Patent Application
20230181509
The subject invention relates to novel methods for the treatment of virus and bacteria induced respiratory disease with hypoxemia.
Carotenoids are a class of hydrocarbons consisting of isoprenoid units. The backbone of the molecule consists of conjugated carbon-carbon double and single bonds, and can have pendant groups. Carotenoids such as crocetin and trans sodium crocetinate (TSC) are known to increase the diffusivity of oxygen in water.
U.S. Pat. No. 6,060,511 relates to trans sodium crocetinate (TSC) and its uses. The patent covers various uses of TSC such as improving oxygen diffusivity and treatment of hemorrhagic shock.
U.S. Pat. No. 7,759,506 relates to synthesis methods for making bipolar trans carotenoids (BTC), including bipolar trans carotenoid salts (BTCS), and methods of using them.
U.S. Pat. No. 8,030,350 relates to improved BTC synthesis methods and novel uses of the BTC.
U.S. Pat. No. 8,293,804 relates to the use of bipolar trans carotenoids as a pretreatment and in the treatment of peripheral vascular disease.
U.S. Pat. No. 8,206,751 relates to a new class of therapeutics that enhance small molecule diffusion.
U.S. application Ser. No. 12/801,726 relates to diffusion enhancing compounds and their use alone or with thrombolytics.
There are no known efficacious treatments for pneumonia caused by SARS coronavirus, MERS coronavirus, adenovirus, hantavirus, or parainfluenza. Care is largely supportive. New methods for treating a viral or bacterial induced respiratory disease with hypoxemia are needed.
The subject invention provides methods of treatment of human patients having, or diagnosed as having, a viral or bacterial induced respiratory disease with hypoxemia, with a diffusion enhancing compound of the invention. Included are methods of treating influenza, a corona virus infection including Covid-19, and bacterial or viral pneumonia.
Provided is a method of treating a patient in need thereof having a viral or bacterial induced respiratory disease with hypoxemia comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of hypoxemia consequent to a viral or bacterial induced respiratory disease in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of acute respiratory distress syndrome associated with a viral or bacterial respiratory disease in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of multiple organ failure consequent to a viral or bacterial respiratory disease in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided are methods of mitigation, control, and/or treatment of one or more of hypoxemia, acute respiratory distress syndrome, and multiple organ failure consequent to a viral or bacterial respiratory disease in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of improving blood oxygenation in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of treating a patient in need thereof having a viral or bacterial induced respiratory disease comprising administering a diffusion enhancing compound to said patient.
In any of the above methods, the diffusion enhancing compound is a bipolar trans carotenoid, advantageously a bipolar trans carotenoid salt (e.g., TSC). In a further embodiment, the bipolar trans carotenoid salt is formulated with a cyclodextrin. The diffusion enhancing compound is advantageously administered IV or IM. If the diffusion enhancing compound is TSC, a dose of about 0.05-5 mg/kg, e.g., 0.05-2.5 mg/kg, advantageously a dose of about 0.25-1.5 mg/kg is used. Advantageously, the diffusion enhancing compound is administered 3 days per week.
The invention also relates to a kit comprising a first vial with a diffusion enhancing compound such as TSC (which can be lyophilized), a second vial with diluent such as water for injection, and a syringe for administration. The kit may be used for any of the methods described herein.
The invention also includes a kit comprising:
a) a container comprising a diffusion enhancing compound such as TSC, and
b) instructions for using the diffusion enhancing compound to treat a patient having a viral or bacterial induced respiratory disease with hypoxemia, by administering the diffusion enhancing compound at a dose of about 0.05-5 mg/kg, e.g., 0.05-2.5 mg/kg to the patient. The kit may be used for any of the methods described herein.
Further the invention relates to a double chamber container or syringe for separately holding in the two chambers (and combining just before administration): a) a solid, in particular a lyophilizate of a diffusion enhancing compound such as TSC, and b) a liquid reconstitution medium therefor such as water for injection. The container or syringe may be used in any of the methods described herein.
The subject invention provides methods for the treatment of human patients, having, or diagnosed as having, a viral or bacterial induced respiratory disease with hypoxemia, with a diffusion enhancing compound of the invention. Included are methods of treating influenza, a corona virus infection including Covid-19, and bacterial or viral pneumonia.
Provided is a method of treating a patient (e.g., a human) in need thereof having a viral or bacterial induced respiratory disease with hypoxemia comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of hypoxemia consequent to a viral or bacterial induced respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of acute respiratory distress syndrome associated with a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of mild acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of moderate acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of severe acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method of prophylaxis and/or treatment of multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided are methods of mitigation, control, and/or treatment of one or more of hypoxemia, acute respiratory distress syndrome, and multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided are methods of mitigation, control, and/or treatment of one or more of hypoxemia, acute respiratory distress syndrome, and multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient, wherein said patient has mild acute respiratory distress syndrome, moderate acute respiratory distress syndrome, or severe acute respiratory distress syndrome.
Further provided is a method of improving blood oxygenation in a patient in need thereof comprising administering a diffusion enhancing compound to said patient.
As used herein, patient includes human and non-human. Preferably, a patient is human. In some embodiments of the methods described herein, the patient (e.g., a human) in need of treatment is a patient diagnosed with a viral or bacterial respiratory disease and at risk of developing one or more of acute respiratory distress syndrome, hypoxemia, and multiple organ failure. Patients at risk of developing one or more of acute respiratory distress syndrome, hypoxemia, and multiple organ failure include patients over age 60 (e.g., 65 or older, e.g., 70 or older, e.g., 75 or older), immunocompromised, and/or with one or more of diabetes, hypertension, congestive heart failure, chronic liver disease, and chronic renal disease.
Acute respiratory distress syndrome (ARDS) can be divided into mild ARDS (e.g., a human having 200 mm Hg<PaO2/FiO2≤300 mm Hg with positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP)≥5 cm H2O), moderate ARDS (e.g., a human having 100 mm Hg<PaO2/FiO2≤200 mm Hg with positive end-expiratory pressure (PEEP)≥5 cm H2O), and severe ARDS (e.g., a human having PaO2/FiO2≤100 mm Hg with positive end-expiratory pressure (PEEP)≥5 cm H2O). If altitude is higher than 1000 m, then a correction factor should be calculated as follows: [PaO2/FiO2×(barometric pressure/760)].
FiO2 is fraction of inspired oxygen. PaO2 is arterial partial pressure of oxygen.
SpO2/FiO2 may be used as a non-invasive alternative to PaO2/FiO2.
In some embodiments of the methods disclosed herein, the patient (e.g., human) has mild ARDS, moderate ARDS, or severe ARDS or is at risk of developing mild ARDS, moderate ARDS, or severe ARDS. For instance, in some embodiments of the methods disclosed herein, the patient (e.g., human) has mild ARDS or is at risk of developing mild ARDS. Also, for instance, in some embodiments of the methods disclosed herein, the patient (e.g., human) has moderate ARDS or is at risk of developing moderate ARDS. Also, for instance, in some embodiments of the methods disclosed herein, the patient (e.g., human) has severe ARDS or is at risk of developing severe ARDS.
Patients suffering from moderate to severe COVID-19 disease present with abnormal chest radiography indicating bilateral and peripheral ground glass and consolidative opacities, with many progressing to acute respiratory distress syndrome (ARDS). These patients often go on to require transfer to an intensive care unit, mechanical ventilatory support, and possibly extra-corporeal membrane oxygenation (ECMO). COVID-19 leading to severe ARDS is associated with a high degree of morbidity and mortality. Prior to developing ARDS, COVID-19 patients may experience a period of so-called silent hypoxemia, consisting of observable hypoxemia by oxygen saturation (SaO2) measurements, but showing minimal outward signs of respiratory distress.
In some embodiments, the methods disclosed herein result in preventing a patient from being supported with mechanical ventilation or extracorporeal membrane oxygenation.
TSC has been shown to have beneficial effects in hypoxemic situations. For example, TSC has been shown to increase whole-body oxygen consumption after hemorrhagic shock in rats. TSC increases oxygen levels in hypoxemic states, both in arterial and tissue levels, but does not in normoxic states. TSC has these effects because it increases the diffusivity of oxygen through plasma. The diffusion rate is known to be affected by both concentration and diffusivity (i.e. Fick's law).
Not only does TSC seem to enhance systemic oxygenation of tissues, but it may also affect passage of oxygen from the alveoli to erythrocytes to enhance the oxygen carrying capacity of blood in acute respiratory distress syndrome (ARDS).
A respiratory virus is a virus that can enter and invade the respiratory system, the system from the nose to lungs that allows taking in oxygen and breathing out carbon dioxide. There are many kinds of respiratory viruses such adenoviruses, rhinoviruses, respiratory syncytial viruses (RSV), influenza, and coronaviruses. Some of these viruses tend to stay in the upper respiratory tract while others may make it down to the lower respiratory tract.
The many viruses that cause the common cold including four other types of coronaviruses (OC43, HKU1, NL63, and 229E) behave very differently from the SARS-CoV2. Similarly, the SARS-CoV2 is not the same as the flu virus (influenza).
After viruses make more and more of themselves, they may invade additional cells lining the respiratory tract and begin to cause damage. Shortness of breath, chest pain or tightness, a deeper cough, and other difficulties breathing can be signs that these viruses have made it to the lower respiratory tract. These symptoms can come from inflammation of the respiratory tree, otherwise known as the bronchial tree.
Alveoli are tiny elastic air sacs within the lungs that allow oxygen and carbon dioxide to move between the lungs and bloodstream. Alveoli are also intertwined with a network of blood vessels. These blood vessels bring blood from the rest of the body that is low in oxygen and high in carbon dioxide, a waste product of metabolism. The alveoli is where oxygen from the air is exchanged with the carbon dioxide in the blood. The carbon dioxide goes into the alveoli, where it may be exhaled up through the respiratory tract and out through the nose and mouth. The blood that is newly infused with more oxygen subsequently travels to the rest of the body to provide cells with the oxygen.
If the viruses travel to the lungs and alveoli, it can become a pneumonia. As the damage to the lungs continues, acute respiratory distress syndrome (ARDS) can develop, which is when the lungs have suffered so much widespread injury that there is not enough functioning alveoli to do the gas exchange work. ARDS occurs when fluid builds up in the alveoli. The fluid keeps the lungs from filling with enough air, which means less oxygen reaches the bloodstream, which can cause hypoxemia. This deprives organs of the oxygen they need to function.
If the damage gets to the point that the lungs can no longer effectively exchange enough oxygen and carbon dioxide, respiratory failure can occur.
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first identified in 2019 in Wuhan, the capital of China's Hubei province, and has since spread globally, resulting in the ongoing 2019-20 coronavirus pandemic. Common symptoms include fever, cough, and shortness of breath. Other symptoms may include muscle pain, sputum production, diarrhea, sore throat, loss of smell, and abdominal pain. While the majority of cases result in mild symptoms, some progress to pneumonia and multi-organ failure. As of March 2020, the overall rate of deaths per number of diagnosed cases is 4.6 percent; ranging from 0.2 percent to 15 percent according to age group and other health problems. In comparison, the overall mortality rate of the 1918 Spanish Flu were approximately 3% to 5%.
The virus is spread mainly through close contact and via respiratory droplets produced when people cough or sneeze. Respiratory droplets may be produced during breathing but the virus is not generally airborne. People may also contract COVID-19 by touching a contaminated surface and then their face. It is most contagious when people are symptomatic, although spread may be possible before symptoms appear. The virus can survive on surfaces up to 72 hours. Time from exposure to onset of symptoms is generally between two and fourteen days, with an average of five days. The standard method of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab. The infection can also be diagnosed from a combination of symptoms, risk factors and a chest CT scan showing features of pneumonia.
Currently, there is no specific antiviral treatment for COVID-19. Management involves treatment of symptoms, supportive care, isolation, and experimental measures.
Those infected with the virus may be asymptomatic or develop flu-like symptoms, including fever, cough, fatigue, and shortness of breath. Emergency symptoms include difficulty breathing, persistent chest pain or pressure, confusion, difficulty waking, and bluish face or lips. Less commonly, upper respiratory symptoms, such as sneezing, runny nose, or sore throat may be seen. Symptoms such as nausea, vomiting, and diarrhea have been observed in varying percentages. Some cases in China initially presented only with chest tightness and palpitations. In March 2020 there were reports indicating that loss of the sense of smell (anosmia) may be a common symptom among those who have mild disease, although not as common as initially reported. In some, the disease may progress to pneumonia, multi-organ failure, and death. In those who develop severe symptoms, time from symptom onset to needing mechanical ventilation is typically eight days.
