Clinical trial NCT05164120: Safety, Tolerability, and Treatment Effect of Belnacasan in Patients With COVID-19
Official title: A Proof of Concept, Randomized, Double-blind, Placebo-controlled Trial of Orally Administered Belnacasan Tablets for the Treatment of Mild to Moderate COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Lead sponsor: Medstar Health Research Institute
Sponsor class: OTHER
First posted: 2021-12-20
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Subject (or legally authorized representative) provides written informed consent prior to the initiation of any study procedures
2. Subject understands and agrees to comply with planned study procedures, including using the diary
3. Subject agrees to the collection of nasopharyngeal swabs and venous blood per protocol
4. 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
5. Subject has a laboratory confirmed SARS-CoV-2 infection as determined by RT-PCR assay prior to enrollment
6. 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:

   1. 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
   2. 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)
7. 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
8. Subject's overall health condition is deemed as suitable to fully and safely participate in this trial as determined by the investigator

Exclusion Criteria:

1. 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
2. Hospitalization for COVID-19, or consideration thereof
3. ICU level of care and/or non-mechanical/mechanical ventilation and/or oxygen supplementation at time of enrollment
4. Pregnant or breast-feeding subjects
5. Subjects who cannot swallow tablets
6. History of any pre-existing organ impairment, such as:

   1. Severe kidney disease (known or estimated GFR \<30 mL/minute) or on dialysis
   2. Uncontrolled, clinically significant heart diseases such as arrhythmias, angina or heart failure as defined by AHA/ACC Grade C and D
   3. Chronic respiratory disease requiring supplemental oxygen
   4. Moderate and severe hepatic impairment as defined by Child-Pugh scoring Class B and Class C
7. Elevated liver function test (determined by ALT, AST, GGT, or ALP \>2x upper limit of normal, and/or total Bilirubin \> upper limit of normal)
8. History of malignancy or immunodeficiency within the prior 5 years
9. Acute respiratory illness other than COVID-19
10. Acute bacterial, viral or fungal infection (including HIV, hepatitis B, hepatitis C)
11. While dosed with IP, the taking of prohibited concomitant medication or the ingestion of food that interferes with the IP, including:

    1. Non-COVID19-related anti-viral medication such as lopinavir, ritonavir, ribavirin, or interferon-1β
    2. Systemically administered immunosuppressive and anti-inflammatory agents, other than background standard of care for COVID-19 at the time
    3. 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
12. 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

Primary outcomes:
measure: Safety and Tolerability of Belnacasan
timeFrame: Through 60 days post enrollment
Secondary outcomes:
measure: Sustained Recovery and Resolution Rates of Common COVID-19 Symptoms
timeFrame: Baseline and Days 4, 7, 10, 14, 21, 28, 42, and 60 post randomization
measure: Sustained Improvement of Global Impression Rates
timeFrame: Days 4, 7, 10, 14, 21, 28, 42, and 60 post randomization
measure: Time to Sustained Recovery or Resolution of Common COVID-19 Symptoms
timeFrame: Over 60 days post randomization
measure: Time to Sustained Improvement of Global Impression
timeFrame: Over 60 days post randomization
measure: Rates of Fever
timeFrame: Days between enrollment and day 2 post randomization
measure: Oxygenation Levels
timeFrame: Over 60 days post randomization
measure: Time in Days to Normalization of Fever and Oxygenation Levels.
timeFrame: 28 Days
measure: Experiences of COVID-19 Related Deterioration and Mortality
timeFrame: Days 14, 28 and 60 post randomization
measure: The Number of Subjects With COVID-19 Related Deterioration and Mortality Experiences
timeFrame: Over 28 days
measure: Changes on the WHO 9-Point Ordinal Scale
timeFrame: Days 4, 7, 10, 14, 21, 28, 42, and 60 post randomization
measure: Values on the WHO 9-Point Ordinal Scale
timeFrame: Days 14, 28, and 60 post randomization
measure: Time to Improvement on the WHO 9-Point Ordinal Scale
timeFrame: Post treatment to Day 60
measure: Mean Number of Days of Experiencing WHO 9-Point Ordinal Scale Values
timeFrame: Post treatment through Day 60
measure: IL-6
timeFrame: Baseline and Days 7, 14, 21, 28
measure: IL-1ra
timeFrame: Baseline and Days 7, 14, 21, 28
measure: IL-18
timeFrame: Baseline and Days 7, 14, 21, and 28
measure: TNF-alpha
timeFrame: Baseline and Days 7, 14, 21, and 28
measure: Caspase-1
timeFrame: Baseline and Days 7, 14, 21, and 28
measure: Gasdermin D
timeFrame: Baseline and Days 7, 14, 21, and 28
measure: G-CSF
timeFrame: Baseline and Days 7, 14, 21, and 28
Other outcomes:
Locations:
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Baltimore
country: United States
facility: MedStar Franklin Square
state: Maryland
Study officials:
affiliation: MedStar Health
name: Glenn Wortmann, MD
role: PRINCIPAL_INVESTIGATOR
References: