medication schedule for each treatment group.
After eligibility of the patient is confirmed during the screening period, patient will be randomized in the IRT Platform at least 7 days before the scheduled visit 2 date. Randomization will initiate the direct shipment of trial medication to the patient. Each patient will receive trial medication from an external depot contracted by the sponsor. Patient's name and address will not be made available to the sponsor. Patient will receive sufficient trial medication for the entire 12-week duration of the treatment period.
Prior to shipment of the trial medication, study site staff will train the patient on handling, storage, and use of the trial medication. Site staff should contact the patient by telephone (video call if possible) in about 24 hours (or next working day) after the site receives the delivery notification from the courier. During this contact, the site should remind the patient of the proper storage requirements for the medication. The patient should also be instructed not to open the trial medication package and to bring all the medication to the clinic for visit 2.
Medication from one of the bottles will be used to dose the patient at visit 2. Site staff will inspect the shipment to ensure patient has received all the medication. All trial medication (except the capsule used for dosing at visit 2) will be returned to the patient with instructions for administration of medication at home.
The route of administration is by mouth (p.o.). Trial treatment may be restarted after temporary discontinuation. Dose reduction or increase are not allowed.
On study visit days, trial medication will be administered at the specified time (see Table 6).
1Post dose ECG should be performed either before or at least 10 min after PK blood sample.
2At selected sites, additional PK samples at planned times 673:00, 1343:55 and 2022:00 will be taken and acidified for CD 7949 quantification. Details on the handling and acidification of these specific samples will be provided in the laboratory manual.
3+/−15 minutes for post dose sample draws.
Patient should be instructed to bring all used and unused bottles to the clinic for each study visit. Site staff will inspect all the trial medication and also calculate compliance by capsule count. Site will destroy the empty bottles with documentation and re-dispense the remaining medication to the patient at each study visit. At the EoT visit all remaining used and unused bottles with trial medication will be collected from the patient. Study visits should be rescheduled if trial medication is not available for dosing the patient after the pre-dose PK sample is drawn.
If local regulations or site procedures or if the patient does not permit shipment of the trial medication directly to the patient, medication can be shipped to the study site. Randomization will still be completed at least 7 days before the scheduled visit 2 date to initiate trial medication shipment to the site. Site staff will dispense the trial medication to the patient.
Unscheduled supply of trial medication can be initiated by the study site in the IRT. Patient should contact the site if a need for additional medication supply arises.
A paper diary will be dispensed and collected at time points shown in Table 2. Patient will record the date and time of trial medication intake in the diary on the 3 days before EoT visit, and on the previous day for all other visits. Patients should be instructed to bring the completed diary for review by the site staff. Date and time of medication intake for the 3 days prior to EoT as well as the previous day for all other visits will be entered in the eCRF. Date and time of medication intake during the study visit will also be entered in the eCRF. A copy of the paper diary will be placed in the ISF.
For patients participating in the trial remotely via the DCT model, the MRN will visit the patient's home for the study visit and complete the trial procedures including inspection of the trial medication, providing instructions for administration of medication at home, administering trial medication at the specified time during the study visit, and review of the paper diary. Additional guidance on remote study visits will be provided in a separate DCT operational manual which will include instructions for handling used empty bottles and unused trial medication.
During the COVID-19 pandemic physical visits to the sites (for patients not participating in the DCT model) may need to be restricted to ensure patient safety. Based on a thorough assessment of the benefits and risks, the investigator may still decide to continue the trial treatment, after discussion with the sponsor.
The trial has a double-blind design. The randomization schemes and medication kit lists (i.e. the treatment information) will be handled according to the sponsor's Standard Operating Procedures (SOPs).
Below (Table 7) is a summary of the roles/function and the timing of unblinding.
Refer to Unblinding and Breaking the Code for rules of breaking the code for an individual or for all patients in emergency situations.
Unblinding and breaking the code Emergency unblinding will be available to the investigator via IRT. It must be used only in an emergency situation when the identity of the trial drug must be known to the investigator in order to provide appropriate medical treatment or otherwise assure safety of trial participants.
The reason for unblinding must be documented in the source documents and/or appropriate CRF page. If the patient is unblinded by the investigator, patient will have to be discontinued from the trial. Discontinued patients will complete the EoT and follow-up visits.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions (SUSARs), it may be necessary for a representative from BI's Pharmacovigilance group to access the randomization code for individual patients during trial conduct. The access to the code will only be given to authorized Pharmacovigilance representatives for processing in the PV database system and not be shared further.
The investigational medicinal products will be provided by BI or a designated contract research organization (CRO). They will be packaged and labelled in accordance with the principles of Good Manufacturing Practice. Re-supply (if necessary) will be managed via the IRT system. For details of packaging and the description of the label, refer to the ISF.
Drug supplies will be kept in their original packaging according to the recommended storage conditions on the medication label. Patients will be instructed to store the medication in a secure area. Site staff will train the patients on storage conditions. Patients will not maintain a temperature log.