As is common with infections, there is a delay between the moment when a person is infected with the virus and the time when they develop symptoms. This is called the incubation period. The incubation period for COVID-19 is typically five to six days but may range from two to 14 days. 97.5% of people who develop symptoms will do so within 11.5 days of infection.
Reports indicate that not all who are infected develop symptoms, but their role in transmission is unknown. Preliminary evidence suggests asymptomatic cases may contribute to the spread of the disease. The proportion of infected people who do not display symptoms is currently unknown and being studied, with South Korea's CDC reporting that 20% of all confirmed cases remained asymptomatic during their hospital stay.
The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is primarily spread between people during close contact and via respiratory droplets from coughs and sneezes.
Pathophysiology
The lungs are the organs most affected by COVID-19 because the virus accesses host cells via the enzyme ACE2, which is most abundant in the type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a “spike” (peplomer) to connect to ACE2 and enter the host cell. The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and some have suggested that decreasing ACE2 activity might be protective, though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective and that these hypotheses need to be tested. As the alveolar disease progresses, respiratory failure might develop and death may follow.
The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine.
The WHO has published several testing protocols for the disease. The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR). The test is typically done on respiratory samples obtained by a nasopharyngeal swab, however a nasal swab or sputum sample may also be used. Results are generally available within a few hours to two days. Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value. As of 19 Mar. 2020, there were no antibody tests though efforts to develop them are ongoing. The FDA approved the first point-of-care test on 21 Mar. 2020 for use at the end of that month.
Few data are available about microscopic lesions and the pathophysiology of COVID-19. The main pathological findings at autopsy are:
Influenza, commonly known as “the flu”, is an infectious disease caused by an influenza virus. Symptoms can be mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle and joint pain, headache, coughing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks. In children, there may be diarrhea and vomiting, but these are not common in adults. Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as “stomach flu” or the “24-hour flu”. Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure.
Three of the four types of influenza viruses affect humans: Type A, Type B, and Type C. Type D has not been known to infect humans, but is believed to have the potential to do so. Usually, the virus is spread through the air from coughs or sneezes. This is believed to occur mostly over relatively short distances. It can also be spread by touching surfaces contaminated by the virus and then touching the eyes, nose, or mouth. A person may be infectious to others both before and during the time they are showing symptoms. The infection may be confirmed by testing the throat, sputum, or nose for the virus. A number of rapid tests are available; however, people may still have the infection even if the results are negative. A type of polymerase chain reaction that detects the virus's RNA is more accurate.
Frequent hand washing reduces the risk of viral spread, as does wearing a surgical mask. Yearly vaccinations against influenza are recommended by the World Health Organization (WHO) for those at high risk, and by the Centers for Disease Control and Prevention (CDC) for those six months of age and older. The vaccine is usually effective against three or four types of influenza. It is usually well tolerated. A vaccine made for one year may not be useful in the following year, since the virus evolves rapidly. Antiviral drugs such as the neuraminidase inhibitor oseltamivir, among others, have been used to treat influenza.
Influenza spreads around the world in yearly outbreaks, resulting in about three to five million cases of severe illness and about 290,000 to 650,000 deaths. About 20% of unvaccinated children and 10% of unvaccinated adults are infected each year. In the northern and southern parts of the world, outbreaks occur mainly in the winter, while around the equator, outbreaks may occur at any time of the year. Death occurs mostly in high risk groups—the young, the old, and those with other health problems. Larger outbreaks known as pandemics are less frequent. In the 20th century, three influenza pandemics occurred: Spanish influenza in 1918 (17-100 million deaths), Asian influenza in 1957 (two million deaths), and Hong Kong influenza in 1968 (one million deaths). The World Health Organization declared an outbreak of a new type of influenza A/H1N1 to be a pandemic in June 2009.
Pneumonia is an inflammatory condition of the lung affecting primarily the small air sacs known as alveoli. Typically, symptoms include some combination of productive or dry cough, chest pain, fever and difficulty breathing. The severity of the condition is variable.
Pneumonia is usually caused by infection with viruses or bacteria and less commonly by other microorganisms, certain medications or conditions such as autoimmune diseases. Risk factors include cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, diabetes, heart failure, a history of smoking, a poor ability to cough such as following a stroke and a weak immune system. Diagnosis is often based on the symptoms and physical examination. Chest X-ray, blood tests, and culture of the sputum may help confirm the diagnosis. The disease may be classified by where it was acquired, such as community- or hospital-acquired or health care-associated pneumonia.
Vaccines to prevent certain types of pneumonia are available. Other methods of prevention include hand washing and not smoking. Treatment depends on the underlying cause. Pneumonia believed to be due to bacteria is treated with antibiotics. If the pneumonia is severe, the affected person is generally hospitalized. Oxygen therapy may be used if oxygen levels are low.
Pneumonia affects approximately 450 million people globally (7% of the population) and results in about 4 million deaths per year. Pneumonia was regarded by Canadian pathologist William Osler in the 19th century as “the captain of the men of death”. With the introduction of antibiotics and vaccines in the 20th century, survival greatly improved. Nevertheless, in developing countries, and also among the very old, the very young and the chronically ill, pneumonia remains a leading cause of death.
Bacterial and viral cases of pneumonia usually result in similar symptoms. Some causes are associated with classic, but non-specific, clinical characteristics. Viral pneumonia presents more commonly with wheezing than bacterial pneumonia. Pneumonia was historically divided into “typical” and “atypical” based on the belief that the presentation predicted the underlying cause. However, evidence has not supported this distinction, therefore it is no longer emphasized.
Pneumonia is due to infections caused primarily by bacteria or viruses and less commonly by fungi and parasites. Although there are over 100 strains of infectious agents identified, only a few are responsible for the majority of the cases. Mixed infections with both viruses and bacteria may occur in roughly 45% of infections in children and 15% of infections in adults. A causative agent may not be isolated in approximately half of cases despite careful testing.
The term pneumonia is sometimes more broadly applied to any condition resulting in inflammation of the lungs (caused for example by autoimmune diseases, chemical burns or drug reactions); however, this inflammation is more accurately referred to as pneumonitis.
