Safety, Tolerability, and Treatment Effect of Belnacasan in Patients With COVID-19

Study Overview
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Brief Summary
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The purpose of this trial is to assess the safety, tolerability and treatment effect of the orally administered Caspase-1 inhibitor, belnacasan, for the treatment of patients with mild to moderate COVID-19 and to generate proof of concept for future trials.

Detailed Description
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COVID-19 is an acute respiratory disease caused by the SARS-CoV-2 virus which has impacted the lives of millions of patients. Though vaccines and preventive treatments such as monoclonal antibodies, steroids, and anti-virals have been established, they do not specifically target the resulting inflammatory response and complications the virus causes. This study aims to evaluate how safe and effective a particular oral medication, Belnacasan, is in diminishing your body's inflammatory response, which may go into overdrive when infected with the virus. This overly activated immune response can become uncontrolled resulting in cell death and the release of damaging proteins which can cause major harm to all organs throughout the body. Belnacasan prevents the activation of a particular enzyme, Caspase-1, which plays a major role in activating this damaging immune response brought on by COVID-19. The goal of this medication being a more targeted treatment that aims to prevent the devastating immune response.

Official Title
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A Proof of Concept, Randomized, Double-blind, Placebo-controlled Trial of Orally Administered Belnacasan Tablets for the Treatment of Mild to Moderate COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Belnacasan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject (or legally authorized representative) provides written informed consent prior to the initiation of any study procedures Subject understands and agrees to comply with planned study procedures, including using the diary Subject agrees to the collection of nasopharyngeal swabs and venous blood per protocol Subject is male or non-pregnant female adult ≥18 years of age at time of consent a. Women with a history of menstruation must agree to use two methods of contraception, at least one of which is highly effective, for the duration of the study as well as to undergo additional pregnancy testing during the study Subject has a laboratory confirmed SARS-CoV-2 infection as determined by RT-PCR assay prior to enrollment Subject has evidence of either mild or moderate COVID-19 illness of less than 7 days from first onset, with minimal baseline symptom severity based on patient-reported FDA scoring system defined as follows: Subject presents with at least two common symptoms of COVID-19 from the following list: Stuffy or runny nose, sore throat, cough, low energy or tiredness, muscle or body ache, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, diarrhea, shortness of breath with exertion (without supplemental oxygen requirement) with a score of 2 or higher, impairment in sense of smell or taste with a score of 1 or higher OR Subject presents with any (i.e., at least one) symptom of COVID-19 as defined above AND clinical evidence of moderate COVID-19 as defined by FDA guidance for industry (such as respiratory rate >20 breaths per minute, heart rate >90 beats per minute, with oxygen saturation >93% on room air at sea level) Subject presents with high-risk for COVID-19-related inflammation determined by at least one comorbidity, including obesity, diabetes, hypertension, stable heart disease, respiratory disease, and/or non-severe fatty liver disease Subject's overall health condition is deemed as suitable to fully and safely participate in this trial as determined by the investigator Exclusion Criteria: Any clinical signs indicative of severe or critical COVID-19 as defined by FDA guidance for Industry at the time, including SpO2 <93% and/or oxygen requirement Hospitalization for COVID-19, or consideration thereof ICU level of care and/or non-mechanical/mechanical ventilation and/or oxygen supplementation at time of enrollment Pregnant or breast-feeding subjects Subjects who cannot swallow tablets History of any pre-existing organ impairment, such as: Severe kidney disease (known or estimated GFR <30 mL/minute) or on dialysis Uncontrolled, clinically significant heart diseases such as arrhythmias, angina or heart failure as defined by AHA/ACC Grade C and D Chronic respiratory disease requiring supplemental oxygen Moderate and severe hepatic impairment as defined by Child-Pugh scoring Class B and Class C Elevated liver function test (determined by ALT, AST, GGT, or ALP >2x upper limit of normal, and/or total Bilirubin > upper limit of normal) History of malignancy or immunodeficiency within the prior 5 years Acute respiratory illness other than COVID-19 Acute bacterial, viral or fungal infection (including HIV, hepatitis B, hepatitis C) While dosed with IP, the taking of prohibited concomitant medication or the ingestion of food that interferes with the IP, including: Non-COVID19-related anti-viral medication such as lopinavir, ritonavir, ribavirin, or interferon-1β Systemically administered immunosuppressive and anti-inflammatory agents, other than background standard of care for COVID-19 at the time Drugs and foods that are potent inhibitors or inducers of CYP3A4 and/or P-gp, as listed in FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, including herbal medications such as St. John's Wort within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug Any other diseases or medical conditions or concomitant medications that are deemed as not compatible or appropriate for the subject's ability to fully and safely participate in this trial as determined by the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional<br>900mg dose TID Administration Total: 2700mg | Drug: Belnacasan<br>* Oral administration<br>|
