Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

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.

Arms:
arm 1: 900mg dose TID Administration Total: 2700mg arm 2: 0 mg dose TID Administration Total: 0 mg

Interventions: intervention 1: Belnacasan intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration intervention 2: Tablet containing 0mg of API

Protocol document:
Prot_SAP_000.pdf: 
 
 
Title of Study: 
Safety, tolerability, and treatment effect of belnacasan in patients with 
COVID-19: A proof of concept, randomized, double-blind, placebo-
controlled trial of orally administered belnacasan tablets for the treatment 
of mild to moderate COVID-19 
 
 
NCT #: 
 
NCT05164120 
 
 
Date:  
 
December 23, 2021 


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Safety, tolerability, and treatment effect of belnacasan in patients with COVID-19 
A proof of concept, randomized, double-blind, placebo-controlled trial of orally administered 
belnacasan tablets for the treatment of mild to moderate COVID-19
Clinical Trial Protocol
Name of product
Belnacasan (VX-765/RVT-201/MSR-001)
Phase
2 / Proof of Concept
Protocol Number
MedStar-COVID-19-belnacasan-2001
IND Number
155290
Sponsor
MedStar Health
Protocol Authors
Alexander Kroemer, MD
Email: alexander.h.kroemer@medstar.net
Office: 202-444-4052 | Cell: 202-830-7371
___________________
Khalid Khan, MD
Email: khalid.m.khan@medstar.net
Office: 202-444-6047 | Cell: 202-805-4289
___________________
Thomas M. Fishbein, MD
Email: thomas.m.fishbein@medstar.net
Office: 202-444-6396 | Cell: 202-316-3487
___________________
Clinical Trial Protocol Version / Date
2.2 / December 23, 2021
Protocol Amendment Number / Date
NA
CONFIDENTIALITY STATEMENT
This study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki 
and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the US Code of 
Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and applicable 
regulatory requirements.
This document is confidential and proprietary to MedStar Georgetown Transplant Institute and MedStar Health. 
Acceptance of this document constitutes agreement by the recipient that no unpublished information contained 
herein will be reproduced, published, or otherwise disseminated or disclosed without prior written approval of 
MedStar Health, except that this document may be disclosed in any medium to appropriate clinical providers, the 
Institutional Review Board, and others directly involved in the clinical investigation that is the subject of this 
information under the condition that they keep the information strictly confidential.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS .....................................................................................................................4
SUMMARY OF CHANGES FROM PROTOCOL VERSION 2.1 TO 2.2............................................6
SUMMARY OF CHANGES FROM PROTOCOL VERSION 2.0 TO 2.1............................................8
SUMMARY OF CHANGES FROM PROTOCOL VERSION 1.0 TO 2.0............................................9
STUDY SYNOPSIS ...................................................................................................................................10
1
BACKGROUND, STUDY RATIONALE AND DOSING RATIONALE...................................18
1.1
Background and study rationale................................................................................................................18
1.2
Belnacasan (VX-765/RVT-201/MSR-001) ..............................................................................................21
1.3
Dosing rationale ........................................................................................................................................21
1.4
Brief summary of known systemic safety profile of belnacasan (VX-765/RVT-201/MSR-001) ............22
1.5
Ongoing clinical studies with belnacasan (VX-765/RVT-201/MSR-001)...............................................22
2
SUMMARY .......................................................................................................................................23
3
OBJECTIVES AND ENDPOINTS .................................................................................................24
3.1
Primary Objective .....................................................................................................................................24
3.2
Primary Endpoint ......................................................................................................................................24
3.3
Secondary Objective .................................................................................................................................24
3.4
Secondary Endpoints.................................................................................................................................24
4
SAFETY AND TOLERABILITY ...................................................................................................29
5
STUDY DESIGN...............................................................................................................................29
5.1
Study Description......................................................................................................................................29
5.2
Study Assessments....................................................................................................................................33
5.3
Selection Criteria.......................................................................................................................................34
5.4
Concomitant and Prohibited Medication ..................................................................................................37
6
MATERIALS.....................................................................................................................................37
6.1
Study Drugs...............................................................................................................................................38
6.2
Storage, Dispensing and Reconciliation of Study Drug and Identity of Investigational Products ...........38
7
STUDY PROCEDURES...................................................................................................................39
7.1
Observations and Measurements ..............................................................................................................39
7.2
Instructions to Subjects .............................................................................................................................40
7.3
NCI CTCAE Definitions of Dose Limiting Adverse Events....................................................................41
7.4
Pre-Existing Medical Conditions..............................................................................................................41
7.5
Acute Conditions Brought on by COVID-19 ...........................................................................................41
7.6
Treatment Emergent Adverse events ........................................................................................................42
7.7
Laboratory Abnormalities.........................................................................................................................43
7.8
Adverse Event Assessment and Recording...............................................................................................44
7.9
Reporting Requirements ...........................................................................................................................45
7.10
Serious Adverse Events ............................................................................................................................46
7.11
Notification of Serious Adverse Events....................................................................................................47
7.12
Reporting a Serious Adverse Event ..........................................................................................................47
7.13
Departure from Protocol for Emergency or Adverse Event......................................................................47
7.14
Safety Monitoring .....................................................................................................................................47
7.15
Stopping Rules ..........................................................................................................................................48
7.16
Follow-Up and Final Reports....................................................................................................................48
7.17
Regulatory Aspects ...................................................................................................................................48
8
DATA MANAGEMENT AND STATISTICS................................................................................48
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8.1
Populations for Analyses ..........................................................................................................................48
8.2
Analysis Methods......................................................................................................................................49
8.3
Analysis of Subject Disposition, History, and Baseline Characteristics...................................................49
8.4
Safety & Tolerability Analyses.................................................................................................................49
8.5
Treatment Effect Analyses........................................................................................................................51
8.6
Handling of Missing Data.........................................................................................................................51
8.7
Sample Size Considerations......................................................................................................................52
9
ESTIMATED DURATION OF THE STUDY ...............................................................................52
10
ADMINISTRATIVE PROCEDURES AND ETHICAL CONSIDERATIONS..........................52
10.1
Subject Information and Informed Consent..............................................................................................52
10.2
In person consent ......................................................................................................................................52
10.3
Remote Consent ........................................................................................................................................52
10.4
Documentation of Consent........................................................................................................................53
In all cases consent will be documented before research procedures begin. Standard documentation of consent 
may be used including presentation of a paper consent for to a potential participant for signature. This form of 
documentation of consent may be used for either with an in person or remote consent process. In all cases 
documentation of consent will be obtained in accordance with institutional policy and procedures (MG.O-004.01, 
MG.O-004.06)..........................................................................................................................................................53
Electronic Consent...................................................................................................................................................53
10.5
Study Monitoring ......................................................................................................................................53
10.6
Audits and Inspections..............................................................................................................................54
10.7
Ethics Committee Review.........................................................................................................................54
10.8
Standards...................................................................................................................................................54
10.9
Confidentiality ..........................................................................................................................................54
10.10
Protocol Adherence...................................................................................................................................55
10.11
Amendments to the Protocol.....................................................................................................................55
10.12
Protocol Deviations...................................................................................................................................55
10.13
Study Termination.....................................................................................................................................56
10.14
Inspection of Records................................................................................................................................56
10.15
Data Management .....................................................................................................................................56
10.16
Liability and Insurance..............................................................................................................................57
10.17
Retention of Records.................................................................................................................................57
10.18
Data Quality Assurance ............................................................................................................................57
11
USE OF INFORMATION................................................................................................................58
12
APPENDIX ........................................................................................................................................59
12.1
Labs and Tests...........................................................................................................................................59
12.2
Illustrative Subject Diary Excerpts ...........................................................................................................60
12.3
Illustrative Randomization Table..............................................................................................................63
13
REFERENCES..................................................................................................................................64
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LIST OF ABBREVIATIONS
9-POS
9-Point Ordinal Disease Severity Scale
ADL
Activities of daily living
AE
Adverse event
ALC
Absolute lymphocyte count
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMI
Body mass index
CFR
Code of Federal Regulations
CRF
Case report form
CRP
C-reactive protein
CS
Clinically significant
CT
Computed tomography
COVID-19
Coronavirus disease 2019
CTCAE
Common terminology criteria for adverse events
CXR
Chest x-ray
DLT
Dose limiting toxicity
DSMB
Data and safety monitoring board
ECMO
Extracorporeal membrane oxygenation
EDC
Electronic data capture
EKG
Electrocardiogram
ET
Early termination
FDA
Food and Drug Administration
G-CSF
Granulocyte colony-stimulating factor  
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart rate
I/E
Inclusion/Exclusion
ICH
International Council for Harmonization
IDS
Investigational Drug Services
IND
Investigational New Drug
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IP
Investigational product (belnacasan or placebo)
IRB
Institutional review board
LAR
Legally authorized representative
LDH
Lactate dehydrogenase
LOC
Level of consciousness
NCS
Not clinically significant
PE
Physical examination
P-gp
P-glycoprotein
QID
Four times a day
RP
MedStar Health Research Pharmacy
RR
Respiratory rate
RT-PCR
Reverse transcriptase polymerase chain reaction
SAE
Serious adverse events
SAP
Statistical analysis plan
SARS
Severe acute respiratory syndrome
SBP
Systolic blood pressure
SOC
Standard of care
SpO2
Peripheral capillary oxygen saturation
TID
Three times a day
TNF-α
Tumor necrosis factor alpha
WHC
Washington Hospital Center
WHO
World Health Organization
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SUMMARY OF CHANGES FROM PROTOCOL VERSION 2.1 TO 2.2
1. Initial Date and Completion Date changed in the Study Synopsis to November 2021 and 
April 2022, respectively.
2. Version date updated on the title page and footer of Protocol.
3. Revision to Section 5.1 Study Description allowing PCR confirmation by a home health 
agency with virtual and e-consent practices stating, “Some patients identified will 
require a PCR-confirmed COVID test, having only had a rapid antigen test.  Patients 
requiring a PCR test can either have one collected with screening labs prior to leaving 
the MedStar enrollment site or have these labs collected via a home-health research visit.  
Prior to study-specific procedures the study team will obtain their consent in-person or 
remotely.  An e-consent platform, Interlace, can also be used to consent potential subjects 
via electronic platform.  Once their COVID-19 status is confirmed via PCR they will 
complete the remainder of their screening/enrollment visit at at either MedStar 
Washington Hospital Center or MedStar Franklin Square within the next 1 to 3 days.  
Virtual consent or e-consent will follow MedStar institutional policies and procedures.”  
Under Background of Care adding that individuals will additionally be screened from 
Urgent Cares.  Addition of Urgent Care under Study Population and home health PCR. 
Under Recruitment Methods describing MedStar process, methods and materials that 
will be used to identify and recruit potential subjects.
4. Revision to Section 5.2, Table 1 Schedule of Events superscript 3 with addition of home 
health agency option to collect RT-PCR sample in the subjects’ home in the event their 
initial testing did not include PCR, to ensure expeditious resulting and appropriate 
inclusion in the trial.  Clarification made that subjects will return to a MedStar site for 
completion of the screening/enrollment visit 1 to 3 days following confirmation.  
Superscript 12 also updated to indicate laboratory tests collected at the 
screening/enrollment visit may be collected by a home health agency in the subjects’ 
home. 
5. Revision to Section 5.2, Table 1 Schedule of Events superscript 6 adding detail that 
outside laboratories will result certain labs, with locations included as part of Appendix 
12, 12.1 Labs and Tests.  Specifically, CD3+ counts/cell isolation/storage for future use 
samples and markers of inflammation will be sent to respective laboratories.
6. Revision to Section 5.2, Table 1 Schedule of Events superscript 4 adding detail of 
pregnancy testing schedule
7. Revision to Section 5.2, Table 1 Schedule of Events superscript 13 adding clarification to 
chest x-ray and chest CT requirement.
8. Revision to Section 6.1 clarifying that the screening/enrollment visit may occur over 
more than one day if confirmatory PCR testing is needed.
9. Revision to Section 7.1 adding description of virtual consent or e-consent practices and 
communications and operations flow with the home health agency and the subject.
10. Revision to Section 7.5 clarifying initial screening will be at a MedStar site or via home 
health.
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11. Revision to Sections 10.1 through 10.4 clarifying remote and in-person consent as well 
as documentation of consent and e-consent.
12. Addition of Troponin I, High Sensitivity (hs-TnI) to chemistry labs in Appendix 12, 12.1 
Labs and Tests given myocardial organ involvement is an endpoint to be monitored 
throughout the trial (5 of 5).
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SUMMARY OF CHANGES FROM PROTOCOL VERSION 2.0 TO 2.1
1. Table 1: Schedule of Events, the Subjects section was revised to clarify that the “subject 
will report via telephone to study team at Day 42 & 60 their temperature, SpO2 resting, 
and symptom tracking. Diary completion for the subject ends at Day 28.”
2. Per request of the reviewing Institutional Review Board, the following clarification was 
added as a footnote to Section 5.2 Study Assessments, Table 1: Schedule of 
Assessments, “12These laboratory tests will be collected at a one-time blood draw at 
each visit, a total of 5 collections at the 5 visits (Screening, Day 7, Day 14, Day 21, and 
Day 28).  The amount drawn at each timepoint is as follows: Screening visit (56 mL or 11 
teaspoons), Day 7 (44 mL or 9 teaspoons), Day 14 (56 mL or 11 teaspoons), Day 21 (20 
mL or 4 teaspoons), and Day 28 (48 mL or 10 teaspoons).  The early termination visit 
would be in lieu of one of the in-person visits, it is not included in the total.”  The IRB 
requested that the number of blood draws, the timepoints for collection, and the volume 
collected be added.”
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SUMMARY OF CHANGES FROM PROTOCOL VERSION 1.0 TO 2.0
1. Exclusion Criteria
The exclusion criteria related to liver function, which appears in the Synopsis as well as Sections 
5.3 and 7.5 has been changed to “Elevated liver function tests (determined by ALT, AST, GGT, or 
ALP > 2 x upper limit of normal, and/or total Bilirubin > upper limit of normal).”
2. Laboratory Abnormalities
Additional text has been added to Section 7.7 that reads as follows:
“Particular attention will be paid to determine the possibility of drug induced liver injury (DILI) 
as detailed in the FDA guidance document “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation.” Liver tests (ALT, AST, ALP, and total Bilirubin) will be performed at enrollment and 
at days 7, 14, and 28 throughout the drug administration period.  For patients exhibiting signs of 
liver disease such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, or 
rash, extensive laboratory testing will be performed that includes above liver chemistries 
immediately. Otherwise, on routine weekly testing an increase of serum aminotransferase levels 
to >3x upper limit of normal would automatically trigger repeat testing within 48 to 72 hours of 
all four of the usual serum measures (ALT, AST, ALP, and total Bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. If symptoms and/or 
aminotransferase levels remain >3x upper limit of normal, the participant will be monitored more 
closely with lab schedule, in-person or virtual evaluation twice weekly or more. A thorough 
evaluation for additional causes of liver test anomalies will be conducted in consultation with 
Hepatology. A case report form page will be created and DSMB review triggered. Otherwise, 
discontinuation of treatment will be considered immediately if: 
•
ALT or AST >8x upper limit of normal
•
ALT or AST >5x upper limit of normal for more than 2 weeks 
•
ALT or AST >3x upper limit of normal and total Bilirubin >2x upper limit of normal 
or INR >1.5 
•
ALT or AST >3x upper limit of normal with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).”
3. Serious Adverse Events
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The definition of Serious Adverse Events, which appears in Section 7.9, has been updated to 
read:
“Serious Adverse Event: An untoward event or reaction that at any dose:

results in death

is life-threatening

results in hospitalization or prolongs existing hospitalization

results in permanent or significant disability or incapacity

requires intervention to prevent permanent impairment/damage

results in congenital anomaly or birth defect
In addition, any important medical event that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.”
4. Stopping Rules
The study stopping rules, which appear in the Synopsis as well as Sections 4, 7.15, and 8.4 have 
been changed to “should two or more subjects develop a similar Grade 3 SAE that is at least 
possibly related to belnacasan or should one or more subjects develop a ≥ Grade 4 SAE that is 
at least possibly related to belnacasan, the trial will be paused for DSMB safety review.”
STUDY SYNOPSIS
Study Title
Safety, tolerability, and treatment effect of belnacasan in patients with COVID-
19: A phase 2, proof of concept, randomized, double-blind, placebo-controlled trial of 
orally administered belnacasan tablets for the treatment of mild to moderate COVID-
19 
Protocol Number
MedStar-COVID-19-belnacasan-2001
Study Phase 
2 / Proof of Concept
Methodology
This study is conducted as a proof of concept safety, tolerability and treatment effect 
Phase 2 trial in subjects with confirmed SARS-CoV-2 infection and mild to moderate 
COVID-19.
In this hypothesis generating, randomized, double-blind, placebo-controlled trial, 20 
subjects will be given 900 mg TID of belnacasan and 20 subjects will be given a 
placebo TID. Belnacasan or placebo will be given for 28 days and assessments of 
safety, tolerability, and treatment effect will be performed for 60 days. Subjects in both 
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treatment arms will also be treated with the background standard of care that is at that 
time appropriate and commensurate with their COVID-19 disease severity.
Subjects will use a diary to record study drug intake as well as symptoms and activity 
levels; assess physical parameters using a study-provided thermometer and pulse 
oximeter; be assessed at regular intervals by the Study Team via the telephone and in-
person follow-up clinic visits at MedStar Washington Hospital Center or MedStar 
Franklin Square Medical Center; and give blood for laboratory tests. A Data Safety & 
Monitoring Board (DSMB) will be engaged throughout for data monitoring and safety 
evaluation. 
Study Duration
Subjects will be in the study for 60 days. The study will last 3-6 months.
Study Centers
This study will be conducted at MedStar Washington Hospital Center (WHC) and/or 
MedStar Franklin Square and/or other MedStar hospital and/or urgent care sites.
Objectives
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 hypotheses for future trials.
Primary Objective: To determine the safety and tolerability of belnacasan (VX-
765/RVT-201/MSR-001) administered orally for 28 days in subjects with mild to 
moderate COVID-19 as determined by Adverse Events and Serious Adverse Events.
Secondary Objective: To generate data on the treatment effect of belnacasan (VX-
765/RVT-201/MSR-001) administered orally for 28 days in subjects with mild to 
moderate COVID-19 as determined by its effect size on outcomes in five areas: 
1. Clinical recovery and resolution of COVID-19 symptoms
2. Physical functions and parameters relevant to COVID-19
3. COVID-19 related deterioration and mortality 
4. WHO 9-point ordinal scale for clinical improvement
5. Surrogate markers of COVID-19-related inflammation and organ involvement
The hypothesized end result of treatment with belnacasan would be to reduce the 
symptomatic and clinical burden, length of disease course, and disease progression of 
COVID-19.
Number of 
Subjects
The intent is to enroll 40 subjects to participate in a 1:1 allocation in this randomized, 
double-blind, placebo-controlled safety, tolerability and treatment effect trial. 
Study Description
A Phase 2, proof of concept randomized, double-blind, placebo-controlled trial of orally 
administered belnacasan tablets for the treatment of mild to moderate COVID-19. 
Belnacasan or placebo will be administered for 28 days and follow-up will occur for 
60 days, alongside background standard of care.
Study Population
Subjects with an RT-PCR assay confirmed SARS-CoV-2 infection and mild to 
moderate COVID-19 at time of enrollment.
Study Drug 
Administration
Oral, three times per day as per protocol.
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Inclusion / 
Exclusion Criteria
The study population is defined as subjects who meet the following criteria:
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.
o 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:
o 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
o 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:
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o
Severe kidney disease (known or estimated GFR <30 mL / minute) or on 
dialysis.
o
Uncontrolled, clinically significant heart diseases such as arrhythmias, 
angina or heart failure as defined by AHA / ACC Grade C and D. 
o
Chronic respiratory disease requiring supplemental oxygen.
o
Moderate and severe hepatic impairment as defined by Child-Pugh 
scoring Class B and Class C
Elevated liver function tests (determined by ALT, AST, GGT, or ALP >2 x 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.
Active bacterial, viral or fungal infection (including HIV, hepatitis B, hepatitis C).
While dosed with the IP, the taking of prohibited concomitant medication or the 
ingestion of food that interferes with the IP, including:
o Non-COVID19-related anti-viral medication such as lopinavir, ritonavir, 
ribavirin or interferon-1β.
o Systemically administered immunosuppressive and anti-inflammatory agents, 
other than background standard of care for COVID-19 at the time.
o 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.
Study Product, 
Dose, Route, 
Regimen
40 subjects will participate in this randomized, double-blind, placebo-controlled safety, 
tolerability and treatment effect trial. In a 1:1 allocation, 20 subjects will receive 900 mg 
(three tablets each containing 300 mg) TID of orally administered belnacasan and 20 
subjects will receive placebo tablets (three placebo tablets) TID, whereby randomization 
will be determined via a randomization table.
Study Endpoints
Primary Endpoint:
Incidence of Adverse Events and Serious Adverse Events assessed out to day 60. 
Secondary Endpoints:
Secondary endpoints relate to generating data on the treatment effect of belnacasan as 
determined by its effect size on outcomes in five areas:
1. Clinical recovery and resolution of COVID-19 symptoms
1a. Sustained recovery and resolution rates of common COVID-19 symptoms: 
(i.e., 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) 
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Proportion of subjects in treatment group versus placebo group, respectively, who 
per symptom questionnaire on days 4, 7, 10, 14, 21, 28, 42, 60 post randomization 
have achieved for two consecutive days: 
o
scores not higher than 0 for all symptoms 
o
scores not higher than 1 for all symptoms 
o
scores not higher than 0 for all symptoms other than impairment of taste or 
smell 
o
scores not higher than 1 for all symptoms other than impairment of taste or 
smell
1b. Sustained improvement of global impression rates: Proportion of subjects in 
treatment group versus placebo group, respectively, who per symptom questionnaire 
on days 4, 7, 10, 14, 21, 28, 42, 60 post randomization have answered for two 
consecutive days
o
“Yes” to “In the past 24 hours, have you returned to your usual health (before 
your COVID-19 illness)?” 
o
“Yes” to “In the past 24 hours, have you returned to your usual activities 
(before your COVID-19 illness)?”
o
“None” to “In the past 24 hours, what was the severity of your overall 
COVID-19 related symptoms at their worst?”
o
“Mild” to “In the past 24 hours, what was the severity of your overall 
COVID-19 related symptoms at their worst?”
1c. Time to sustained recovery, resolution or improvement: comparison in 
treatment group versus placebo group, respectively of the number of days from 
randomization to the first day of achieving each item in 1a and 1b above.
2. Physical functions and parameters relevant to COVID-19
2a. Parameter rates: Proportion of subjects in treatment group versus placebo group, 
respectively, who on days 4, 7, 10, 14, 21, 28, 42, 60 post randomization per thermometer 
or pulse oximeter reading experienced:
o
fever at any point between enrollment and day 2 post randomization and who 
were afebrile <38C 
o
oxygenation of SpO2>=96% or >93% in room air when resting
2b. Time to and length of parameters: comparison in treatment group versus 
placebo group, respectively of the number of days
o
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
o
with temperature <38C or >=38C experienced in total during the first 28 days 
post randomization
o
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
o
with oxygenation of SpO2>= 96% or SpO2>93% in room air, when resting, 
in total during the first 28 days post randomization
3. COVID-19 related deterioration and mortality
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3a. Deterioration and mortality rates: Proportion of treatment group, versus placebo 
group, respectively, who per subject reporting or medical records by day 14, day 28 
and by day 60 post randomization had experienced:
o
an emergency department visit, other than at study enrollment or study visits
o
hospitalization for COVID-19
o
hospitalization for COVID-19 requiring oxygen
o
hospitalization for COVID-19 requiring ICU
o
hospitalization for COVID-19 requiring ventilation
o
COVID-19 related death
o
death
o
hospitalization or death
3b. Time to and length of deterioration: Comparison of treatment group versus 
placebo group, respectively, in the number of days 
o
from randomization until the first day of experiencing hospitalization for 
COVID-19
o
of hospitalization for COVID-19 experienced in total by day 14, by day 28 
and by day 60 post randomization
o
of hospitalization for COVID-19 requiring oxygen experienced in total by day 
14, by day 28 and by day 60 post randomization
o
of hospitalization for COVID-19 requiring ICU experienced in total by day 
14, by day 28 and by day 60 post randomization
o
of hospitalization for COVID-19 requiring ventilation experienced in total by 
day 14, by day 28 and by day 60 post randomization
4. WHO 9-Point Ordinal Scale
0.
Uninfected or “no clinical or virological evidence of infection”
o defined as subject answering “Yes” to “In the past 24 hours, have you 
returned to your usual health (before your COVID-19 illness)?”
1.
Not hospitalized, no limitations on activities
o defined as subject answering “Yes” to “In the past 24 hours, have you 
returned to your usual activities (before your COVID-19 illness)?”
2.
Not hospitalized, limitation on activities
o defined as subject answering “No” to “In the past 24 hours, have you 
returned to your usual activities (before your COVID-19 illness)?”
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
4a) Ordinal scale rates: proportion of treatment group versus placebo group, 
respectively who had experienced:
o
an improvement from scale 2 at randomization to scale 1 or 0 on days 4, 7, 
10, 14, 21, 28, 42, 60 post randomization, 
o
an improvement from scale 1 at randomization to scale 0 on days 4, 7, 10, 14, 
21, 28, 42, 60 post randomization
o
a sustainment from scale 1 at randomization to scale 1 on days 4, 7, 10, 14, 
21, 28, 42, 60 post randomization
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o
any improvement of the scale (i.e., at least a 1-point decrease) between 
enrollment and days 7, 14, 28, 42, 60 post randomization
o
any worsening of the scale (i.e., at least a 1-point increase) between 
enrollment and days 7, 14, 28, 42, 60 post randomization
o
scale 4 or higher by day 28 or day 60 post randomization
o
scale 6 or higher by day 28 or day 60 post randomization
4b) Ordinal scale averages, highs, and lows: Comparison of treatment group versus 
placebo group, respectively, at days 14, 28 and 60 post randomization in the 
o
average of daily scale value on that day
o
overall average of daily scale value experienced since enrollment
o
in the worst (i.e., highest) daily scale value experienced since enrollment
o
in the best (i.e., lowest) daily scale value experienced since enrollment
4c) Time to improvement: 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 by day 14, day 28 and by day 60 post 
randomization
4d) Length of ordinal scale experience: Comparison of treatment group versus 
placebo group, respectively, in the total number of days by day 14, day 28 and by 
day 60 post randomization on which subjects experienced a given scale value (i.e., 3, 
4, 5, 6, 7)
5. Surrogate markers of COVID-19-related inflammation and organ involvement