Viral pneumonia is a pneumonia caused by a virus. Viruses are one of the two major causes of pneumonia, the other being bacteria; less common causes are fungi and parasites. Viruses are the most common cause of pneumonia in children, while in adults bacteria are a more common cause. Symptoms of viral pneumonia include fever, non-productive cough, runny nose, and systemic symptoms (e.g. myalgia, headache). Different viruses cause different symptoms.
Common causes of viral pneumonia are:
Rarer viruses that commonly result in pneumonia include:
Viruses that primarily cause other diseases, but sometimes cause pneumonia include:
The most commonly identified agents in children are respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses.
Viruses must invade cells in order to reproduce. Typically, a virus will reach the lungs by traveling in droplets through the mouth and nose with inhalation. There, the virus invades the cells lining the airways and the alveoli. This invasion often leads to cell death either through direct killing by the virus or by self-destruction through apoptosis.
Further damage to the lungs occurs when the immune system responds to the infection. White blood cells, in particular lymphocytes, are responsible for activating a variety of chemicals (cytokines) which cause leaking of fluid into the alveoli. The combination of cellular destruction and fluid-filled alveoli interrupts the transportation of oxygen into the bloodstream.
In addition to the effects on the lungs, many viruses affect other organs and can lead to illness affecting many different bodily functions. Some viruses also make the body more susceptible to bacterial infection; for this reason, bacterial pneumonia often complicates viral pneumonia.
In cases of viral pneumonia where influenza A or B are thought to be causative agents, patients who are seen within 48 hours of symptom onset may benefit from treatment with oseltamivir or zanamivir. Respiratory syncytial virus (RSV) has no direct acting treatments, but ribavirin is indicated for severe cases. Herpes simplex virus and varicella-zoster virus infections are usually treated with aciclovir, whilst ganciclovir is used to treat cytomegalovirus. There is no known efficacious treatment for pneumonia caused by SARS coronavirus, MERS coronavirus, adenovirus, hantavirus, or parainfluenza. Care is largely supportive.
Blood oxygen level is a measure of how much oxygen your red blood cells are carrying. Blood oxygen level can be measured with an arterial blood gas (ABG) test and/or a pulse oximeter. A measurement of blood oxygen level is called oxygen saturation level. The measurement may be referred to as SaO2. Blood oxygen level may also be called PaO2 when an ABG test is done or an O2 sat (SpO2) when it is measured with a pulse oximeter. A normal ABG level for healthy lungs falls between 80 and 100 millimeters of mercury (mm Hg). If a pulse oximeter is used, a normal reading may be between 95 and 100%. A below-normal blood oxygen level is hypoxemia. As used herein, hypoxemia includes an ABG level below 80 mm Hg (e.g., at or below 70 mm Hg, e.g., at or below 60 mm Hg, e.g., at or below 50 mm Hg, e.g., below 50 mm Hg) and/or an SpO2 below 95% percent (e.g., below 90%).
The methods of the subject invention include administration of a therapeutically effective amount of a diffusion enhancing compound such as TSC.
The diffusion enhancing compound is a bipolar trans carotenoid salt having the formula:
YZ-TCRO-ZY,
Advantageously, the bipolar trans carotenoid salt is trans sodium crocetinate (TSC) (e.g., synthetic TSC), shown as Formula I below.
In one embodiment, the absorbency (e.g., in an aqueous solution) of the bipolar trans carotenoid salt (e.g., trans sodium crocetinate) at the highest peak which occurs in the visible wavelength range divided by the absorbency of a peak occurring in the ultraviolet wavelength range is greater than 7 (e.g., 7 to 8.5), e.g., greater than 7.5 (e.g., 7.5 to 9, e.g., 7.5 to 8.5), e.g., greater than 8 (e.g., 8 to 8.8), e.g., greater than 8.5. In another embodiment, the absorbency (e.g., in an aqueous solution) of the TSC at the highest peak which occurs in the visible wavelength range divided by the absorbency of a peak occurring in the ultraviolet wavelength range is greater than 7 (e.g., 7 to 8.5), e.g., greater than 7.5 (e.g., 7.5 to 9, e.g., 7.5 to 8.5), e.g., greater than 8 (e.g., 8 to 8.8), e.g., greater than 8.5.
The bipolar trans carotenoid salt (e.g., trans sodium crocetinate) is at least 90% pure as measured by high performance liquid chromatography (HPLC), e.g., ≥95% pure as measured by HPLC, e.g., ≥96% pure as measured by HPLC. In an advantageous embodiment, the TSC is at least 90% pure as measured by high performance liquid chromatography (HPLC), e.g., ≥95% pure as measured by HPLC, e.g., ≥96% pure as measured by HPLC.
In an advantageous embodiment, the bipolar trans carotenoid salt is in a composition also comprising a cyclodextrin. For instance, wherein TSC is in a composition also comprising a cyclodextrin (e.g., wherein the TSC is in a lyophilized composition with a cyclodextrin).
Advantageously, the cyclodextrin is gamma-cyclodextrin. For instance, the bipolar trans carotenoid salt is TSC which is in a composition also comprising gamma-cyclodextrin (e.g., wherein the TSC is in a lyophilized composition with gamma-cyclodextrin).
In an embodiment of the invention, the composition further comprises mannitol.
The diffusion enhancing compound is administered intravenously or intramuscularly (e.g., as an intravenous injection or infusion or intramuscular injection).
Advantageously, the diffusion enhancing compound is admixed with sterile water for injection to form an injection. TSC is administered intravenously or intramuscularly (e.g., as an intravenous injection or infusion or intramuscular injection). For instance, wherein TSC is admixed with sterile water for injection to form an injection.
Advantageously, the diffusion enhancing compound is TSC and is administered at a dose of 0.05-5 mg/kg, e.g., 0.05-2.5 mg/kg, e.g., 0.2-2 mg/kg, e.g., 0.15-0.35 mg/kg, e.g., 0.25 mg/kg. Specifically, TSC can be administered at a dose of 0.05-2.5 mg/kg, e.g., 0.2-2 mg/kg, e.g., 0.15-0.35 mg/kg, e.g., 0.25 mg/kg, three or more days per week, e.g., five or more days per week, e.g., each day of the week.
In another embodiment, provided is a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC) for use in any of the methods described herein.