If shipment of trial medication to the site becomes necessary, sites should store the medication in a secure limited access storage area according to the recommended storage conditions on the medication label and maintain a temperature log until the medication is dispensed to the patient. If the storage conditions are found outside the specified range, procedure described in the ISF has to be followed and a Clinical Research Associate (CRA) should be contacted immediately.
The patient will receive the investigational drug delivered by the sponsor when the following requirements are fulfilled at the study site:
Investigational drugs are not allowed to be used outside the context of this protocol. They must not be forwarded to other investigators or clinics. Patients should be instructed to return all unused investigational drug.
The investigator or designee must maintain records of the product's delivery to the patient, the use by each patient, and the return to the sponsor or warehouse/drug distribution center or alternative disposal of unused products. If applicable, the sponsor or warehouse/drug distribution center will maintain records of the disposal. These records will include dates, quantities, batch/serial numbers, expiry (‘use-by’) dates, and the unique code numbers assigned to the investigational medicinal product and trial patients. The investigator or designee will maintain records that document adequately that the patients were provided the doses specified by the Clinical Trial Protocol and reconcile all investigational medicinal products the patient received from the sponsor. At the time of return to the sponsor and/or appointed CRO, the investigator or designee must verify that all unused or partially used drug supplies have been returned by the patient and that no remaining supplies are in the investigator's possession.
There are no special emergency procedures to be followed in this trial.
Table 8 shows restrictions regarding concomitant treatment
Additional information, including a list of drugs that should be avoided, is provided in the ISF for the following classes of medications: immunosuppressive agents, strong inhibitors/inducers of CYP3A4/5, UGT1A4, drugs which are known P-gp substrates of narrow therapeutic window, and OCT2, MATE1, or MATE2-K substrates as well as agents known to prolong the QT interval.
Medications listed under the exclusion criteria are not allowed during the trial. When possible, use of restricted medications and impact on treatment discontinuation should be discussed with the sponsor. There are no restrictions for trial participant to receive vaccination for COVID-19 during or after the study period.
Restrictions on Diet and Lifestyle Patients should avoid high protein, high salt diet. Avoidance of dietary protein load and strenuous exercise is especially important within 24 hours prior to the start and until the completion of the 24-hour urine collections.
WOCBP and their male sexual partner must use two medically approved methods of birth control during the treatment period and for a period of at least 5 days after last trial drug intake. Male partner of a WOCBP trial participant who is able to father a child must use a condom.
WOCBP (trial participant) must use a highly effective method of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and correctly. Birth control methods with low user dependency, as indicated with an asterisk (*) below are preferable.
Acceptable methods of birth control will include abstinence from male-female sex or having a vasectomized partner, provided that partner is the sole sexual partner of the trial participant who is a WOCBP, and that the vasectomized partner has received medical assessment of the surgical success.
Abstinence from male-female sex is defined as being in line with the preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the duration of exposure to study drug; and withdrawal are not acceptable.
Since the TRPC6 inhibitor is not expected to lead to a clinically relevant reduction in the exposure of oral contraceptives due to an increased metabolism via enzyme induction, oral contraceptives are allowed in this trial.
Patients are requested to bring all remaining trial medication including empty bottles with them when attending visits. Based on capsule counts, treatment compliance will be calculated as shown in the formula below.
Compliance will be verified by the CRA authorized by the sponsor or delegate. The target for medication compliance should be 100%. If patient is non-compliant, site staff will explain to the patient the importance of treatment compliance. Randomized patients will not be discontinued from the trial for poor medication compliance without prior discussion with the Clinical Trial Manager (CT Manager) appointed by the sponsor.
For patients participating in the trial remotely via the DCT model, compliance will be calculated by the MRN, and all unused trial medication and empty bottles will be collected by the MRN and returned to the study site or an alternative location for disposal. Shipment schedule and guidelines will be described in the DCT operational manual. The investigator or designee must verify that all unused trial medication has been returned by the patient and that no remaining supplies are at the patient's home.
The primary endpoint is patients achieving at least 25% reduction in UPCR from 24-hour urine relative to baseline after 12 weeks of treatment. The baseline UPCR will be from the average of two 24-hour urine samples collected before visit 2.
Secondary and further endpoints are listed in under Secondary Endpoints and Further Endpoints., respectively, and they will be assessed as follows:
For additional information on urine sample collections and the time points, see the Visit Schedule and Table 2.
3.1.2 eGFR Assessments
For the assessment of the further endpoint, eGFR measurements collected at visit 2 (before first dose) will be used as baseline and compared to the measurements at week 12 and 13. The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula based on serum cystatin C will be used for efficacy analysis.
A complete physical examination will be performed at the time points specified in Table 2. It includes at a minimum general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. Measurement of height and body weight will be performed at the time points specified in Table 2. The results must be included in the source documents available at the site.
For patients participating in the trial remotely via the DCT model, a physical examination per protocol will be performed at the patient's home at the time points specified in the study protocol. The investigator or a designee (as indicated in the site trial staff list) will supervise the physical examination remotely. A MRN will facilitate the physical examination in the patient's home.