5a) 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
o
values on days 1 (enrollment), 7, 14, 21, 28 post randomization
o
changes from enrollment to days 7, 14, 21, or 28 post randomization
o
changes between days 7, 14, 21, 28 post randomization
5b) Reference range rates: proportion of treatment group versus placebo group, 
respectively, who experience normal / in-range values for a given marker at days 7, 
14, 21, 28 post randomization
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Statistical 
Considerations
Study Populations:
Safety & Tolerability Population: All enrolled subjects who have received at least 
1 dose of IP (belnacasan or placebo) will be studied. Even if subjects have 
discontinued study treatment, as long as they maintain consent, they will continue 
to be in the study and included in analysis, i.e., their safety and tolerability 
information will continue to be collected for at least 60 days. 
Treatment Effect Evaluable Populations: All enrolled subjects who have received 
at least 1 dose of IP (belnacasan or placebo) will be studied. Even if subjects have 
discontinued study treatment, as long as they maintain consent, they will continue 
to be in the study and included in analysis, i.e., their outcome information will 
continue to be collected for at least 60 days.
Analysis Methods:
FDA Data Standard Guidelines will be followed. Continuous variables will be 
summarized using the number of observations, number of observations above the limit 
of quantification (if applicable), mean, standard deviation (SD) median, and range. 
Categorical variables will be summarized using frequency counts and percentages. 
Comparison of belnacasan and placebo groups will utilize Poisson regression for 
counts, Cox proportional hazards regression for time-to-event data and mixed effects 
models for continuous and categorical data obtained over study days.
Primary Safety and Tolerability Analysis:
All safety & tolerability analyses will be performed on the Safety Population. The 
safety data will be presented in individual listings and summary tables. Overall 
safety will be assessed by the number of belnacasan dosed subjects experiencing a 
grade 4 or 5 SAE during the trial. Of 20 subjects enrolled in the belnacasan group, 3 
or more developing grade 4 or 5 SAE probably related to belnacasan would be 
considered unlikely due to chance. Therefore, belnacasan will be determined safe if 
no more than 2 subjects develop a grade 4 or 5 SAE in the belnacasan group 
probably related to belnacasan.
In terms of stopping rules, should two or more subjects develop a similar Grade 3 
SAE that is at least possibly related to belnacasan or should one or more subjects 
develop a ≥ Grade 4 SAE that is at least possibly related to belnacasan, the trial will 
be paused for DSMB safety review.
Secondary Treatment Effect Endpoint Analysis:
Event counts over 60 days will be analyzed by Poisson regression. Time to events 
will be analyzed by Cox regression. Differences between belnacasan and placebo 
with respect to change in continuous endpoints will be assessed by mixed effects 
models for continuous repeated measures data and mixed effects logistic models for 
repeated categorical variables. Endpoint proportions of belnacasan and placebo 
groups will be assessed by contingency table analysis (chi-square).   
Sample Size Considerations: 
As this is a proof-of-concept study, it will likely not be powered to detect belnacasan 
– placebo differences that are clinically meaningful. For example, the observed 
difference in endpoint rate ratios would need to be over 60% to achieve 80% power 
with an alpha error rate of 5% for 20 subjects in each group. This study will provide 
an estimate of the belnacasan effect size to inform a larger trial where a more clinically 
meaningful difference can be detected.
Initial Date
November 2021
Completion Date
April 2022
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1
BACKGROUND, STUDY RATIONALE AND DOSING RATIONALE 
1.1
Background and study rationale
For more than one year, coronavirus disease 2019 (COVID-19) – an acute respiratory disease 
caused by SARS-CoV-2 that also has profound multi-systemic inflammatory involvement – has 
cost countless lives and livelihoods, especially for vulnerable populations with comorbidities 
characterized by chronic inflammation. The full spectrum of COVID-19 ranges from 
asymptomatic, to a mild, self-limiting respiratory tract illness, to severe progressive pneumonia, 
multi-organ failure, and death [1]. Since its first discovery, the virus has continued to spread, even 
with attempted control with a variety of public health measures. There are more than 36 million 
cases in the United States, accounting for a quarter of the worlds documented cases, and over 
620,000 deaths [2]. In general, there is likely an underestimate of total cases since the prevalence 
of asymptomatic carriers is yet unknown. What is clear, is that individuals at highest risk are those 
over 65 years and / or those with concomitant chronic conditions most notably hypertension, 
diabetes, pre-diabetes, obesity, chronic cardiorespiratory disorders and chronic renal and liver 
impairment [1, 3-6]. While there are racial disparities in the greater number of Black and Hispanic 
patients experiencing a more severe course there is no evidence that this is related to anything 
other than underlying comorbidities and socioeconomic factors, often limiting their ability to 
socially distance. 
There have been promising scientific breakthroughs for preventing and treating severe COVID-
19, including via vaccines, monoclonal antibody and steroid treatments. However, there is to-date 
no targeted treatment for SARS-CoV-2-mediated inflammation and subsequent complications in 
COVID-19. In general drug treatments aimed at the virus have so far not lived up to their promise. 
Most notably the nucleotide analog remdesivir was demonstrated to mitigate the course of the 
illness when given early in the course [7]. Subsequent data however failed to show a benefit. While 
antibody for treatment has been available the uptake of this therapy has been limited by parenteral 
administration. While efficacious in patients with mild to moderate COVID-19 who are at high 
risk of progressing to severe disease [8], monoclonal antibodies (e.g., bamlanivimab, casirivimab, 
and imdevimab) are costly and their administration is complicated for outpatients and providers as 
it is given intravenously, in an hour long infusion that must take place in a separate unit since 
recipients are infectious. A late 2020 report from the Department of Health and Human Services 
found that only 5-20% of available supply had been used. Currently the most widely accepted and 
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available treatment is dexamethasone having shown a clear benefit in seriously affected, 
hospitalized patients [9]. 
The most hopeful remedy for the population at large is vaccination and at this time vaccines from 
three sources (Pfizer/BioNTech, Moderna, Johnson & Johnson) have been authorized for 
emergency use in the United States after having demonstrated the ability to prevent disease in up 
to 95% of individuals [10]. However, vaccines may not be sufficient to address COVID-19 across 
the US population for four reasons. First, vaccine hesitancy persists (https://aspe.hhs.gov/pdf-
report/vaccine-hesitancy). Second, vaccination may only confer immunity for a limited number of 
months, necessitating the need for booster shots (https://www.cnbc.com/2021/04/21/scientist-
who-helped-develop-pfizer-biontech-covid-vaccine-agrees-third-shot-is-needed-as-immunity-
wanes.html), which may not be taken, or taken on time, by all who need them. Third, 
immunocompromised people, such as transplant recipients on immunosuppressive medication, 
have recently been shown to not develop sufficient antibodies through vaccination [11, 12]. Fourth, 
it remains to be seen to what extent vaccines are effective against emerging new variants with 
immune-escape properties [13-15], especially the delta variant.
Moreover, given that even mild COVID-19 cases can result in devastating, likely inflammatory-
driven, persisting effects (https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html), 
there is clearly an unmet need for a therapeutic option, especially an oral one, that can mitigate 
harmful uncontrolled inflammation and dysfunctional immune responses during a SARS-CoV-2 
infection. 
Fortunately, over the past year there has been better understanding of the immunologic 
pathophysiology of COVID-19, which in later stages is driven primarily by host immune responses 
to the virus [16]. In the spring of 2020, our team was the first to publish data linking the 
inflammasome / caspase-1 / pyroptosis axis to heightened pro-inflammatory IL-18 levels, 
lymphopenia and poor outcome in COVID-19 patients [6]. Over the summer of 2020, a Brazilian 
study in over 100 patients expanded our findings, and also showed direct evidence of NLRP3 
inflammasome activation and caspase-1 mediated pyroptosis in SARS-CoV-2-infected monocytes 
in vitro, as well as in blood and lung tissue of COVID-19 patients [17, 18]. Inflammasome 
formation, as evidenced by expression of caspase-1 and NLRP3 in leukocytes and endothelial 
cells, was also found in the lungs of patients with fatal COVID-19 pneumonia [19, 20]. Most 
recently, several studies further corroborated and expanded these findings by showing that SARS-
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CoV-2 infects monocytes and directly activates the inflammasome / caspase-1 / pyroptosis axis 
leading to pro-inflammatory cell death and cytokine release [21, 22].  Importantly, it was further 
demonstrated that a caspase-1 specific inhibitor was effective in blocking pyroptotic cell death of 
SARS-CoV-2-infected monocytes and subsequent release of the pro-inflammatory cytokines IL-
1β, IL-6, and TNF-α [21]. In addition, from a mechanistic standpoint, it was recently shown that 
SARS-CoV-2 viroporin encoded by ORF3a activates the NLRP3 inflammasome and caspase-1 via 
potassium efflux [23]. Moreover, key ORF3a amino acid residues required for inflammasome 
activation were found to be conserved in virus isolates across continents, highlighting the 
universality of this inflammatory pathway [23].
Taken together, a growing body of evidence demonstrates that upstream SARS-CoV-2-mediated 
inflammasome and caspase-1 activation leading to pyroptosis, trigger uncontrolled hyper-
inflammation via cytokine release (IL-18, IL-1β, IL-6, and TNF-α) as well as immune dysfunction 
of monocytes and lymphocytes downstream [16, 24-28]. Moreover, activation of the 
inflammasome / caspase-1 / pyroptosis axis could also explain COVID-19 related organ damage 
and tissue pathology of the heart, kidney, lungs, liver, pancreas and nervous systems, as it has been 
shown that SARS-CoV-2 also appears to cause pyroptosis in a variety of other cell types, including 
lung pneumocytes and endothelial cells in these organs [27-32]. 
Illustration 1
The Inflammasome and COVID-19: Rationale for belnacasan
Caspase-1 activation
SARS-CoV-2
Comorbidities
Inflammasome activation
Pyroptosis
Poor clinical outcome
Adaptive immune
dysfunction
Hyper-
inflammation
chronic
acute
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Based on this growing body of evidence, this trial proposes that the orally-administered 
belnacasan, which following hydrolysis on contact with water is a highly specific caspase-1 
inhibitor (also known as IL-1β converting enzyme) upstream of pyroptosis and pro-inflammatory 
cytokine release, is a much more targeted and potentially safer alternative to current generalized 
anti-inflammatory COVID-19 treatments such as corticosteroids, especially for comorbid patients 
with an already chronically-activated inflammasome [6, 25, 27, 28, 33-36] (Illustration 1).
1.2
Belnacasan (VX-765/RVT-201/MSR-001)
The drug substance has a molecular formula of C24N33CIN4O6 and has molecular weight of 509.0 
and comes as a tablet preparation. It is hydrolyzed on contact with water to an active form and is 
a caspase-1 inhibitor (caspase-1 is also known as IL-1β converting enzyme). Blocking this enzyme 
with belnacasan (VX-765/RVT-201/MSR-001) has been shown to prevent production of IL-1β, 
IL-18, and pyroptosis in healthy and disease states. The drug has been extensively developed 
originally by Vertex Pharma and more recently Roivant Sciences but currently has no FDA or IND 
approved usage for any indication. 
1.3
Dosing rationale
Belnacasan (VX-765/RVT-201/MSR-001) has previously been studied in rodents and large 
animals including dogs and monkeys to doses of up to 2000mg/kg/day for toxicity studies in dogs. 
Dosing at these levels and in multi-dosing schedules have not shown any severe and particularly 