In another embodiment, provided is use of a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC) in the manufacture of a medicament for any of the methods described herein.
In another embodiment, provided is a pharmaceutical composition comprising an effective amount of a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC) for use in any of the methods described herein.
The diffusion enhancing compounds of the invention include those compounds described in U.S. Pat. Nos. 7,759,506, 8,030,350, 8,901,174 and 8,206,751, each of which is hereby incorporated by reference in its entirety.
Included are bipolar trans carotenoid compounds having the formula:
YZ-TCRO-ZY
where:
More specifically, the subject invention relates to trans carotenoids including trans carotenoid diesters, dialcohols, diketones and diacids, bipolar trans carotenoids (BTC), and bipolar trans carotenoid salts (BTCS) compounds and synthesis of such compounds having the structure:
YZ-TCRO-ZY
where:
The compounds of the subject invention are trans. The cis isomer typically is a detriment—and results in the diffusivity not being increased. In one embodiment, a cis isomer can be utilized where the skeleton remains linear. The placement of the pendant groups can be symmetric relative to the central point of the molecule or can be asymmetric so that the left side of the molecule does not look the same as the right side of the molecule either in terms of the type of pendant group or their spatial relationship with respect to the center carbon.
The pendant groups X (which can be the same or different) are hydrogen (H) atoms, or a linear or branched hydrocarbon group having 10 or less carbons, advantageously 4 or less, (optionally containing a halogen), or a halogen. X could also be an ester group (COO—) or an ethoxy/methoxy group. Examples of X are a methyl group (CH3), an ethyl group (C2H5), a phenyl or single aromatic ring structure with or without pendant groups from the ring, a halogen-containing alkyl group (C1-C10) such as CH2Cl, or a halogen such as Cl or Br or a methoxy (OCH3) or ethoxy (OCH2CH3). The pendant groups can be the same or different but the pendant groups utilized must maintain the skeleton as linear.
Although many carotenoids exist in nature, carotenoid salts do not. Commonly-owned U.S. Pat. No. 6,060,511 hereby incorporated by reference in its entirety, relates to trans sodium crocetinate (TSC). The TSC was made by reacting naturally occurring saffron with sodium hydroxide followed by extractions that selected primarily for the trans isomer.
The presence of the cis and trans isomers of a carotenoid or carotenoid salt can be determined by looking at the ultraviolet-visible spectrum for the carotenoid sample dissolved in an aqueous solution. Given the spectrum, the value of the absorbence of the highest peak which occurs in the visible wave length range of 380 to 470 nm (the number depending on the solvent used and the chain length of the BTC or BTCS. The addition of pendant groups or differing chain lengths will change this peak absorbance but someone skilled in the art will recognize the existence of an absorbance peak in the visible range corresponding to the conjugated backbone structure of these molecules.) is divided by the absorbency of the peak which occurs in the UV wave length range of 220 to 300 nm can be used to determine the purity level of the trans isomer. When the trans carotenoid diester (TCD) or BTCS is dissolved in water, the highest visible wave length range peak will be at between 380 nm to 470 nm (depending on the exact chemical structure, backbone length and pendant groups) and the UV wave length range peak will be between 220 to 300 nm. According to M. Craw and C. Lambert, Photochemistry and Photobiology, Vol. 38 (2), 241-243 (1983) hereby incorporated by reference in its entirety, the result of the calculation (in that case crocetin was analyzed) was 3.1, which increased to 6.6 after purification.
Performing the Craw and Lambert analysis, using a cuvette designed for UV and visible wavelength ranges, on the trans sodium salt of crocetin of commonly owned U.S. Pat. No. 6,060,511 (TSC made by reacting naturally occurring saffron with sodium hydroxide followed by extractions which selected primarily for the trans isomer), the value obtained averages about 6.8. Performing that test on the synthetic TSC of the subject invention, that ratio is greater than 7.0 (e.g. 7.0 to 8.5), advantageously greater than 7.5 (e.g. 7.5-8.5), most advantageously greater than 8. The synthesized material is a “purer” or highly purified trans isomer.
A detailed description of formulation and administration of diffusing enhancing compounds can be found in commonly owned U.S. Pat. No. 8,293,804, U.S. application Ser. No. 12/801,726, and U.S. Pat. No. 8,206,751, each of which is hereby incorporated by reference in its entirety. A detailed description of formulation and administration of diffusing enhancing compounds can also be found in commonly owned U.S. Pat. No. 8,030,350, which is hereby incorporated by reference in its entirety.
A diffusion enhancing compound such as TSC can be administered by various routes for rapid delivery to the hypoxic tissue. For example, the compound, which can be formulated with other compounds including excipients, can be administered at the proper dosage as an intravenous injection (IV) or infusion, or an intramuscular injection (IM).
The IV injection route is an advantageous route for giving TSC for many of the uses of the subject application. Typically, a diffusion enhancing compound such as TSC is administered as soon as possible if a thrombus is believed present.
In addition to intravenous injection, routes of administration for specially formulated trans carotenoid molecules include intramuscular injection, delivery by inhalation, oral administration and transdermal administration.
In order to administer some pharmaceuticals, it is necessary to add another compound which will aid in increasing the absorption/solubility/concentration of the active pharmaceutical ingredient (API). Such compounds are called excipients, and cyclodextrins are examples of excipients. Cyclodextrins are cyclic carbohydrate chains derived from starch. They differ from one another by the number of glucopyranose units in their structure. The parent cyclodextrins contain six, seven and eight glucopyranose units, and are referred to as alpha, beta and gamma cyclodextrins respectively. Cyclodextrins were first discovered in 1891, and have been used as part of pharmaceutical preparations for several years.
Cyclodextrins are cyclic (alpha-1,4)-linked oligosaccharides of alpha-D-glucopyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface. In the pharmaceutical industry, cyclodextrins have mainly been used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs, and to increase their bioavailability and stability. In addition, cyclodextrins are used to reduce or prevent gastrointestinal or ocular irritation, reduce or eliminate unpleasant smells or tastes, prevent drug-drug or drug-additive interactions, or even to convert oils and liquid drugs into microcrystalline or amorphous powders.
Although the BTC compounds are soluble in water, the use of the cyclodextrins can increase that solubility even more so that a smaller volume of drug solution can be administered for a given dosage.