For patients participating in the trial remotely, if during the physical examination (PE) or at any time during the trial it is deemed that the patient requires in-person follow-up, the patient will be advised to visit the study site or their healthcare provider or a local facility for consultation. When applicable, the study site staff will contact the local healthcare facility to obtain the medical records.
Vital signs will be evaluated at the time points specified in Table 2, prior to blood sampling. This includes systolic and diastolic blood pressure and pulse rate (electronically or by palpation count for 1 minute) in a seated position after 5 minutes of rest. Assessment for uncontrolled hypertension is completed at Visit 1 only. Three blood pressure measurements will be taken approximately 2 minutes apart after the patient has rested quietly and is in a seated position for at least 5 minutes. The average of the last two measurements for the triplicate systolic blood pressure measurements should be <160 mmHg for assessment of exclusion criteria 5 at the screening visit. For subsequent visits, triplicate measurements are needed only if the first reading is >160 mmHg, the average of the last two measurements are taken as the final reading. The results must be included in the source documents available at the site.
Safety laboratory parameters to be assessed are listed in Table 9. Sampling time points are provided in Table 2.
All analyses will be performed by a central laboratory, and the respective reference ranges will be provided in the laboratory manual. Instructions regarding sample collection, sample handling, processing, and shipping are provided in the laboratory manual.
If central lab services or the lab kits provided by the central lab are not available at the study site, safety labs may be done at a local lab. The results of the lab tests should be entered in the eCRF. Please note the local labs should be used only if it becomes necessary, and the CT Manager should be informed.
For patients participating in the trial remotely via the DCT model, laboratory kits will be made available at the patient's home for the respective visits. The MRN will collect, process, and ship lab samples to the central laboratory or the study site (when applicable). Additional information will be provided in the DCT operations manual.
Patients do not have to be fasted for the blood sampling for the safety laboratory.
The central laboratory will send laboratory reports to the investigator. It is the responsibility of the investigator to evaluate the reports. Clinically relevant abnormal findings as judged by the investigator will be reported as AEs.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be performed (see the Definition of AEs and the DILI Checklist provided in the electronic data capture (EDC) system). The amount of blood taken from the patient concerned will be increased due to this additional sampling for DILI assessments. The central laboratory will transfer the data to the sponsor periodically.
For assessment of eGFR exclusion criterion, the CKD-EPI formula based on serum creatinine and serum cystatin C will be used. The serum cystatin C-based CKD-EPI formula will be used for the calculation of eGFR in the evaluation of efficacy. For sensitivity analysis, eGFR will also be calculated using CKD-EPI formula based on serum creatinine. Inker L A et al., “CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C,” N Engl J Med 2012; 367(1):20-29.
1If initial CK is elevated, re-test CK with CK-MB and troponin I.
2Reported to the investigator only up to visit 2.
3eGFR based on serum creatinine and cystatin C will be reported to the investigator only up to visit 2.
4eGFR based on serum cystatin C will be reported to the investigator from visit 2 onwards.
5Only at screening visit.
Centralized ECG services will be provided by an external vendor. Standardized equipment and a quick guide will be provided by the vendor. ECGs should be collected according to the study-specific recommendations, using the standardized equipment provided by the vendor.
The 12-lead ECGs will be recorded at the time points shown in the Table 2. ECGs should be recorded or at least 10 minutes after before blood samples are drawn. Patients should be supine for approximately 5 to 10 minutes before ECG collection. Patients should remain supine, but awake, during the ECG collection process.
After the screening visit, the investigator must review the ECG results from central reading to ensure that patient is eligible to participate in the study. Starting at visit 2, ECGs will be recorded at two time points at each study visit: pre-dose and at 1 to 2 hours post-dose. ECGs may be repeated for quality or safety reasons.
ECG recordings will be transmitted electronically to a vendor for central reading. ECGs will be centrally evaluated and rated as normal, abnormal, or unable to evaluate, and the results will be sent to the study site. The investigator should review the report from central reading. If the ECG is rated as abnormal, the investigator will determine if the abnormal findings are clinically significant. The investigator will have the responsibility to follow up with the patient if there are any clinically significant findings in the ECG report.
At the screening visit, ECGs are done in triplicate (3 single ECGs recorded within 180 seconds). The QTcF value used to check eligibility at the screening visit is the average of the three recordings. Any pre-existing conditions should be recorded as baseline conditions.
Pre-dose ECGs at the first dosing visit should be evaluated by the investigator before the patient receives the first dose. If abnormalities are observed by the investigator in the ECG readings at the first dosing visit, the investigator may wait until the results from central reading are available, and the first dosing visit may be rescheduled.
After the first dose is taken at visit 2, ECG will be done 1 to 2 hours post-dose. In each of the remaining study visits until EoT, ECG will be recorded pre-dose and 1 to 2 hours post-dose. At the FUP1 visit, ECG will be recorded only once. ECGs will not be recorded at EoS visit.