life-threatening side effects. In human trials, including for conditions such as seizure disorders, the 
drug has been trialed in increments of 300mg/dose on a TID or QID regimen up to 900mg QID for 
13 weeks, in nearly 100 patients. 
Detailed pharmacokinetic studies from Vertex / Roivant are available for review. In brief, ex-vivo 
studies have demonstrated that Lipopolysaccharide stimulated IL-1β production is 50% suppressed 
by the active metabolite of belnacasan at a concentration of 0.8mcg/ml. This translated in to 50% 
suppression of IL-1β by single oral dose of 400mg while 80% suppression was achieved with 
doses of 800 and 1600mg. There was gradual but marked inhibition of IL-18 over 14 days in 
healthy controls as compared to placebo and 60% inhibition with 900mg TID as well as 1200mg 
TID and 1800mg TID during the duration of the study. For this study we have therefore chosen 
our primary dose as 900mg TID in the absence of data on acute viral infection / COVID-19.
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The drug has previously been manufactured with appropriate due diligence in tablet form at 
300mg/tablet (Data available from Roivant Sciences) and will be manufactured by the same 
compounding pharmacy (Metrics), in the original format for immediate use in this trial.
For this trial we will treat for a maximum of 28 days. Our rationale for this timeframe is that while 
there is an expectation that the illness lasts up to 12-15 days in those who recover without 
complication, others will endure a longer duration, and some will experience persistent, new onset 
or worsening disease related symptoms. A recent study from the Centers for Disease Control and 
Prevention 
(https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e3.htm?s_cid=mm7017e3_w)  
found that among 3,171 non-hospitalized adult COVID-19 patients, 69% had one or more 
outpatient visits 28–180 days after the diagnosis. Two thirds had a visit for a new primary 
diagnosis, and approximately one third had a new specialist visit. Symptoms potentially related to 
COVID-19 were common new visit diagnoses. Visits for these symptoms decreased after 60 days 
but for some patients continued through 120–180 day. Furthermore, some individuals develop 
sequela that are likely related to post-viral immune dysregulation in the first few months albeit 
there is little known about this group. Though we are unlikely to learn about the effect of the drug 
in this latter population we do need to establish safety for a duration that includes the other groups 
mentioned above. 
1.4
Brief summary of known systemic safety profile of belnacasan (VX-765/RVT-
201/MSR-001)
Based on files held by Vertex and Roivant Sciences, which contains evidence from animal and 
human studies, there is no indication that belnacasan (VX-765/RVT-201/MSR-001) causes severe 
or life-threatening side effects. The only preclinical finding on toxicity studies was a reduction of 
the heart rate in dogs at 2000mg/kg/day, a dose that was estimated to be 10-25 times higher than 
the maximum in this study (900mg QID). In humans with epilepsy the drug has been used at 
dosages of 3600mg/day for up to 13 weeks. Adverse effects reported in humans were headache, 
dizziness, nausea and vomiting, abdominal discomfort and rash. Seizure was reported in more than 
one patient in one study on epilepsy.
1.5
Ongoing clinical studies with belnacasan (VX-765/RVT-201/MSR-001)
 None, that have been declared by Roivant Sciences or evident on an extensive web search.
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2
SUMMARY
In modern history there is been no greater health threat to life and livelihood than COVID-19, 
especially in the United States. While progress is being made to find treatments, there are potential 
drawbacks to all options. First, even with the prospect of vaccines being successful, there is a 
likelihood that patients with co-morbid conditions will likely suffer a protracted illness at least; 
that it will take time for the vaccine and any needed boosters to reach critical mass in the 
population, especially in the face of vaccine hesitancy; and that vaccines might not always be 
effective, especially as new virus strands and variants continue to emerge and early data show that 
immunosuppressed patients may struggle to develop anti-bodies. Second, while the most 
frequently heralded therapeutic of remdesivir offers the potential for earlier clearance of the virus, 
the inflammatory cascade results in continued need for inpatient and especially intensive care in 
high-risk patients. Furthermore, as an IV drug, the treatment itself requires inpatient treatment and 
likely needs specific timing to be optimally effective. Third, the prospect of immunosuppression, 
for example with a broad therapy such as dexamethasone or other equivalent corticosteroid, affects 
the inflammatory cascade but any use beyond a few days carries risks and therefore disadvantages 
that we believe will come to light with greater use of the drug and scrutiny of outcomes going 
forward. Over the next 12 months it is reasonable to expect that a large part of the United States 
population will undergo vaccination with the majority of these individuals being afforded some 
immunity for what is yet an undetermined length of time. What is clear however is that this form 
of coronavirus is likely to be around for the foreseeable future and though fewer people will be at 
risk for COVID-19, an effective treatment is necessary. While antiviral treatment may have an 
effect, it is clear from the pathophysiology that clearing virus may not be enough and such specific 
therapies to mitigate the individual’s inflammatory response is important to reduce morbidity and 
mortality. We believe that what is needed is an immunologically targeted medication that can 
be taken orally - and without the prospect of major immunosuppression in at-risk patients - 
and that can even be taken for early treatment in high-risk patients. Based on the data 
presented here we believe that belnacasan (VX-765/RVT-201/MSR-001) may fulfil this role.
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3
OBJECTIVES AND ENDPOINTS
3.1
Primary Objective
To determine the safety and tolerability of belnacasan (VX-765/RVT-201/MSR-001) administered 
orally for 28 days in subjects with mild to moderate COVID-19 as determined by Adverse Events 
and Serious Adverse Events.
3.2
Primary Endpoint
Incidence of Adverse Events and Serious Adverse Events assessed out to day 60. 
3.3
Secondary Objective
To generate data on the treatment effect of belnacasan (VX-765/RVT-201/MSR-001) administered 
orally for 28 days in subjects with mild to moderate COVID-19 as determined by its effect size on 
outcomes in five areas: 
1. Clinical recovery and resolution of COVID-19 symptoms
2. Physical functions and parameters relevant to COVID-19
3. COVID-19 related deterioration and mortality 
4. WHO 9-point ordinal scale for clinical improvement
5. Surrogate markers of COVID-19-related inflammation and organ involvement
The hypothesized end result of treatment with belnacasan would be to reduce the symptomatic and 
clinical burden, length of disease course, and disease progression of COVID-19.
3.4
Secondary Endpoints
1. Clinical recovery and resolution of COVID-19 symptoms
1a. Sustained recovery and resolution rates of common COVID-19 symptoms: 
(i.e., 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) 
Proportion of subjects in treatment group versus placebo group, respectively, who per symptom 
questionnaire on days 4, 7, 10, 14, 21, 28, 42, 60 post randomization have achieved for two 
consecutive days: 
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o
scores not higher than 0 for all symptoms 
o
scores not higher than 1 for all symptoms 
o
scores not higher than 0 for all symptoms other than impairment of taste or smell 
o
scores not higher than 1 for all symptoms other than impairment of taste or smell
1b. Sustained improvement of global impression rates: Proportion of subjects in treatment 
group versus placebo group, respectively, who per symptom questionnaire on days 4, 7, 10, 14, 
21, 28, 42, 60 post randomization have answered for two consecutive days
o
“Yes” to “In the past 24 hours, have you returned to your usual health (before your 
COVID-19 illness)?” 
o
“Yes” to “In the past 24 hours, have you returned to your usual activities (before your 
COVID-19 illness)?”
o
“None” to “In the past 24 hours, what was the severity of your overall COVID-19 related 
symptoms at their worst?”
o
“Mild” to “In the past 24 hours, what was the severity of your overall COVID-19 related 
symptoms at their worst?”
1c. Time to sustained recovery, resolution or improvement: comparison in treatment group 
versus placebo group, respectively of the number of days from randomization to the first day of 
achieving each item in 1a and 1b above.
2. Physical functions and parameters relevant to COVID-19
2a. Parameter rates: Proportion of subjects in treatment group versus placebo group, respectively, 
who on days 4, 7, 10, 14, 21, 28, 42, 60 post randomization per thermometer or pulse oximeter reading 
experienced:
o
fever at any point between enrollment and day 2 post randomization and who were 
afebrile <38C 
o
oxygenation of SpO2>=96% or >93% in room air when resting
2b. Time to and length of parameters: comparison in treatment group versus placebo group, 
respectively of the number of days
o
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
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o
with temperature <38C or >=38C experienced in total during the first 28 days post 
randomization
o
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
o
with oxygenation of SpO2>= 96% or SpO2>93% in room air, when resting, in total during 
the first 28 days post randomization
3. COVID-19 related deterioration and mortality
3a. Deterioration and mortality rates: Proportion of treatment group, versus placebo group, 
respectively, who per subject reporting or medical records by day 14, day 28 and by day 60 post 
randomization had experienced:
o
an emergency department visit, other than at study enrollment or study visits
o
hospitalization for COVID-19
o
hospitalization for COVID-19 requiring oxygen
o
hospitalization for COVID-19 requiring ICU
o
hospitalization for COVID-19 requiring ventilation
o
COVID-19 related death
o
death
o
hospitalization or death
3b. Time to and length of deterioration: Comparison of treatment group versus placebo group, 
respectively, in the number of days 
o
from randomization until the first day of experiencing hospitalization for COVID-19
o
of hospitalization for COVID-19 experienced in total by day 14, by day 28 and by day 60 
post randomization
o
of hospitalization for COVID-19 requiring oxygen experienced in total by day 14, by day 
28 and by day 60 post randomization
o
of hospitalization for COVID-19 requiring ICU experienced in total by day 14, by day 28 
and by day 60 post randomization
o
of hospitalization for COVID-19 requiring ventilation experienced in total by day 14, by 
day 28 and by day 60 post randomization
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4. WHO 9-Point Ordinal Scale
0. Uninfected or “no clinical or virological evidence of infection”
a.
defined as subject answering “Yes” to “In the past 24 hours, have you returned to 
your usual health (before your COVID-19 illness)?”
1. Not hospitalized, no limitations on activities
a.
defined as subject answering “Yes” to “In the past 24 hours, have you returned to 
your usual activities (before your COVID-19 illness)?”
2. Not hospitalized, limitation on activities
a.
defined as subject answering “No” to “In the past 24 hours, have you returned to 
your usual activities (before your COVID-19 illness)?”
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
4a) Ordinal scale rates: proportion of treatment group versus placebo group, respectively who 
had experienced:
o
an improvement from scale 2 at randomization to scale 1 or 0 on days 4, 7, 10, 14, 21, 28, 
42, 60 post randomization, 
o
an improvement from scale 1 at randomization to scale 0 on days 4, 7, 10, 14, 21, 28, 42, 
60 post randomization
o
a sustainment from scale 1 at randomization to scale 1 on days 4, 7, 10, 14, 21, 28, 42, 60 
post randomization
o
any improvement of the scale (i.e., at least a 1-point decrease) between enrollment and 
days 7, 14, 28, 42, 60 post randomization
o
any worsening of the scale (i.e., at least a 1-point increase) between enrollment and days 7, 
14, 28, 42, 60 post randomization
o
scale 4 or higher by day 28 or day 60 post randomization
o
scale 6 or higher by day 28 or day 60 post randomization
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4b) Ordinal scale averages, highs, and lows: Comparison of treatment group versus placebo 
group, respectively, at days 14, 28 and 60 post randomization in the 
o
average of daily scale value on that day
o
overall average of daily scale value experienced since enrollment
o
in the worst (i.e., highest) daily scale value experienced since enrollment
o
in the best (i.e., lowest) daily scale value experienced since enrollment
4c) Time to improvement: 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 by day 14, day 28 and by day 60 post randomization
4d) Length of ordinal scale experience: Comparison of treatment group versus placebo group, 
respectively, in the total number of days by day 14, day 28 and by day 60 post randomization on 
which subjects experienced a given scale value (i.e., 3, 4, 5, 6, 7)
5. Surrogate markers of COVID-19-related inflammation and organ involvement
Heart: troponin; Kidney: creatinine, blood urea nitrogen (BUN), electrolytes (calcium, carbon 
dioxide, chloride, potassium, sodium, magnesium); Pancreas: glucose, HbA1c, lipase; Liver: 
ALT, AST, ALP, total bilirubin; Muscle weakness: creatinine kinase; Hematology: red blood cell 
count, hemoglobin, platelet count, prothrombin time (PT), partial thromboplastin time (PTT), d-
dimer; Immunology: white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, T 
cells, SARS-CoV-2 viral load in nasopharyngeal sample, SARS-CoV-2 serology in blood; 
Inflammation: CRP, ferritin, LDH, caspase-1, IL-18, IL-1β, IL-1 receptor antagonist, gasdermin 
D, IL-6, TNF-α, G-CSF 
5a) 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
o
values on days 1 (enrollment), 7, 14, 21, 28 post randomization
o
changes from enrollment to days 7, 14, 21, or 28 post randomization
o
changes between days 7, 14, 21, 28 post randomization
5b) Reference range rates: proportion of treatment group versus placebo group, respectively, 
who experience normal / in-range values for a given marker at days 7, 14, 21, 28 post 
randomization
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4
SAFETY AND TOLERABILITY
The drug in an oral form has been used in nearly one hundred patients without a history of major 
side effects. During the trial, it is therefore anticipated that no more than 2 subjects out of 20 will 
have an adverse event of grade 4 or 5 that is probably related to belnacasan (VX-765/RVT-
201/MSR-001). In terms of stopping rules, should two or more subjects develop a similar Grade 3 
SAE that is at least possibly related to belnacasan or should one or more subjects develop a ≥ 
Grade 4 SAE that is at least possibly related to belnacasan, the trial will be paused for DSMB 
safety review. Safety Monitoring processes are identified in Section 7.14. 
5
STUDY DESIGN
5.1
Study Description
This is a phase 2 proof of concept randomized, double-blind, placebo-controlled trial with the 
purpose of assessing 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. 
20 subjects will be given 900 mg TID of belnacasan and 20 subjects will be given a placebo TID 
for 28 days, and assessments of safety, tolerability, and treatment effect will be performed for up 
to 60 days.
At the screening / baseline / day 1 Visit, subjects will provide informed consent and be screened 
for eligibility based on the Inclusion / Exclusion criteria identified in Section 5.3. Subjects will 
also receive the first dose of study drug at this visit once study eligibility has been confirmed, and 
the second dose of study drug will be taken approximately 8-12 hours after the first dose. Study 
drug will be continued three times daily (morning, mid-day, and nighttime doses) through day 28.  
Some patients identified will require a PCR-confirmed COVID test, having only had a rapid 
antigen test.  Patients requiring a PCR test can either have one collected with screening labs prior 
to leaving the MedStar enrollment site or have these labs collected via a home-health research visit 
at no cost to the potential participant.  Prior to study-specific procedures the study team will obtain 
their consent in-person or by remote consent process.  An e-consent platform, Interlace, may also 
be used to document consent electronically.  Once their COVID-19 status is confirmed via PCR 
they will complete the remainder of their screening/enrollment visit at either MedStar Washington 
Hospital Center or MedStar Franklin Square within the next 1 to 3 days.  The remote consent 
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process and e-consent will follow MedStar institutional policies and procedures (MG.O-004.06 
and MG.O-004.07). 
The trial duration will be approximately 60 days (8.5 weeks) for all subjects enrolled. As outlined 
in the Schedule of Events Table in Section 5.2, over the course of the study duration, all subjects 
will use a diary to record IP intake as well as symptoms and activity levels with guidance to do so 
at the same time each day; assess physical parameters using a study-provided thermometer and 
pulse oximeter for which detailed instructions will be provided at enrollment; be assessed at 
regular intervals by the Study Team via telephone calls and in-person follow-up clinic visits; and 
give blood for laboratory tests. 
An experienced and appropriately licensed Study Team member will conduct the telephone study 
visits and be the point of contact if subjects experience deterioration, such as high temperatures 
(above 38C) or low oxygen saturation levels (below 93%). The primary coordinator of the trial 
will be a registered nurse, experienced in vital sign and symptom review, with the ability to escalate 
any medical concerns to the Principal Investigator as it relates to worsening of the subjects’ illness 
or adverse event identification. The Principal Investigator or delegated Sub-Investigator, as 
documented on the study delegation log, is well-versed in delegation of appropriate tasks as 
defined by licensure and scope of practice and will work closely with the study team to assure 
delegation remains appropriate through the duration of the trial. Medical advice or direction will 
only be given by sufficiently licensed study personnel, either mid-level providers or physicians, in 
partnership with their primary care team.
Subjects will be instructed to fill in symptoms assessment, overall health assessment, temperature 
and oxygen saturation levels in the diary each morning; and to note in the diary 3 times per day 
that they have taken the study drug. The Study Team will conduct in-person visits with the subjects 
on days 7, 14, 21, and 28 and telephonic visits with subjects on days 1, 4, 10, 42, and 60; as well 
as when / if subjects contact them due to symptom deterioration as instructed. Subjects will receive 
reminders to complete the diary via text message and / or email. Subjects who prematurely 
discontinue study drug for any reason will be asked to have an Early Termination (ET) visit the 
day the last study drug dose is administered; moreover, they will be encouraged to stay enrolled 
so that further safety and outcome information can be collected and analyzed.
All data collected by the Study Team and recorded by the subjects will be entered into the EDC 
per the schedule of events. OnCore, a Clinical Trial Management System in which subject visits 
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can be monitored as well as Case Report Forms developed, will be used for this trial. Subjects will 
be asked to hand in their subject diary during visits on days 7, 14, 21, and 28.
Background Standard of Care
All eligible subjects will receive background standard of care, however there are certain prohibited 
medications subjects cannot be given while dosed with the IP as outlined in Section 5.4. 
Background standard of care will be commensurate with disease severity and aligned to standards 
at the time of the trial. At present, standard of care includes vaccines, antiviral treatment with 
remdesivir, monoclonal antibodies against SARS-CoV-2, dexamethasone, supplemental oxygen, 
noninvasive and invasive ventilation, antibiotics, vasopressors, anti-coagulation and ECMO; but 
this may evolve over the coming months as new therapies or treatments come online including off-
label use of other drugs.
Patients recruited to the study will not be asked to forgo background standard of care in any way. 
Recruitment will be based on inclusion and exclusion criteria and include individuals evaluated 
for suspected COVID-19 in a MedStar Urgent care or the Emergency Room setting, and triaged 
not to need in-hospital care. These individuals have the potential but not the likelihood for hospital 
admission with worsening COVID-19 disease progression. Current outpatient standard of care 
includes symptomatic treatment and this will not be altered to the point that analgesics and 
antipyretics will be held. Patients whose COVID-19 related illness deteriorates to the point that 
they need ambulatory medical care or hospitalization will remain in the study and medical care as 
determined by managing physicians will not be subverted in any manner as part of the study. 
Patient data collection as per study diary and study visits will be maintained for the minimum 60 
days and study drug will be provided and monitored for compliance unless there is an indication 
for discontinuation of study drug, see section on drug discontinuation.
Study Population
Urgent Care or Emergency Department presenting subjects, who are not under immediate 
consideration for inpatient admission and with onset of at least one moderate COVID-19 symptom 
of less than 7 days, will be assessed for eligibility on the basis of a positive antigen test or reverse 
transcriptase polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in a respiratory tract 
sample on presentation to a MedStar Urgent care or the Emergency Department  facility.  If only 
a rapid test is resulted, a home health research visit will be arranged, following consent, to obtain 
a confirmatory RT-PCR test with initial screening labs. 
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Enrollment of Diverse Study Population
Recognizing that COVID-19 disproportionately impacts racial and ethnic minorities, the study will 
seek to enroll a diverse patient population. For example, one of the main trial sites, MedStar 
Washington Hospital Center, is the largest hospital in the District of Columbia. Its primary service 
area includes 11 zip codes, most of which are the zip codes that make up Wards 5, 7, and 8. 
Minorities represent 58% of the population in DC overall, and 69%, 97%, and 96% of the 
population in Wards 5, 7, and 8, respectively. Three Metrobuses service the campus and MedStar 
provides free, wheelchair-accessible shuttle buses from two Metrorail stations. Moreover, subjects 
will receive financial support for travel to and from study visits.
Both in terms of COVID-19 presentation and clinical trial enrollment, communities of color have 
represented the vast majority of patients at WHC. Specifically, over the last 15 months, nearly 
6,000 patients have presented at the WHC emergency department with COVID-19. Of the 97% 
from whom race / ethnicity data were recorded, 7% were White Non-Hispanic, 67% were Black 
or African American Non-Hispanic, 21% were Hispanic and 6% were Other (Asian, American 
Indian, Alaska Native, or more than one race or ethnicity). The MedStar system has enrolled 875 
subjects into COVID-19 trials, 89% (781 subjects) at WHC. Of the 94% from whom race / 
ethnicity data were recorded, 21% were White Non-Hispanic, 47% were Black or African 
American Non-Hispanic, 24% were Hispanic and 8% were Other (Asian, American Indian, Alaska 
Native, or more than one race or ethnicity).
Number of Subjects 
Approximately 40 subjects will be recruited at WHC and / or other MedStar hospital and / or 
critical / clinical care sites. 
Recruitment Methods
A daily COVID-19 testing list is acquired from the laboratory network in the MedStar system 
and will be used for screening purposes. A designated central study coordinator will review the 
list and contact patients directly by phone. The same coordinator will also screen the EMR for 
COVID -19 patients being discharged from the ED in the past 24 hours at Franklin Square and 
Washington Hospital Center. A dedicated phone script will be used to recruit patients by phone. 
The consent will be emailed or provided through the e-consent platform, Interlace, and time 
allowed for the subject to review and for questions to be addressed. A dedicated homecare 
company will be available for home COVID-19 RT-PCR testing and screening blood draw if 
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needed. Completion of screening, randomization and enrollment will be at either MedStar 
Washington Hospital Center or MedStar Franklin Square. The patient will be required to attend 
the same center for all in-person follow-up visits and end of study visits. 
5.2
Study Assessments
Table 1: Schedule of Events: = In-Person;  = Telephone;  = Subject Self-Tracking
Time Point (Days)
Screen / 
enroll
D19
D4
D7
D10
D14
D21
D28
D42
D60
ET10
STUDY TEAM
Inclusion / Exclusion