There are a number of cyclodextrins that can be used with the Compounds of the Invention. See for example, U.S. Pat. No. 4,727,064, hereby incorporated by reference in its entirety. Advantageous cyclodextrins are γ-cyclodextrin, 2-hydroxylpropyl-γ-cyclodextrin and 2-hydroxylpropyl-β-cyclodextrin, or other cyclodextrins which enhance the solubility of the BTC.
The use of gamma-cyclodextrin with TSC increases the solubility of TSC in water by 3-7 times. Although this is not as large a factor as seen in some other cases for increasing the solubility of an active agent with a cyclodextrin, it is important in allowing for the parenteral administration of TSC in smaller volume dosages to humans (or animals). Dosages of TSC and gamma-cyclodextrin have resulted in aqueous solutions containing as much as 44 milligrams of TSC per ml of solution, with an advantageous range of 20-30 mg/ml of solution. The solutions need not be equal-molar. The incorporation of the gamma cyclodextrin also allows for TSC to be absorbed into the blood stream when injected intramuscularly. Absorption is quick, and efficacious blood levels of TSC are reached quickly (as shown in rats).
The cyclodextrin formulation can be used with other trans carotenoids and carotenoid salts. The subject invention also includes novel compositions of carotenoids which are not salts (e.g. acid forms such as crocetin, crocin or the intermediate compounds noted above) and a cyclodextrin. In other words, trans carotenoids which are not salts can be formulated with a cyclodextrin. Mannitol can be added for osmolality, or the cyclodextrin BTC mixture can be added to isotonic saline (see below).
The amount of the cyclodextrin used is that amount which will contain the trans carotenoid but not so much that it will not release the trans carotenoid. Advantageously, the ratio of cyclodextrin to BTC, e.g., TSC, is 4 to 1 or 5 to 1. See also U.S. Pat. No. 8,974,822, the content of which is hereby incorporated by reference in its entirety.
A trans carotenoid such as TSC can be formulated with a cyclodextrin as noted above and a non-metabolized sugar such as mannitol (e.g. d-mannitol to adjust the osmotic pressure to be the same as that of blood). Solutions containing over 20 mg TSC/ml of solution can be made this way. This solution can be added to isotonic saline or to other isotonic solutions in order to dilute it and still maintain the proper osmolality.
A BTCS such as TSC can be formulated with mannitol such as d-mannitol, and a mild buffering agent such as acetic acid or citric acid to adjust the pH. The pH of the solution should be around 8 to 8.5. It should be close to being an isotonic solution, and, as such, can be injected directly into the blood stream.
A BTCS such as TSC can be dissolved in water (advantageously injectable water). This solution can then be diluted with water, normal saline, Ringer's lactate or phosphate buffer, and the resulting mixture either infused or injected.
A buffer such as glycine, bicarbonate, or sodium carbonate can be added to the formulation at a level of about 50 mM for stability of the BCT such as TSC.
The ratio of TSC to cyclodextrin is based on TSC:cyclodextrin solubility data. For example, 20 mg/ml TSC, 8% gamma cyclodextrin, 50 mM glycine, 2.33% mannitol with pH 8.2+/−0.5, or 10 mg/ml TSC and 4% cyclodextrin, or 5 mg/ml and 2% cyclodextrin. The ratios of these ingredients can be altered somewhat, as is obvious to one skilled in this art.
Mannitol can be used to adjust osmolality and its concentration varies depending on the concentration of other ingredients. The glycine is held constant. TSC is more stable at higher pHs. pH of around 8.2+/−0.5 is required for stability and physiological compatibility. The use of glycine is compatible with lyophilization. Alternatively, the TSC and cyclodextrin is formulated using a 50 mM bicarbonate buffer in place of the glycine.
Commercially available pharmaceutical grade cyclodextrin has endotoxin levels that are incompatible with intravenous injection. The endotoxin levels must be reduced in order to use the cyclodextrin in a BTC formulation intended for intravenous injection.
The diffusion enhancing compound such as TSC can be lyophilized and put in a vial which can be part of a vial kit system which also includes a vial with diluent such as water for injection, and a syringe for administration.
Dual-chamber delivery systems allow reconstitution of the lyophilized diffusion enhancing compound directly inside the system be it a syringe or a cartridge. The lyophilized diffusion enhancing compound such as TSC is located in one chamber and the diluent (e.g. water for injection) in the other. The drug is reconstituted just before administration. It is a simple and controllable process completed in a few easy steps.
In one embodiment, the diffusion enhancing compound such as TSC is loaded in an auto-injector. An auto-injector (or auto-injector) is a medical device designed to deliver a dose of a particular drug. Most auto-injectors are spring-loaded syringes. By design, auto-injectors are easy to use and are intended for self-administration by patients, or administration by untrained personnel. The site of injection is typically the thigh or the buttocks. The auto-injector typically keeps the needle tip shielded prior to injection and also has a passive safety mechanism to prevent accidental firing (injection). Injection depth can be adjustable or fixed and a function for needle shield removal can be incorporated. Just by pressing a button, the syringe needle is automatically inserted and the drug is delivered.
The subject invention provides methods for the treatment of human patients having, or diagnosed as having, a viral or bacterial induced respiratory disease with hypoxemia, with a diffusion enhancing compound of the invention. Included are methods of treating influenza, a corona virus infection including Covid-19, and bacterial or viral pneumonia.
The diffusion enhancing compound can be administered by various routes. For example, the compound (which can be formulated with other compounds), can be administered at the proper dosage as an intravenous injection or infusion, an intramuscular injection, or in an oral form. The IV injection route is an advantageous route for giving a diffusion enhancing compound such as TSC. The patient can be given a diffusion enhancing compound such as TSC, e.g., by IV injection or infusion, IM, or orally, or, e.g., 1-2 hours prior to a procedure (e.g., prior to administration of supplemental oxygen, for example, by nasal cannula, noninvasive ventilation (e.g., via mask), mechanical ventilation (e.g., endotracheal intubation or tracheostomy and mechanical ventilation), and/or extracorporeal membrane oxygenation)), at a dosage in the range of 0.05-5 mg/kg, e.g., 0.05-2.5 mg/kg or 0.1-2 mg/kg.