After the patient receives the first dose, if a clinically significant increase in the QTcF interval from baseline (defined as visit 2, pre-dose measurement) or any other clinically significant quantitative or qualitative change from baseline is identified the investigator will assess the symptoms (e.g., palpitations, near syncope, or syncope) and decide if the patient will continue in the trial. The investigator must also check if the patient meets any of the treatment discontinuation criteria. Any new pathological findings (including clinically relevant abnormal ECG findings) or deterioration of previous findings observed during the trial will be recorded as AEs or SAEs, and should be followed up and/or treated as medically appropriate per local standards.
Although the ECGs are transmitted to the vendor for central reading, the investigator has the responsibility to complete an initial review of the ECG recordings the same day as the study visit. At any time during the trial, the investigator may decide to place a hold on further dosing of the patient if there is an indication of any new pathologic abnormalities in the ECG, and would prefer to wait until the results from the central reading are available.
All ECGs that are read in the central location will be stored in the vendor's database and will be transmitted to the sponsor periodically.
For patients participating in the trial remotely via DCT, ECGs are completed at the patient's home. The MRN will upload the ECGs to the DCT Platform (when applicable), and they will be available for the investigator or the site staff for review. If necessary, the MRN should consult with the investigator or designee before dosing the patient.
Eye exams including the evaluation of cataract by slit lamp will be performed by an ophthalmologist or an optometrist in both eyes to evaluate the presence of lens disorders and cataract during the screening period. Results from the eye exams must be available to the investigator before the patient is randomized in the IRT and trial medication shipment is initiated. The eye assessments will be repeated at EoT, and 30 days after last dose of trial medication (EoS) to monitor eye health and to observe any changes from baseline. The eye exams do not have to be completed on the same day of the study visits. At study entry, eye exams can be completed during the screening period. For EoT and EoS visits, patients should try and complete the eye exams within the protocol allowed window (±3 days) for the respective visits. Eye exams should be completed at the study site or at another healthcare or eye care facility.
Eye assessments will be performed according to the Eye Examination Worksheet provided by the sponsor. All cataracts will be graded using LOCS Ill. A copy of the worksheet will be available in the ISF. The results from the eye exams should be entered in a separate eCRF. Safety related findings will be reported as AEs if applicable. If documented medical history of cataract surgery in both eyes is available at the time of screening, eye assessments are not required, and patient will not undergo eye exams during the screening period, EoT, and EoS. If it is confirmed at the screening visit (by slit lamp exam) that the patient had cataract surgery in both eyes, eye assessments are not required at EoT and EoS.
Patients participating in the trial remotely via the DCT model will complete the eye exams at a facility referred to by the investigator or patient could complete these exams at a local healthcare facility close to the patient's home. Results from the eye exams must be sent to the study site.
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline conditions and should be collected in the eCRF only.
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the following criteria:
In accordance with the European Medicines Agency initiative on Important Medical Events, BI has set up a list of AEs, which by their nature, can always be considered to be “serious’ even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the EDS system. A copy of the latest list of “Always Serious AEs” will be provided upon request. These events should always be reported as SAEs.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious event regardless of the time since discontinuation of the drug and must be reported as described in AE Collection and AE Reporting to Sponsor and Timelines.
The term adverse events of special interest (AESI) relates to any specific AE that has been identified at the project level as being of particular concern for prospective safety monitoring and safety assessment within this trial, e.g. the potential for AEs based on knowledge from other compounds in the same class. AESIs need to be reported to the sponsor's Pharmacovigilance Department within the same timeframe that applies to SAEs.
The following are considered as AESIs:
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up defined by the following alterations of hepatic laboratory parameters:
These lab findings constitute a hepatic injury alert and the patients showing these lab abnormalities need to be followed up according to the “DILI checklist” provided in the EDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results (ALT, AST, total bilirubin) available, the investigator should make sure these parameters are analyzed, if necessary, in an unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the procedures described in the DILI checklist should be followed
The intensity (severity) of the AE should be judged based on the following:
Medical judgement should be used to determine the relationship between the adverse event and the BI investigational compound, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship could be:
Arguments that may suggest that there is no reasonable possibility of a causal relationship could be:
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the investigator:
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the reported SAE or AESI, on the BI SAE form to the sponsor's unique entry point within 24 hours of becoming aware of the event. Country specific process will be specified in the ISF. The same timeline applies if follow-up information becomes available. In specific occasions, the investigator could inform the sponsor upfront via telephone. This does not replace the requirement to complete the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be provided. For follow-up information the same rules and timeline apply as for initial information. All (S)AEs, including those persisting after individual patient's end of trial must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no further information can be obtained.
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the clinical trial and has taken trial medication, the investigator must report any drug exposure during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor's unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up and reported to the sponsor's unique entry point on the Pregnancy Monitoring Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form must be completed in addition.
In addition to the standard AE and SAE reporting, additional information will be collected in a separate eCRF on the following:
Blood samples for PK will be collected according to planned dates and times provided in Table 6. The date and clock times of drug administration and pharmacokinetic sampling will be recorded in the eCRF. The actual sampling times will be used for determination of pharmacokinetic parameters as defined in Secondary Endpoints. PK samples collected from this study will be also used for population PK and/or PK/PD analyses.