Consent

Screening Tests1, 12


Demographics

CXR or CT13

Physical Exam






Vitals2






EKG






CoV-2 N/P3




Standard labs4, 12





Blood draws5, 12






Immunology tests6, 12






CoV-2 blood7, 12


AE assessment











Symptoms assessment 











WHO 9-Point Scale8











SUBJECTS (as recorded in study diary)
IP/placebo intake
 | Three times per day through day 28 or ET......................
Temperature11 
 | Daily via thermometer through day 28 or ET; subject will report via telephone to 
study team at Day 42 & 60
SpO2 resting11
 | Daily via pulse oximeter through day 28 or ET; subject will report via telephone to 
study team at Day 42 & 60
Symptom tracking
 | One time per day through day 28 or ET; subject will report via telephone to study 
team at Day 42 & 60
1Screening tests: HIV, Hepatitis B, Hepatitis C, and pregnancy (serum pregnancy test for women of child-bearing 
potential per MedStar definition at enrollment and at day 14).
2Vital signs: oral temperature, heart rate, systolic blood pressure.
3Quantitative nasopharyngeal SARS-CoV-2 RNA testing (RT-PCR): nasopharyngeal or throat swabs will be used; 
any FDA-approved or commercial testing method will be acceptable. A home health agency may be used to confirm 
COVID-19 by RT-PCR in the subjects’ home in the event their initial testing did not include PCR, to ensure 
expeditious resulting and appropriate inclusion into the trial.  If home health is used to collect the PCR test or there is 
a delay in PCR resulting at initial screening, the subject will return to either MedStar Washington Hospital Center or 
MedStar Franklin Square for completion of the screening/enrollment visit in 1 to 3 days, once positive PCR is 
confirmed, to complete all study procedures including randomization and medication dosing under 
observation.4Standard labs: serum chemistry, coagulation tests and hematology. Pregnancy tests for women of 
childbearing potential at screening, day 14 and end of treatment.
5Blood draws: serum and peripheral blood mononuclear cells for later immunological analysis.
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6Immunology tests: COVID-19 relevant immunology labs (see Appendix 12.1 for complete list).  See footnote to 
Appendix 12.1 as certain labs will be sent to and resulted from outside lab facilities.
7Quantitative blood SARS-CoV-2 antibody testing: Blood samples will be used; any FDA-approved or commercial 
testing method will be acceptable.
8WHO 9-point scale: see description of secondary end points for details.
9Day 1 (i.e., the first day of drug intake) is most likely also the screen / enroll day; subjects will receive a phone call 
from Study Team a few hours after first dose is taken to check up on how they are doing.
10ET: Subjects who prematurely discontinue study drug for any reason are asked to have an Early Termination (ET) 
visit the day the last study drug dose was taken.
11 Subjects will be given a digital thermometer and portable pulse oximeter to record their temperature and oxygenation 
daily in the provided subject diary.
12 These laboratory tests will be collected at a one-time blood draw at each visit, a total of 5 collections at the 5 visits 
(Screening, Day 7, Day 14, Day 21, and Day 28).  The amount drawn at each timepoint is as follows: Screening visit 
(56 mL or 11 teaspoons), Day 7 (44 mL or 9 teaspoons), Day 14 (56 mL or 11 teaspoons), Day 21 (20 mL or 4 
teaspoons), and Day 28 (48 mL or 10 teaspoons).  The early termination visit would be in lieu of one of the in-person 
visits, it is not included in the total.  Laboratory tests collected at the screening/enrollment visit may be collected by a 
home health agency in the subjects’ home.
13Chest x-ray or CT of the chest will be completed as standard of care but not required for screening or randomization 
or enrollment
5.3
Selection Criteria
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.
o 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:
o 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, 
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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
o 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:
o
Severe kidney disease (known or estimated GFR <30 mL / minute) or on dialysis.
o
Uncontrolled, clinically significant heart diseases such as arrhythmias, angina or heart 
failure as defined by AHA / ACC Grade C and D. 
o
Chronic respiratory disease requiring supplemental oxygen.
o
Moderate and severe hepatic impairment as defined by Child-Pugh scoring Class B 
and Class C
Elevated liver function tests (determined by ALT, AST, GGT, or ALP >2 x upper limit of 
normal, and/or total Bilirubin > upper limit of normal).
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History of malignancy or immunodeficiency within the prior 5 years.
Acute respiratory illness other than COVID-19.
Active bacterial, viral or fungal infection (including HIV, hepatitis B, hepatitis C).
While dosed with the IP, the taking of prohibited concomitant medication or the ingestion of 
food that interferes with the IP, including:
o Non-COVID19-related anti-viral medication such as lopinavir, ritonavir, ribavirin or 
interferon-1β.
o Systemically administered immunosuppressive and anti-inflammatory agents, other than 
background standard of care for COVID-19 at the time.
o 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.
Discontinuation Criteria and Early Termination Procedures
Subjects may withdraw voluntarily from participation in the study at any time and for any reason. 
Subjects may also be withdrawn on the basis of the Investigator’s clinical judgment. This study 
may be terminated at the discretion of MedStar Health or of any regulatory agency for reasons 
including safety and/or treatment effect. 
For enrolled subjects we anticipate that the main reasons for discontinuation of therapy will be 
either withdrawal of consent for continuation in the study or inability to tolerate the study. Other 
instances may include patient death, inability to take the study drug from severity of illness or in-
hospital complexity of illness. Subjective intolerance of the drug from minor side effects or 
alternatively cessation of COVID-19 related symptoms well ahead of the 28-day schedule may 
cause patients to want to discontinue the drug. With regards to drug toxicity itself, we anticipate 
minor symptomatology from adverse effects, such as headache, dizziness, nausea and vomiting, 
abdominal discomfort and rash (see also 1.4) based on prior human trial experience with the study 
drug. Should any subject dosed on the study drug experience seizures, which was reported as an 
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unrelated adverse event in an epilepsy trial, that individual would be subject to discontinuation out 
of an abundance of caution. Any emergent symptom that has no clear cause will result in a hold 
on subsequent study drug dosing until protocol assessment by the Study Investigator. The reasons 
for discontinuation of study drug will be documented clearly. In all cases study protocol 
monitoring will continue for the entire 60 days of the protocol as long as the subject stays 
consented.
When a subject withdraws or is withdrawn before completing the study, the date and reason for 
withdrawal are to be documented. Subjects who withdraw or who are withdrawn prematurely are 
to attend an early termination, at which time they will complete all assessments as outlined in the 
Schedule of Events (Table 1); moreover they will be encouraged to stay enrolled so that further 
safety and outcome information can be collected and analyzed. 
In the event that a subject is withdrawn prematurely due to an adverse event or serious adverse 
event, the adverse event or serious adverse event will be followed until it resolves or stabilizes, or 
until it is judged by the Investigator to be no longer clinically significant. 
5.4
Concomitant and Prohibited Medication
At time of enrollment, and at any point during the study, medication or the ingestion of food that 
interferes with the IP would preclude participation in the study, 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.

In vitro studies suggest that CYP-mediated metabolism is not a major route of clearance for 
belnacasan (VX-765/RVT-201/MSR-001) or VRT-043198. However, belnacasan (VX-
765/RVT-201/MSR-001) was metabolized by CYP3A4 in a recombinant enzyme system. 