The diffusion enhancing compound (e.g., bipolar trans carotenoid salt, e.g., TSC) may be administered up to four times a day, e.g., up to four times a day for up to 15 days, e.g., four times a day for 5 days. The diffusion enhancing compound (e.g., bipolar trans carotenoid salt, e.g., TSC) may be administered every 6 hours, e.g., every 6 hours for up to 15 days, e.g., every 6 hours for 5 days.
In certain embodiments, the diffusion enhancing compound, e.g. TSC, is administered in conjunction with the patient receiving supplemental oxygen or other compounds used in the treatment of viral or bacterial induced respiratory disease such as antivirals and/or antibiotics.
Provided is a method (Method 1) of treating a patient (e.g., a human) in need thereof having a viral or bacterial induced respiratory disease with hypoxemia comprising administering a diffusion enhancing compound to said patient. Provided is a method (Method 1) of treating a viral or bacterial induced respiratory disease with hypoxemia in a patient in need thereof (e.g., a human) comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 2) of prophylaxis and/or treatment of hypoxemia consequent to a viral or bacterial induced respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 3) of prophylaxis and/or treatment of acute respiratory distress syndrome associated with a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 4) of prophylaxis and/or treatment of acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of mild acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of moderate acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided is a method of prophylaxis and/or treatment of severe acute respiratory distress syndrome consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 5) of prophylaxis and/or treatment of multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 6) of mitigation, control, and/or treatment of one or more of hypoxemia, acute respiratory distress syndrome, and multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient. For instance, provided are methods of mitigation, control, and/or treatment of one or more of hypoxemia, acute respiratory distress syndrome, and multiple organ failure consequent to a viral or bacterial respiratory disease in a patient (e.g., a human) in need thereof comprising administering a diffusion enhancing compound to said patient, wherein said patient has mild acute respiratory distress syndrome, moderate acute respiratory distress syndrome, or severe acute respiratory distress syndrome.
Further provided is a method (Method 7) of improving blood oxygenation in a patient in need thereof (e.g., a human with a viral or bacterial respiratory disease, e.g. a human with hypoxemia consequent to a viral or bacterial respiratory disease) comprising administering a diffusion enhancing compound to said patient.
Further provided is a method (Method 8) of treating a patient (e.g., a human) in need thereof having a viral or bacterial induced respiratory disease comprising administering a diffusion enhancing compound to said patient. Provided is a method (Method 8) of treating a viral or bacterial induced respiratory disease in a patient in need thereof (e.g., a human) comprising administering a diffusion enhancing compound to said patient. For instance, a method of treating a viral or bacterial induced respiratory disease in a patient in need thereof (e.g., a human) comprising administering a diffusion enhancing compound to said patient, wherein said patient has no respiratory disease symptoms (e.g., no hypoxemia).
Further provided are any one of Methods 1-8 as follows:
YZ-TCRO-ZY,
Further provided is a kit comprising:
Further provided is a kit comprising:
Further provided is a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC)), e.g., as described in any one of Methods 1-8 or 1.1-1.70, for use in any one of Methods 1-8 or 1.1-1.70.
Further provided is use of a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC)), e.g., as described in any one of Methods 1-8 or 1.1-1.70, in the manufacture of a medicament for any one of Methods 1-8 or 1.1-1.70.
Further provided is a pharmaceutical composition comprising an effective amount of a diffusion enhancing compound (e.g., a bipolar trans carotenoid salt (e.g., TSC)), e.g., as described in any one of Methods 1-8 or 1.1-1.70, for use in any one of Methods 1-8 or 1.1-1.70.
In the methods disclosed herein (e.g., any one of Methods 1-8 or 1.1-1.70), the World Heath Organization ordinal scale score is as described in Example 1 below.
The National Early Warning Score is a tool developed by the Royal College of Physicians. At present, NEWS2, released in 2017, is the latest version.
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) associated with substantial morbidity and mortality. This clinical trial is designed to evaluate the safety and efficacy of trans sodium crocetinate (TSC) to improve oxygenation in SARS-CoV-2 infected patients with hypoxemia as a means of mitigating the unfortunate progression to acute respiratory distress syndrome (ARDS) and systemic organ injury.
The trial is composed of an open-label, pharmacokinetic, pharmacodynamic, ascending dose, safety and tolerability lead-in study to a single-center, randomized, placebo-controlled, double-blind, adaptive, safety and efficacy pilot study of TSC in SARS-CoV-2 infected patients with hypoxemia. The study includes assessment of blood oxygenation via continuous pulse-oximetry (SpO2) with calculation of the SpO2:FiO2 ratios (S:F ratio). The lead-in phase as well as the randomized phase also include serial blood gas (ABG) measurements on Day 1 prior to TSC administration and at 1 minute, 30 minutes, 3 hours and 6 hours with matching pharmacokinetic blood sampling.
WHO ordinal severity scale score:
Each TSC dose will be administered as an IV bolus injection to subjects per dose level administered four times per day (every 6 hours) for up to 5 days. TSC dose levels will be studied. Subjects will be assigned to dose levels in ascending order. The dose range is as follows.
This study will utilize an ascending dose scheme, starting at 0.25 mg/kg.
As subjects complete 5 days of treatment they may continue at their assigned TSC dose for up to 15 days at the investigator's discretion.
At the completion of the lead-in the SMC will examine the safety and blood oxygenation (S:F) data for all subjects and determine the optimum, safe and tolerable dose of TSC for use in the pilot study.
TSC dosing will be at the selected optimum, safe and tolerable biologic dose with an active to placebo ratio of 2:1 or 2:2:1 if two TSC doses are to be studied. The treatment arms are as follows.
Each TSC dose will be administered as an IV bolus injection 4 times per day (every 6 hours) for up to 15 days.
Subjects randomized to placebo will receive an IV bolus injection of Normal Saline at a volume which is matched to the volume that they would receive if they were receiving TSC, 4 times per day (every 6 hours) for up to 15 days.
All study drug administration will be performed by unblinded medical staff.
Blood oxygenation will be measured via recorded continuous pulse oximetry and the S:F ratio calculated.
For both the lead-in phase and randomized phase, provided that an arterial line is established, serial arterial blood gas measurements will be collected and recorded prior to TSC administration and at 1 minute, 30 minutes, 3 hours and 6 hours post TSC administration and the P:F ratio calculated, but only once per subject per TSC dose level. Alternatively, the S:F ratio will be used.