For the quantification of TRPCi plasma concentrations, blood samples will be collected at time points indicated in Table 6 and Table 2. The actual sampling times and time of dosing will need to be recorded in the eCRF. At selected sites, additional samples will be taken for the exploratory investigation of metabolites. These additional samples will be acidified as described in the laboratory manual.
Plasma samples should be shipped to the central laboratory preferably on the same day of collection. Samples should be stored at approximately −20° C. or below. Detailed instructions on sampling, preparation, processing, shipment and storage are provided in the laboratory manual.
After completion of the trial the plasma samples may be used for further methodological or exploratory investigations, e.g. for stability and metabolite testing. However, only data related to the analyte and/or its metabolites will be generated by these additional investigations. The study samples will be discarded after completion of the additional investigations but not later than 5 years after the final study report has been signed.
The TRPC6 inhibitor concentrations in plasma will be determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. All details of the analytical method will be available prior to the start of sample analysis. Metabolite concentrations in plasma will be determined by an exploratory assay. Results will be reported separately.
All samples from subjects on active drug will be analyzed. From subjects on placebo, only one time point will be analyzed in order to demonstrate absence of drug. In case there are quantifiable drug concentration, all PK samples from the placebo subject in question would be analyzed.
The analysis will be performed under the responsibility of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany at a suitable contract research organization. The bioanalyst will be unblinded during sample analysis to allow pharmacokinetic analyses during the course of the trial as described herein.
Exploratory analysis of PK-PD relationship will be performed with Cpre,ss, Cmax,ss and AUC0-6,ss of the TRPC6 inhibitor (if feasible; from week 12) and the following endpoints/biomarkers,
In addition, the relationship between the TRPC6 inhibitor plasma concentrations and ECG variables (e.g. HR, QTcF, QTc) will be explored. Details will be described in the TSAP.
In order to characterize the effect of the TRPC6 inhibitor in patients with chronic kidney disease/FSGS, a number of biomarker panels will be analyzed that represent the key mechanisms of kidney pathophysiology, such as inflammation, fibrosis, tubulo-interstitial injury, oxidative stress, glomerular injury, and endothelial dysfunction. It is planned to utilize the results of these measurements for comparison of the TRPC6 inhibitor with other compounds targeting chronic kidney disease or data from the literature or for use in pharmacometric modelling. Plasma, serum and urine samples will be collected as per Table 2. The full list of planned exploratory biomarkers is provided in Table 10.
The time points and methods for collection of samples for biomarkers are described below. All blood and urine samples will be discarded one year after the last patient has completed the trial.
All blood samples for measurements in plasma or serum will be taken from an antecubital or forearm vein by means of either an indwelling venous catheter or by venipuncture with a metal needle at the time points indicated in the Table 2.
For the measurement of exploratory biomarkers, at each time point indicated in Table 2, blood will be drawn into a potassium ethylenediaminetetraacetic acid (K-EDTA)-anticoagulant blood drawing tube, and into a serum gel tube. Details of sample processing, including preparation of aliquots will be provided in a study-specific laboratory manual.
For exploratory biomarkers, spot urine will be collected during the study visits as designated in Table 2. If the visits are conducted remotely, urine biomarker samples will not be collected. For the measurement of the mechanistic biomarkers of podocyte health such as podocin and nephrin mRNA and drug target modulation such as TRPC6 mRNA (see Pharmacodynamic Endpoints and Table 10, urine aliquots from spot urine will be centrifuged to obtain urine sediment. The resulting supernatant will be used for the isolation of extracellular vesicles and molecular profiling of their cargo.
Details of sample processing, including centrifugation where required, preparation of aliquots, and the sequence in which the aliquots will be prepared will be described in the laboratory manual.
All measurements are considered exploratory biomarkers and measured using fit-for-purpose validated method. Apart from routine central laboratory tests, all analytical methods will be described in detail along with the measurement results in a separate biomarker report.
All analyses will be performed at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany or a CRO duly authorized by BI.
Pharmacogenomics investigates genetic variations to explain and to predict an individual's response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from each subject. In case of unexplainable variability of PK or PD parameters, DNA may be extracted from these samples and used for exploratory analysis of variants of genes with known association with FSGS, in particular TRPC6, and/or genes involved in absorption, distribution, metabolism and excretion of drugs.
It is not intended to include these data in the clinical trial report. However, the data may be part of the report if necessary. All DNA samples will be destroyed one year after the last patient has completed the trial.
Detailed instructions for pharmacogenomics sampling, handling, and shipment of samples will be provided in the laboratory manual.
Methods and Timing of Sample Collection One blood sample will be taken from an arm vein into a PAXgene blood DNA drawing tube, preferably at Visit 2.
DNA will be extracted from blood samples according to standard molecular genetics methods and analyzed by Drug Metabolism Enzymes and Transporters (DMET) analysis or other standard genotyping technologies.
Not applicable.
Not applicable.