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

Subjects should also be advised against the consumption of grapefruit juice since it is a known 
inhibitor of CYP3A. 
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6
MATERIALS
6.1
Study Drugs
All study medication will be managed by the MedStar Health Research Pharmacy (RP). The 
Pharmacy will store and dispense medication to subjects. 
For all enrolled subjects, the first dose of study drug will be given orally only after the participant 
has documented consent, has completed screening and been verified to meet enrollment criteria.  
This screening visit may occur over more than one day if confirmatory PCR testing is needed.  
Subjects will be closely monitored for at least 30 minutes to assure they do not experience any 
untoward effect. 
For outpatient subjects (and discharged former inpatient subjects), subjects will be instructed to 
take subsequent doses at 0600, 1400, 2200 (+/- 4 hours). They will self-record administration in a 
subject diary (see Appendix) to be reviewed by the study team who will assess compliance at each 
visit. The study team, under direction of the Investigator, will provide any needed medication 
education, including adequate storage requirements, with the subject and any relevant family 
member(s) or caretaker.
For subjects who become inpatients over the course of the trial, study medication will be supplied 
to the unit in which subjects are admitted and will be dosed by clinical nursing, recorded in the 
electronic medical record, and overseen by the study team. Doses will be given at 0600, 1400, 
2200 (+/- 4 hours). Those who cannot swallow tablets will receive crushed tablets suspended in 
water and immediately administered through a nasogastric tube, by hospital nursing staff. At 
discharge and subsequent outpatient visits, enough medication will be dispensed to the subject to 
assure they have adequate supply until their next on-site follow-up visit.
6.2
Storage, Dispensing and Reconciliation of Study Drug and Identity of Investigational 
Products 
All study medication will be stored at room temperature until dispensed. Storage within the RP is 
locked and secure, accessible only to investigational pharmacy staff. Storage condition 
temperatures are recorded 24 hours a day, 7 days a week, and 365 days per year and the RP is 
immediately made aware of any temperature excursions. In such an event, study medication will 
not be utilized until MedStar Health provides further direction. It is the Investigator’s 
responsibility to ensure that accurate records of study medication dispensation and administration 
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are maintained. The RP will support the Investigator in medication accountability and dispensation 
tracking, they have a clear process for return and destruction of investigational medications.
Table 2: Identification of Investigation Product
Product Name
Belnacasan (VX-765/RVT-201/MSR-001)
Dosage form
Tablet containing 300mg of API
Route/dosage
Oral
Dosing Instructions
Three tablets, three times per day (0600, 1400, 2200 +/- 4 hours)
Product Name
Placebo 
Dosage form
Tablet containing 0mg of API
Route/dosage
Oral
Dosing Instructions
Three tablets, three times per day (0600, 1400, 2200 +/- 4 hours)
7
STUDY PROCEDURES
7.1
Observations and Measurements
Subject informed consent must be obtained prior to conducting any study-specific procedures. The 
informed consent can be signed by the subjects’ legally authorized representative (LAR) if 
necessary. The Investigator will assure that each subject/LAR is adequately consented to the 
requirements of participation including the potential risks and benefits and voluntary nature of the 
trial that he or she is free to discontinue participating in the study at any time. The subject/LAR 
will be given the opportunity to ask questions and allowed adequate time to consider the 
information provided. All assessments and procedures will be completed according to the Schedule 
of Events. A custom subject diary has been developed for this study. The diary will be tested for 
basic comprehensibility before finalizing and using with subjects.  The study teams may consent 
subjects by remote consent process that may include the use of an e-consent platform, Interlace, 
for documentation of consent if they are no longer at a MedStar site.  In this circumstance initial 
contact will be made with potential subjects via telephone to discuss the trial followed by any 
subsequent discussions needed to assure consent is obtained per Institutional policy and procedure, 
as approved by the IRB.  The study team will communicate with the home health agency directly 
to schedule the collection of the RT-PCR and screening labs, once consent is obtained, for a time 
that is convenient to the subject.  Following collection, the agency will transport these tests to 
MedStar Georgetown University Hospital for resulting.  Once eligibility is confirmed by PCR the 
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subject will return to either MedStar Washington Hospital Center or MedStar Franklin Square to 
complete the remainder of the screening/enrollment visit. 
7.2
Instructions to Subjects
At enrollment, the Study Team will explain the subject diary (see Appendix) and ensure they 
understand what to enter in each field. They will be told about the importance of collecting the 
information in the diary for scientific purposes, and that even if they discontinue intake of the 
study drug, they should continue to participate in the study, continue to fill in the diary, and 
continue to attend planned study visits.
For outpatient subjects (and discharged former inpatient subjects), subjects will be instructed to 
take 3 tablets of IP at 0600, 1400, 2200 (+/- 4 hours) for up to 28 days. They will self-record 
administration of the IP in the subject diary to be reviewed by the study team who will assess 
compliance at each visit. The study team, under direction of the Investigator, will provide any 
needed medication education, including adequate storage requirements, with the subject and any 
relevant family member(s) or caretaker.
For subjects who become inpatients over the course of the trial, study medication will be supplied 
to the unit in which subjects are admitted and will be dosed by clinical nursing, recorded in the 
electronic medical record, and overseen by the study team. Doses will be given at 0600, 1400, 
2200 (+/- 4 hours). Those who cannot swallow tablets will receive crushed tablets suspended in 
water and immediately administered through a nasogastric tube, by hospital nursing staff. As study 
medication will be administered by hospital staff, and there are no specific instructions to subjects. 
At discharge and subsequent outpatient visits, enough medication will be dispensed to the subject 
to assure they have adequate supply until their next on-site follow-up visit. 
Women with a history of menstruation must agree to use effective method of contraception and 
protections that align with International Council on Harmonization M3 R2 guidelines for highly 
effective methods of contraception for the duration of the study (i.e., two forms of contraception, 
whereby one result in a less than 1 percent per year failure rate when used consistently and 
correctly), as well as to undergo additional pregnancy testing during the study on day 14. Details 
of all pregnancies in female participants will be collected for 60 days after randomization.
Warnings and Precautions
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Subjects will be watched carefully for signs of previously documented symptoms in human 
patients that have received belnacasan (VX-765/RVT-201/MSR-001), as well as symptoms to 
indicate a drug reaction or new symptoms that could be temporally attributable to the drug. The 
most frequent adverse effects in humans have been mild and mainly include headache, nausea, 
lethargy and dizziness. No serious side effects have been described in human and animal studies.
7.3
NCI CTCAE Definitions of Dose Limiting Adverse Events 
The National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events 
(CTCAE) will be used for monitoring adverse events throughout study including those related to 
dose limitation. As noted above in section 7.2, adverse events with belnacasan (VX-765/RVT-
201/MSR-001) have been mild and of no consequence (grade 1 and 2 by CTCAE criteria, see 
below section 7.8). There is no dose escalation in this trial that could result in new symptoms 
though it is possible that mild symptoms may become more severe. 
7.4
Pre-Existing Medical Conditions
All subjects enrolled in the study will have SARS-CoV-2 infection and at least two moderate 
COVID-19 symptoms or one moderate symptom and clinical evidence of moderate COVID-19. 
Subjects will present with high-risk for COVID-19-related inflammation, due to at least one 
comorbidity, including obesity, diabetes, hypertension, stable heart disease, respiratory disease, 
and / or non-severe fatty liver disease.
7.5
Acute Conditions Brought on by COVID-19
The development of acute kidney and/or hepatic injury has been reported as a possible 
complication during the disease progression of COVID-19. Acute kidney and/or hepatic injury 
will be addressed in the following manner depending on whether at, (1) enrollment, (2) during the 
study period when drug is being administered in an ambulatory setting, (3) or during admission to 
hospital for COVID-19 related deterioration or other illness.
1. Potential participants in this study will undergo initial screening evaluation at a MedStar 
site or via a home health visit which includes background laboratory testing.  If the testing 
indicates renal failure, GFR <30 or features of acute renal failure, most notably anuria, 
edema on examination in a previously healthy individual, the potential participant will not 
be enrolled as per the inclusion criteria or otherwise clarified with the nephrology 
consultant managing the patient. Similarly, potential participants shown to have evidence 
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of elevated liver function tests (determined by ALT, AST, GGT, or ALP >2 x upper limit 
of normal, and/or total Bilirubin > upper limit of normal) will not be enrolled in the study. 
2. Laboratory testing throughout the study period (see Section 5.2 Table 1) may, though 
unlikely, show an acute change in renal or liver testing to indicate acute organ-specific 
disease or involvement as a possible complication of COVID-19. In such a circumstance, 
subjects will be directed to seek care from the respective hospital/specialist. In the case of 
acute liver injury with functional impairment, the IP will be discontinued immediately after 
blood has been taken for future assessment of drug levels. In the case of subjects with 
elevated liver function tests suggestive of acute liver injury without functional impairment, 
IP will be held to discern in the first instance the possibility of an adverse event and 
restarted in consultation with the managing hepatologist if it is determined to be COVID-
19 related hepatopathy. In the case of subjects with acute renal injury, IP will be held to 
discern in the first instance the possibility of an adverse event and restarted in consultation 
with the managing nephrologist if it is determined to be COVID-19 related nephropathy. 
DSMB guidelines for unblinding will be followed in these cases as relevant.
3. Acute liver and kidney injury may be seen in the face of hospital admission in patients with 
worsening COVID-19, in which case the patients will be managed similarly to number 2 
above (also see Section 5.3 on discontinuation).
7.6
Treatment Emergent Adverse events 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the treatments or any event already present that worsens in either intensity or 
frequency following the start of IP administration.
Adverse events will be captured following the first dose of IP and could be related or unrelated to 
the study drug. A TEAE is defined as any AE that occurs after the subject takes the first dose of 
IP.
Separate summaries for adverse events that occur during treatment (summary of treatment 
emergent adverse events) will be provided.  
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7.7
Laboratory Abnormalities
Clinical labs will be performed locally at WHC or other MedStar clinical sites. Labs to be drawn 
during the study include serum chemistries, a hematology panel and an immune panel (see 
Appendix 12.1 for more details). A serum pregnancy test must be performed, and the result must 
be negative prior to the entry of women of child-bearing potential. 
Clinical laboratory reports must be reviewed by a physician for out-of-range values within 
12 hours of receipt. Out-of-range values will be evaluated using the following notations:

NCS:  Not clinically significant

LE:  Laboratory Error

PT:  Subject abnormal; relates to the subject's usual state of health

CS:  Clinically Significant. This value cannot be explained by any of the other indicators.
By definition a lab value flagged as "CS" indicates an adverse event and will be captured on the 
CRF. A laboratory test flagged "CS" should be repeated as soon as possible, then the Investigator 
should use his or her judgment as to whether the abnormal finding is sufficient reason to 
immediately withdraw the subject from the study.
If a laboratory value is considered to be serious and life-threatening and at least possibly related 
to the study drug, the subject should be immediately discontinued from the study and appropriate 
therapy started. Refer to Sections 7.8 to Section 7.13 for definition of a serious adverse event and 
related terms, and details on reporting a serious adverse event.
Particular attention will be paid to determine the possibility of drug induced liver injury (DILI) as 
detailed in the FDA guidance document “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation.” Liver tests (ALT, AST, ALP, and total Bilirubin) will be performed at enrollment 
and at days 7, 14, and 28 throughout the drug administration period.  For patients exhibiting signs 
of liver disease such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
or rash, extensive laboratory testing will be performed that includes above liver chemistries 
immediately. Otherwise, on routine weekly testing an increase of serum aminotransferase levels 
to >3x upper limit of normal would automatically trigger repeat testing within 48 to 72 hours of 
all four of the usual serum measures (ALT, AST, ALP, and total Bilirubin) to confirm the 
abnormalities and to determine if they are increasing or decreasing. If symptoms and/or 
aminotransferase levels remain >3x upper limit of normal, the participant will be monitored more 
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closely with lab schedule, in-person or virtual evaluation twice weekly or more. A thorough 
evaluation for additional causes of liver test anomalies will be conducted in consultation with 
Hepatology. A case report form page will be created and DSMB review triggered. Otherwise, 
discontinuation of treatment will be considered immediately if: 
•
ALT or AST >8x upper limit of normal
•
ALT or AST >5x upper limit of normal for more than 2 weeks 
•
ALT or AST >3x upper limit of normal and total Bilirubin >2x upper limit of 
normal or INR >1.5 
•
ALT or AST >3x upper limit of normal with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).
7.8
Adverse Event Assessment and Recording
All adverse events, exacerbations of concomitant illnesses, or events known to be related to 
underlying disease processes or concomitant medications are to be recorded on the CRF 
throughout the study. If a pre-existing condition worsens during the study, the date on which the 
exacerbation began should be recorded. Onset dates for study treatment-related adverse events 
must be on or after the date of initial study treatment use. 
Adverse event recording will include the date of onset, severity, duration, whether or not the study 
medication was discontinued because of the event, the treatment given, and the outcome. The 
Investigator must also assess whether the event was related to the study medication, concurrent 
drug therapy, underlying disease, a combination of these factors, or if it is unknown. Subjects 
experiencing an adverse event should be carefully followed to determine outcome.
The Investigator will use the NCI-CTCAE for adverse event monitoring, version 5.0 will be 
applied in all instances. CTCAE version 4.03 may also be used especially when assessing 
laboratory tests given the complexity in applying version 5.0 in all instances, see  
www.lexjansen.com/phuse-us/2020/dh/DH16.pdf 
Definitions to grade the severity of the event:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
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Grade 2: Moderate; minimal, local, or non-invasive intervention indicated; limiting age-
appropriate ADL.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
Grade 4:  Life-threatening consequences; urgent intervention indicated.
Grade 5:  Death.
The relationship or association of the study medication in causing or contributing to the adverse 
event will be characterized as not related, remote, possible, probable, or definite as defined below:

Not related: Evidence indicates no plausible direct relationship to the study medication

Remote: Suggests other conditions are reasonably likely to account for the event including 
concurrent illness, progression or expression of the disease state, or reaction to concurrent 
medication

Possible: Suggests that the association of the event with the study medication is unknown; 
however, the adverse event is not reasonably supported by other conditions