| Placebo Comparator: Placebo<br>900mg dose TID Administration Total: 2700mg | Drug: Placebo<br>* Tablet containing 0mg of API<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Belnacasan | Incidence of Adverse events and serious adverse events | 60 days post enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained recovery and resolution rates of common COVID-19 symptoms | Proportion of subjects in treatment group versus placebo group, respectively, who per symptom questionnaire rate stuffy or runny nose, sore throat, cough, low energy or tiredness, muscle or body ache, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, diarrhea, shortness of breath with exertion; impairment in sense of smell or taste have achieved for two consecutive days: scores not higher than 0 for all symptoms; scores not higher than 1 for all symptoms; scores not higher than 0 for all symptoms other than impairment of taste or smell; scores not higher than 1 for all symptoms other than impairment of taste or smell. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Sustained improvement of global impression rates | Proportion of subjects in treatment group versus placebo group, respectively, who per symptom questionnaire have answered for two consecutive days: YES to In the past 24 hours, have you returned to your usual health (before your COVID-19 illness)?; YES to In the past 24 hours, have you returned to your usual activities (before your COVID-19 illness)?; NONE to In the past 24 hours, what was the severity of your overall COVID-19 related symptoms at their worst?; MILD to In the past 24 hours, what was the severity of your overall COVID-19 related symptoms at their worst?. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Time to sustained recovery or resolution of common COVID-19 symptoms | Comparison in treatment group versus placebo group, respectively of the number of days from randomization to the first day of achieving sustained recovery and resolution rates of common COVID-19 symptoms. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Time to sustained improvement of global impression | Comparison in treatment group versus placebo group, respectively of the number of days from randomization to the first day of achieving sustained improvement of global impression rates. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Rates of fever | Proportion of subjects in treatment group versus placebo group, respectively, who per thermometer experienced fever at any point between enrollment and day 2 post randomization and who were afebrile <38C. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Oxygenation levels | Proportion of subjects in treatment group versus placebo group, respectively, who per pulse oximeter reading experienced oxygenation of SpO2>=96% or >93% in room air when resting. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Time to normalization of fever and oxygenation levels | Comparison in treatment group versus placebo group, respectively of the number of days from randomization to the first day of achieving sustained (i.e., at least 2 days) resolution of fever for subjects who presented with fever at any point between enrollment and day 2 post randomization; with temperature <38C or >=38C experienced in total during the first 28 days post randomization; from randomization to the first day post randomization of achieving oxygenation of SpO2>=96% in room air when resting for subjects who presented with SpO2>93% and <96% in room air, when resting, at enrollment; with oxygenation of SpO2>= 96% or SpO2>93% in room air, when resting, in total during the first 28 days post randomization. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Experiences of COVID-19 related deterioration and mortality | Proportion of treatment group, versus placebo group, respectively, who per subject reporting or medical records had experienced an emergency department visit, other than at study enrollment or study visits; hospitalization for COVID-19; hospitalization for COVID-19 requiring oxygen; hospitalization for COVID-19 requiring ICU; hospitalization for COVID-19 requiring ventilation; COVID-19 related death; death; hospitalization or death. | days 14, 28 and 60 post randomization | 
| Length of COVID-19 related deterioration and mortality experiences | Comparison of treatment group versus placebo group, respectively, in the number of days from randomization until the first day of experiencing hospitalization for COVID-19; of hospitalization for COVID-19 experienced in total; of hospitalization for COVID-19 requiring oxygen experienced in total; of hospitalization for COVID-19 requiring ICU experienced in total; of hospitalization for COVID-19 requiring ventilation experienced in total. | days 14, 28 and 60 post randomization | 
| Changes on the WHO 9-Point Ordinal Scale | Proportion of treatment group versus placebo group, respectively who per questionnaire on WHO 9-point ordinal scale [0: Uninfected or no clinical or virological evidence of infection; 1: Not hospitalized, no limitations on activities; 2: Not hospitalized, limitation on activities; 3: Hospitalized, not requiring supplemental oxygen; 4: Hospitalized, requiring supplemental oxygen; 5: Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6: Hospitalized, intubated; 7: Hospitalized, advanced life support including invasive mechanical ventilation or ECMO; 8: Death] had experienced an improvement from scale 2 to scale 1 or 0; an improvement from scale 1 to scale 0 ; a sustainment from scale 1 to scale 1; any improvement of the scale; any worsening of the scale; scale 4 or higher; scale 6 or higher. | days 4, 7, 10, 14, 21, 28, 42, 60 post randomization | 
| Values on the WHO 9-Point Ordinal Scale | Comparison of treatment group versus placebo group, respectively, in the average of daily scale value on that day; overall average of daily scale value experienced since enrollment; in the worst (i.e., highest) daily scale value experienced since enrollment; in the best (i.e., lowest) daily scale value experienced since enrollment. | days 14, 28, 60 post randomization | 
| Time to improvement on the WHO 9-Point Ordinal Scale | Comparison of treatment group versus placebo group, respectively, in the number of days from enrollment until first experiencing a 1-point improvement sustained over at least 2 days. | days 14, 28, 60 post randomization | 
| Length of experiencing WHO 9-Point Ordinal Scale values | Comparison of treatment group versus placebo group, respectively, in the total number of days on which subjects experienced a given scale value. | days 14, 28, 60 post randomization | 
| Values and changes in values of surrogate markers of COVID-19-related inflammation and organ involvement | Analysis and comparison of surrogate markers of COVID-19 related inflammation and organ involvement as determined by biochemistry, hematology, and immunology labs and studies, in treatment group versus placebo group, respectively, for values and changes in values from enrollment and between assessment days. | days 7, 14, 21, 28 post randomization | 
| Experiences of normal surrogate markers of COVID-19-related inflammation and organ involvement | Proportion of treatment group versus placebo group, respectively, who experience normal / in-range values for a given marker. | days 7, 14, 21, 28 post randomization |