All measurements except for the exploratory biomarker measurements performed during this trial are standard measurements and will be performed in order to monitor patients' safety and to determine pharmacokinetic and pharmacodynamic parameters. Sampling for the exploratory biomarkers is not associated with any additional risks. The risks related to eye exams are minimal.
The scheduled procedures and measurements will allow monitoring of changes in vital signs, standard laboratory values, eye health, and ECG parameters that might occur as a result of administration of study drug. The safety assessments are standard, and are accepted for evaluation of safety and tolerability, and are widely used in clinical trials. The pharmacokinetic parameters and measurements outlined are generally used for assessments of drug exposure. Approximately 200 mL (14 tablespoons) of blood will be collected from a patient during the course of the study.
The trial consists of a screening period, treatment period, and a follow-up period. Following the screening period, patients will be randomized (prior to visit 2) to one of the four treatment arms. The treatment period is followed by a 30-day follow-up period which consists of 2 follow-up visits. The 2nd follow-up visit which is also the EoS visit will be completed by telephone except for the eye exams. Visit schedule and trial procedures are provided in Table 2 and Table 11. Schedule for PK sampling is presented in Table 6.
1Patients will be contacted by telephone. If there is any follow-up needed, an unscheduled visit may be scheduled. Patients should be reminded to be compliant with the intake of trial medication.
2Patient should be reminded to collect the 24-hour urine before EOT visit.
3Please see footnote #26 for Table 2.
Patients should make all efforts to complete the trial which includes the 2 follow-up visits. Investigators should encourage treatment compliance, and adherence to the protocol procedures. All patients should adhere to the visit schedule as specified in Table 2 and 11. Any deviations from the planned visit schedule should be documented.
All study visits should start preferably in the morning. Patients should be instructed to not take their trial medication at scheduled clinic visit days (from visit 2 to EoT visit). Trial medication must be administered during the clinic study visit as the time points specified in Table 6.
If any visit after the first dosing visit (visit 2) is rescheduled or missed, subsequent visits should follow the original visit date. The total treatment period (visit 2 to EoT visit) should be 12 weeks.
Unscheduled visits may be arranged, and it will be at the discretion of the investigator in order to check the safety or for other reasons.
ECGs should be recorded before blood samples are taken. Post-dose ECGs should be recorded before the PK sample is taken.
Eye exams should be completed at the study site or at another healthcare facility.
For patients participating in the trial remotely via the DCT model, study visits and procedures (except eye exams) will be performed by a MRN deployed by a CRO authorized by BI. Home visits may also be performed by an appropriately qualified member of the investigational site staff (e.g. investigator, study nurse). Investigative sites may also contract their own mobile research nurse to perform the study visits at the patient's home. Phone visits should be conducted by site staff.
The remote visits must adhere to the visit schedule as specified in Table 2. The EoS visit by telephone will be completed by the study site staff.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the investigational plan as per this clinical trial protocol may not be feasible at a site. With the consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue methodology which may include but will not be limited to virtual patient visits and assessments, and home healthcare nurse visits. The implementation of these measures will depend on patient's consent, operational feasibility, local law and regulations. If alternative methodology is implemented, the deviations from the original plan will be precisely documented.
First morning void sample is collected during the screening period to obtain the UPCR needed to determine eligibility for the trial. The first morning void is the urination after the patient wakes up to start their day. If the patient goes back to sleep after urinating early in the morning e.g. at 4 am, this void does not need to be collected and this does not need to be documented. This applies also to any urinations earlier during the night in patients who have nocturia. However, if the patient is an early riser and gets up ‘for good’ e.g. at 4 am, this would qualify as their first morning void. There may be cases when a patient might go back to bed after their usual rising time. In those cases, the void after the usual rising time constitutes the first morning void. The FMV sample can be brought to the site by the patient or may be shipped to the study site via a courier when possible.
Patients can sign a separate screening consent for the purpose of collecting the first morning void urine sample during the screening period or provide a verbal consent. Site will process the urine samples and send them to central lab for UPCR analysis. The UPCR value obtained from the first morning void urine sample will be used to assess eligibility of the patient for the trial. Site staff should ensure sufficient time is available to get the UPCR results from central lab to complete the screening period within the protocol allowed window. If the patient did not meet the inclusion criteria for UPCR from the first morning void, the patient may repeat the assessment once, and the UPCR value obtained from the 2nd first morning void urine sample can be used to determine eligibility for the study.
The schedule for 24-hour urine collection and the time points for dispensing urine collection containers are provided in Table 2. The start and end time of the 24-hour urine collection will be recorded. Patients will be asked to empty their bladders outside the container before start of sampling and into the container during and at the end of the 24-hour collection period. Patients will receive detailed instructions on the collection, storage, and transportation of the urine samples. Processing and analyses of the 24-hour urine samples will be described in the laboratory manual.
The 24-hour urine samples where collection started the day before the study visits should be brought to the clinic by the patient for the respective study visits. Other 24-hour urine samples (collected during the screening period) can be brought to the site by the patient or may be shipped to the study site via a courier when possible.