Subjects will be assessed daily while hospitalized. Discharged subjects will be asked to attend study visits at days 15, 29 and 60. All subjects whether a part of the lead-in phase or randomized pilot will be assessed for survival, serious adverse events and adverse events by requested return to the clinic on Day 60.
All subjects will undergo safety and efficacy assessments including laboratory assays, blood sampling on day 1 through day 15 (while hospitalized) and day 29 by return clinic visit or if still hospitalized.
For both the lead-in phase and randomized phase, at each study day, while hospitalized, the following measures of clinical support should be assessed and recorded.
For both the lead-in phase and randomized phase, the WHO 9-point ordinal scale assessment will the first assessment of the subject's clinical status each day. Each day, the worst score for the previous day will be recorded (i.e. on day 3, the score for day 2 is recorded as day 2). The ordinal scale is as follows.
For both the lead-in phase and randomized phase, the National Early Warning Score (NEWS) will be used each day to record the seven key physiological parameters that form the basis of the scoring system.
For both the lead-in phase and randomized phase, the study population will consist of hospitalized patients with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2<94% on room air or requiring supplemental oxygen, WHO ordinal scale 3, 4 or 5 and further characterized by inclusion and exclusion criteria of this protocol.
For the randomized phase, the population to be analyzed is the Intention-to-Treat (ITT) dataset (i.e., all randomized participants). We do not anticipate subject dropout for the primary outcome, and there will be no ‘drop-in’ of usual care participants receiving TSC. The safety dataset will include all randomized participants.
Subjects participating in the open-label, PK/PD, ascending dose, safety and tolerability lead-in will be assigned to treatment with TSC (not randomized) in ascending dose fashion.
Subjects participating in the single-center, randomized, placebo-controlled, double-blind, adaptive, safety and efficacy pilot will be randomized to the selected optimum, safe and tolerable biologic dose of TSC or placebo with an active to placebo ratio of 2:1 or 2:2:1 if two TSC doses are to be studied. Randomization to treatment will be stratified by the following factors assessed at randomization:
The identified person administering study drug will be unblinded given the orange-red coloration of the reconstituted TSC solution compared to Normal Saline placebo. Unblinded personnel will play no role in making patient assessments.
The lead-in PK/PD dose selection phase is not randomized whereas the follow-on pilot study is randomized. Both phases require four times a day (every 6 hour) dosing for up to 15 days.
Trans sodium crocetinate (TSC) will be administered intravenously as an IV bolus. The concentration of the reconstituted drug is 20 mg/mL.
TSC is dosed based on the patient's baseline weight, obtained on the day of screening, on a milligram per kilogram basis.
For the randomized phase, subjects randomized to placebo will receive an IV bolus injection of Normal Saline at a volume which is matched to the volume that they would receive if they were receiving TSC, four times per day (every 6 hours) for up to 15 days.
Subjects enrolled in this trial may receive any conventional treatment at the discretion of their attending physicians.
Therapy with antivirals including remdesivir or lopinavir/ritonavir (Kaletra®) or other therapeutic agents (e.g., corticosteroids) prior to enrollment in this trial are permitted.
If the local standard of care per written policies or guidelines (i.e., not just an individual clinician decision) includes remdesivir, lopinavir/ritonavir (Kaletra®) or other agents, then continuing these during the study is permitted, but may require additional safety monitoring by the site.
All medications taken in the 7 days prior to the first dose of study drug will be captured in the electronic case report form (eCRF). After the first dose of study drug, concomitant medications to be captured in the eCRF will be vasopressors and any medication given to specifically target COVID-19 (e.g., antivirals and corticosteroids).
Information commonly collected and recorded in source documents at the time of hospital admission for hypoxemia associated with SARS-CoV-2 infection can be used to qualify a subject for the study and hence, need not be repeated.
Following completion of the informed consent process the study coordinator will record the following from source documents or perform the following.
Subjects meeting all inclusion/exclusion criteria and who have completed the informed consent process may be enrolled in the study.
The unblinded bedside nurse and physician who are delegated, may then perform the following:
Time to recovery through Day 28 is the primary efficacy endpoint for the randomized part of the study. Subjects enter the study with a WHO COVID-19 ordinal severity scale score of 3, 4 or 5. To meet the definition of recovery, a subject must achieve a WHO severity score of 1, 2, or 3 and have an improvement of at least 1 point, maintained through the Day 28. In other words, subjects who enter the study with a baseline WHO scale score of 3 and improve to (and maintain to the Day 29 evaluation) a score of 1 or 2 have met the definition of recovery. Subjects who enter the study with a baseline WHO scale score of 4 or 5 and improve to (and maintain to Day 29 evaluation) a score of 1, 2 or 3 have met the definition of recovery. Time to recovery will counted from day of randomization to day of recovery (date of recovery−date of randomization+1).
Note that the evaluation that is performed on Day 29 is an assessment of the subject's WHO severity score of the previous day (Day 28).
The Glasgow Coma Score will be performed daily until hospital discharge and in accordance with the standards established by the Institute of Neurological Sciences NHS Greater Glasgow and Clyde. The Glasgow Coma Score will be calculated by addition of the total points selected under each of the three components including eye, verbal and motor. The score for eye opening, verbal response and best motor response will be recorded individually as well as the total score, daily. The procedure as well as the template for recording the Glasgow Coma Scale is described at the web site www.glasgowcomascale.org.
The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until hospital discharge using the worst parameters measured during the prior 24 hours. Individual system scores and total will be recorded as follows. SaO2/FiO2 data may be substituted when PaO2/FiO2 data is unavailable.
It will be readily apparent to those skilled in the art that numerous modifications and additions can be made to both the present compounds and compositions, and the related methods without departing from the invention disclosed.
This application claim priority to U.S. Provisional Application No. 63/003,259 filed Mar. 31, 2020, U.S. Provisional Application No. 63/003,841 filed Apr. 1, 2020, U.S. Provisional Application No. 63/052,893 filed Jul. 16, 2020, and U.S. Provisional Application No. 63/113,140 filed Nov. 12, 2020, each of which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/025175 | 3/31/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63113140 | Nov 2020 | US | |
| 63052893 | Jul 2020 | US | |
| 63003841 | Apr 2020 | US | |
| 63003259 | Mar 2020 | US |