During the screening period, patient will collect 24-hour urine samples at two separate occasions. The 24-hour urine samples should be collected only after confirmation that the patient met all the eligibility criteria for the trial, and the collections should be close to visit 2 as much as possible. Visit 2 must be rescheduled if UPCR data is not available from at least one 24-hour urine sample.
For visits 3, EoT, and FUP1, one 24-hour urine sample will be collected. Collection should start preferably the day before the respective study visit and end on the day of the visit.
Visit 2 must be rescheduled if at least one of the 24-hour urine sample is not collected. The EoT visit must be rescheduled if the 24-hour urine sample is not collected before the visit. Visits must be rescheduled as soon as possible.
For patients participating in the trial remotely via the DCT model, urine collection containers for all the study visits will be sent to the patient's home, and the urine samples will be shipped to the study site via a courier. If patients live close to the study site, they may also pick up the urine collection containers from the study site and bring the 24-hour urine samples to the study site.
If possible, patients should be reminded (e.g. via telephone) during the screening period and ahead of the applicable visits to collect the 24-hour urine samples.
Collection of 24-hour urine samples may be repeated for logistical reasons (e.g. samples lost or patient could not complete the 24-hour collection) or technical issues (e.g. sample not fit for analysis).
All WOCBP will undergo serum pregnancy test at the screening visit (visit 1). Patients who test positive for the serum pregnancy test will be excluded from the trial. If the patient is a WOCBP, the status of the menstrual cycle should be assessed before the administration of the first dose of trial medication (visit 2): in case of a delayed or missed period, the PI should use their clinical judgement and the results of the pregnancy test at visit 2 to assess the participants pregnancy status and confirm eligibility before intake of trial drug.
Urine pregnancy tests will be done at all study visits starting from visit 2 (except visit 3 and phone visits). If the urine pregnancy test is positive, trial medication will be stopped and a serum pregnancy test will be performed to confirm pregnancy. If the serum pregnancy test is positive, the patient will be discontinued from the trial. EoT visit will be scheduled as soon as possible, and patient should complete the EoS visit. If serum pregnancy is negative, patient may continue in the trial and resume treatment with trial medication. If the urine pregnancy test is positive at the first dosing visit (visit 2), the patient must not be dosed unless the serum pregnancy test is negative.
Trial procedures to be performed during the screening period can be found in Table 2. Screening period is defined as the time between the date of informed consent (or the screening consent) to the date of first dose (visit 2). No trial procedures should be performed until the patient has consented to take part in the trial. The separate screening consent is to allow collection of the first morning void urine sample to obtain the UPCR needed to check eligibility criteria. Each patient will be assigned a unique patient number and enrollment will be recorded in eCRF.
For patients participating in the trial via the DCT model, the consenting process may be completed electronically (via eConsent) within the DCT Platform. Screening consent when applicable will be administered outside the DCT Platform. Prior to initiating the eConsent process, eligibility of potential patients will be assessed after review of medical records by the investigator or site staff. Once this preliminary eligibility is confirmed, a study informed consent discussion will be scheduled. The informed consent materials will be presented in the DCT Platform. The patient will review the documents and during this telephone call with the investigator or designee will have the opportunity to discuss the study, and have their questions answered. If patient agrees to participate in the trial, an electronic signature will be obtained.
Once the patient has consented to collect the first morning void urine sample for screening purposes, the patient is considered to be enrolled in the trial. The patient should be recorded on the enrollment log and be registered in the IRT.
Baseline conditions, medical history, and eligibility criteria will be assessed at visit 1. Concomitant therapy and AE (if any) will be recorded. At the conclusion of visit 1, patients should receive instructions on procedures to be followed during the screening period.
If all the eligibility criteria are met, randomization will be completed by calling the IRT. Randomization will initiate trial medication shipment to the patient and visit 2 will be scheduled. For more information on medication administration.
Screening period may be extended for administrative reasons with approval from the CT Manager.
If screening period exceeds 30 days, the investigator should review the laboratory reports from the screening visit (visit 1) and make a determination if any labs specified in the protocol must be repeated before the first dosing visit. If deemed necessary, test samples should be drawn and sent to the central laboratory.
If patients discontinue from the trial during the screening period, no additional study visits are required, and they will be marked as screen failures. Patient will be registered as a screen failure in IRT.
Patients who screen failed due to a reason that was reversible and has since been resolved or those who were screen failed for administrative reasons (e.g., extended travel, life events) may be rescreened once with approval from the CT Manager or designee.
If the investigator believes that a lab test result is due to an error or other extenuating circumstances, the lab test can be repeated once without the patient having to be rescreened.
Treatment period will begin at visit 2 and will continue for 12 weeks. Procedures to be completed at each study visit can be found in the Table 2. There will be three phone call visits during the treatment period: visit.
Unscheduled visits may be arranged if necessary. Procedures completed during an unscheduled visit will depend on the circumstances under which the visit was scheduled, and at the discretion of the investigator.
EoT must be rescheduled if the 24-hour urine sample is not collected for UPCR measurements. After completion of the treatment period, the patient will enter the 30-day follow-up period.
For discontinued patients, EoT visit must be scheduled as soon as possible. After completion of the EoT visit, patient will complete both follow-up visits (FUP1 and EoS).
The 30-day follow-up period extends from the EoT visit until the EoS phone call visit. The FUP1 visit should be scheduled 7 days after the EoT visit, and EoS phone call visit should be scheduled 30 days after the EoT visit. The EoS visit will be a telephone visit for all patients. For patients participating in the trial remotely, the study site staff will complete EoS visit by telephone. Procedures to be completed at the follow-up visits can be found in Table 2. Investigator should ensure that eye exams (if applicable) are completed as part of the EoS visit and the results are reviewed.
The last study visit will be the EoS visit and this will mark the end of observation period, and the patient has completed the trial.
No confirmatory testing will be performed and hence no null and alternative hypotheses are defined since this is a non-confirmatory study.
The following analysis sets will be defined for statistical analyses:
For the analysis of efficacy, patients will be analyzed as randomized, without regard to any treatment changes.
An intercurrent event (ICE) is defined as an event of,
The strategies for handling intercurrent events in this trial are as follows:
An exploratory inferential analysis for the primary endpoint, in terms of proportion of patients achieving at least 25% UPCR reduction relative to baseline at 12 weeks, will be conducted by providing 95% confidence intervals from each treatment group. The primary estimand of interest is the treatment effect assuming all subjects remained adherent to the assigned trial medication and the study protocol using a hypothetical approach, i.e., study drug is taken as directed. This analysis will include all data collected until time of an ICE.
In addition, an analysis of variance (ANOVA) model (for the UPCR change from baseline at week 12) will be used to see difference across arms. Dose-response relationship based on reduction in log of UPCR may be explored using graphical approach.
Sensitivity analyses to be conducted to assess the robustness of the primary analysis outcome will be described in the trial statistical analysis plan (TSAP).
An additional assessment of the primary endpoint will be conducted using the treatment policy estimand, i.e., effectiveness/intention to treat. The treatment policy estimand will use all available data including data collected after an ICE. All attempts will be made to collect all data per protocol.
No subgroup analysis planned.
All secondary endpoints in except pharmacokinetic parameters of the TRPC6 inhibitor will be analyzed by using descriptive statistics and figures.
Further details will be given in the TSAP.
The following further endpoints will be described by using descriptive statistics.
If additional statistical analyses are needed, methodology similar to those described for the primary and secondary analyses will be utilized. Final details will be covered in the TSAP.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). Standard BI summary tables and listings will be produced. All adverse events with an onset between start of treatment and end of study, which include a 5-day period after last dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients (i.e., all patients who received at least one dose of trial medication) will be included in the safety analysis. In general, safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent adverse events, i.e. all adverse events occurring between start of treatment and end of the study. Adverse events that start before first intake of trial medication and deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system organ class and preferred term after coding according to the current version of the MedDRA at the database lock.
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter will be done via comparison of laboratory data to their reference ranges. Values outside the reference range as well as values defined as clinically relevant will be summarized. Treatment groups will be compared descriptively with regard to distribution parameters as well as with regard to frequency and percentage of patients with abnormal values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, during the course of the study and at the end-of-study evaluation will be assessed with regards to possible changes compared to findings before start of treatment.
Unblinded exploratory data analysis on pharmacokinetic, pharmacodynamic, biomarker and/or other trial data will be performed during the conduct of the trial.
No formal interim analysis is planned.
No missing data will be imputed in the UPCR, UACR, and urinary protein excretion, analyses. Handling of missing PK data will be performed according to the relevant Corporate Procedure. PK parameters that cannot be reasonably calculated based on the available drug concentration-time data will not be imputed. Further details will be specified in the TSAP.
The study will be performed as a double-blind design with respect to the 3 different doses of the TRPC6 inhibitor and placebo in a 1:1:1:1 ratio stratified by use of corticosteroids. Patients will be randomized in blocks to double-blind treatment via the IRT system.
The sponsor will arrange for the randomization as well as packaging and labelling of trial medication. The randomization list will be generated using a validated system that uses a pseudo-random number generator and a supplied seed number so that the resulting allocation is both reproducible and non-predictable.
To explore the clinical principle of the TRPC6 inhibitor it is planned to include a total of 60 patients with FSGS. The planned sample size is not based on a power calculation. The size of 15 patients per treatment arm is considered to be sufficient to detect differences between the different treatment groups and placebo in terms of the primary endpoint.
The goal of the trial is to determine if the difference in UPCR response between at least one dose after baseline and placebo is greater than 25%. Assuming that approximately 40%, 30%, 20% of patients in 80 mg, 40 mg, 20 mg treatment groups, respectively, achieve at least 25% UPCR reduction at 12 weeks while 9% of patients in placebo group achieve 25% UPCR reduction, the proposed sample size provides 73.4% probability for the difference in responder rates between at least one treatment arm and placebo to be greater than 25%.
| Number | Date | Country | |
|---|---|---|---|
| 63533364 | Aug 2023 | US |