Probable: Suggests that a reasonable temporal sequence of the event with medication 
administration exists and based upon the Investigator's clinical experience, the association 
of the event with study medication seems likely

Definite: Suggests that based upon the Investigator’s experience, the association of the 
event with the study medication seems very certain. 
Planned procedures such as surgery should not be recorded as adverse events. However, the 
medical condition for which the procedure was performed should be reported if it meets the 
definition of adverse event.
7.9
Reporting Requirements
Any adverse event, defined below, that begins any time between the start of the first dose and 
within 28 days after the end of the last dose are to be recorded on the appropriate CRF and in detail 
in the source documentation (preferably the electronic medical record directly).
Adverse Event: Any untoward medical occurrence in a subject administered a pharmaceutical 
product, which does not necessarily have to have a causal relationship with this treatment. An 
adverse event can be any unfavorable sign (including an abnormal laboratory finding), symptom, 
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or disease temporally associated with the use of the investigational drug, whether or not considered 
related to the investigational drug.
Serious Adverse Event: An untoward event or reaction that at any dose:

results in death

is life-threatening

results in hospitalization or prolongs existing hospitalization

results in permanent or significant disability or incapacity

requires intervention to prevent permanent impairment/damage

results in congenital anomaly or birth defect
In addition, any important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.
Life-threatening: An event which a subject was at risk of death at the time of event. There is a 
distinction between the severity and the seriousness of an adverse event. Severity is a measurement 
of intensity, thus a severe reaction is not necessarily a serious adverse event. For example, a 
headache may be severe in intensity, but would not be serious unless it met one of the criteria for 
serious adverse events listed previously.
7.10 Serious Adverse Events
Adverse events (AEs) and serious adverse events (SAEs) will be collected from the time the first 
dose of IP is administered until 28 days after the last dose of IP. Medical occurrences that began 
prior to the start of study treatment, but after obtaining informed consent will be captured as 
Medical History/Current Medical Conditions on the CRF. The Investigator or site staff will be 
responsible for the identification and documentation of events meeting the criteria and definition 
of an adverse event or serious adverse event, as provided in the study protocol. SAEs assessed as 
related to study participation (e.g., dosing, protocol mandated procedures, invasive tests, or change 
in existing therapy) or related to a concomitant medication will also be captured once the subject 
has taken the first dose of study medication.
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In the event of an AE or SAE, it will be the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the 
event and attempt to establish a diagnosis of the event based on signs, symptoms, and other clinical 
information. Once the Investigator becomes aware that an SAE has occurred, they are' to report 
the information to MedStar Health within 24 hours and provide an assessment of causality.
7.11 Notification of Serious Adverse Events
The Sponsor will report all serious adverse events to regulatory agencies as required. In addition 
to the serious adverse events described in Section 7.10, other events that in the Investigator's 
opinion suggest a significant hazard, contraindication, or precaution should be considered serious. 
This includes, but is not limited to, blood dyscrasias, endocrine disturbances, hemorrhage from 
any site, or severe skin disorder. Additional examples are intensive treatment for allergic 
bronchospasm, blood dyscrasias or convulsions. 
Subjects who experience an SAE must be given appropriate examinations and treatment. The 
Investigator must provide written information to the Sponsor as soon as possible.
7.12 Reporting a Serious Adverse Event
All appropriate SAEs will be reported immediately to the FDA per reporting criteria for an IND 
Safety Report. The event(s) will also be reported locally to the IRB of record when the event 
meeting reporting criteria per MedStar Health Research Institute IRB policy.
7.13 Departure from Protocol for Emergency or Adverse Event
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from immediate hazard. As soon as possible after removing the subject from hazard, the 
Investigator must contact MedStar Health by telephone to permit a decision as to whether the 
subject may continue in the study. The IRB should also be notified as to the type of emergency 
and the course of action. The CRF for the subject must capture the departure from the protocol and 
state the reason.
7.14 Safety Monitoring
A Data Safety and Monitoring Board (DSMB) will be established to monitor the safety of the 
subjects during the study. The DSMB includes members who are independent of this study and its 
Sponsor Team, and with relevant clinical expertise, including a good understanding of the safety 
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of medications for respiratory illnesses. These members may include one or more of the following- 
a statistician, an infectious disease specialist and/or a pulmonologist. The methodology and the 
operating procedures for the safety reviews will be developed by the infectious disease specialist 
and/or pulmonologist in collaboration with the Investigator and will be documented in the DSMB 
Charter. They will review all SAEs and determine whether the study can proceed or whether 
protocol modifications are required. The Charter will be submitted to the IND before the trial 
would commence.
7.15 Stopping Rules
Should two or more subjects develop a similar Grade 3 SAE that is at least possibly related to 
belnacasan or should one or more subjects develop a ≥ Grade 4 SAE that is at least possibly related 
to belnacasan, the trial will be paused for DSMB safety review.
7.16 Follow-Up and Final Reports
The Investigator shall provide MedStar Health with an accurate final report within 1 month after 
completion, termination or discontinuation of the study. The final report may not precede 
completion of monitoring relevant CRFs.
7.17 Regulatory Aspects
Neither the Investigator nor MedStar Health shall modify this protocol without first obtaining 
concurrence of the other in writing. All modifications must be submitted to the IRB with approval 
prior to implementation. Protocol modifications which impact subject safety or the validity of the 
study must be approved by the IRB and submitted to the FDA before implementation. In the case 
of a medical emergency to increase safety of subjects, a change may occur immediately, and the 
IRB and FDA will be notified as soon as possible.
8
DATA MANAGEMENT AND STATISTICS
8.1
Populations for Analyses
The following populations will be considered for statistical analyses.

Safety & Tolerability Population: All enrolled subjects who have received at least 1 dose 
of IP (belnacasan or placebo) will be studied. Even if subjects have discontinued study 
treatment, as long as they maintain consent, they will continue to be in the study and 
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included in analysis, i.e., their safety and tolerability information will continue to be 
collected for at least 60 days. 

Treatment Effect Evaluable Populations: All enrolled subjects who have received at least 
1 dose of IP (belnacasan or placebo) will be studied. Even if subjects have discontinued 
study treatment, as long as they maintain consent, they will continue to be in the study and 
included in analysis, i.e., their outcome information will continue to be collected for at least 
60 days.
8.2
Analysis Methods 
General Methods
FDA Data Standard Guidelines will be followed. Continuous variables will be summarized using 
the number of observations, number of observations above the limit of quantification (if 
applicable), mean, standard deviation (SD) median, and range. Categorical variables will be 
summarized using frequency counts and percentages. Comparison of belnacasan (VX-765/RVT-
201/MSR-001) and placebo groups will utilize Poisson regression for counts, Cox proportional 
hazards regression for time-to-event data and mixed effects models for continuous and categorical 
data obtained over study days.
8.3
Analysis of Subject Disposition, History, and Baseline Characteristics
Subject disposition, including analysis population allocation, subjects enrolled, completed each 
period, discontinued, and primary reason for discontinuation, will be summarized using frequency 
and percentage. Protocol deviations will be summarized using frequency and percentage. Medical 
history data and prior and concomitant medications will be summarized using frequency and 
percentage. Subjects’ age, height, weight, and baseline disease characteristics will be summarized 
using descriptive statistics. Gender, race, and other categorical variables will be provided using 
frequency and percentage. 
8.4
Safety & Tolerability Analyses
All safety & tolerability analyses will be performed on the Safety Population. The safety data will 
be presented in individual listings and summary tables.
Overall safety will be assessed by the number of belnacasan VX-765/RVT-201/MSR-001 dosed 
subjects experiencing a grade 4 or 5 SAE during the trial. Of 20 subjects enrolled in the belnacasan 
group, 3 or more developing a grade 4 or 5 SAE probably related to belnacasan would be 
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considered unlikely due to chance. Therefore, belnacasan will be determined safe if no more than 
2 subjects develop a grade 4 or 5 SAE in the belnacasan group probably related to belnacasan. 
In terms of stopping rules, should two or more subjects develop a similar Grade 3 SAE that is at 
least possibly related to belnacasan or should one or more subjects develop a ≥ Grade 4 SAE that 
is at least possibly related to belnacasan, the trial will be paused for DSMB safety review.
Primary Endpoint Analysis 
Primary endpoints of adverse and serious adverse events (AE/SAE) will be assessed by Poisson 
regression for count data. Events will be counted out to 60 days from randomization to belnacasan  
or placebo groups. Because some subjects may be followed for less than 60 days, subject follow-
up time will be included in the Poisson regression as the exposure time variable. If counts are not 
Poisson-distributed, either over- or under-dispersed, negative binomial regression will be to 
analyze AE/SAE events with appropriate adjustment for over/under dispersion. Comparison of 
belnacasan vs. placebo will be expressed as the incidence rate ratio (IRR).
Adverse Events
AEs will be coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The intensity/severity of AEs will be graded according to NCI-CTCAE (see 
Section 7.3).
TEAEs, AEs leading to study treatment discontinuation, AEs leading to dose interruption, AEs 
related to study medication, SAEs, and AEs leading to death will be summarized by system organ 
class, preferred term, and study period. A summary of AEs that are CTCAE Grade 3 or higher, as 
well as the most frequent preferred terms, will be provided.
If a subject experiences the same adverse events multiple times within a period, then the event will 
be counted only once within the period and by greatest severity. 
Descriptive statistics will be used to summarize the safety data.
Clinical Laboratory Values
All laboratory test results will be summarized by period together with the change from baseline. 
The frequency distribution for low/normal/high or normal/abnormal will be summarized as well. 
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The denominators for calculating the percentages will be based on the number of subjects with 
non-missing values in the Safety Population.  
Vital Signs
Vital sign results will be summarized by period, together with the change from baseline. 
Physical Examination
Summaries of physical examinations will present frequency distribution of abnormal findings by 
body system and period. The denominators for calculating the percentages will be based on the 
number of subjects evaluated for a particular body system of each dose level in the Safety 
Population.
Electrocardiogram (EKG) 
EKG findings will be classified as normal vs abnormal. The number and percentage of each 
category will be summarized using frequency table for each period. The denominators for 
calculating the percentages will be based on the number of subjects with non-missing values in 
each period.
8.5
Treatment Effect Analyses
Secondary Endpoint Analyses
Event counts over 60 days will be analyzed by Poisson regression as described above in 8.4. Time 
to events will be analyzed by Cox regression. Differences between belnacasan and placebo with 
respect to change in continuous endpoints will be assessed by mixed effects models for continuous 
repeated measures data and mixed effects logistic models for repeated categorical variables. 
Endpoint proportions of belnacasan and placebo groups will be assessed by contingency table 
analysis (chi-square).
8.6
Handling of Missing Data 
Although every effort will be made to obtain complete data, missing values will likely occur when 
data are collected longitudinally. Patterns of missingness over time as well missingness with 
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respect to demographic and clinical variables will be assessed. For Poisson and Cox regression 
analyses, all data can be used up to subject dropout time.  
8.7
Sample Size Considerations
A total of 40 subjects will be randomized, 20 to belnacasan (VX-765/RVT-201/MSR-001) 900 mg 
TID and 20 to placebo. As this is a proof-of-concept study, it will likely not be powered to detect 
belnacasan – placebo differences that are clinically meaningful. For example, the observed 
difference in endpoint rate ratios would need to be over 60% to achieve 80% power with an alpha 
error rate of 5% for 20 subjects in each group. This study will provide an estimate of the belnacasan 
effect size to inform a larger trial where a more clinically meaningful difference can be detected.
9
ESTIMATED DURATION OF THE STUDY
This study has an estimated maximum duration of up to 8.5 weeks for each subject. The study 
duration from first subject enrolled to last subject enrolled is expected to be 3-6 months.
10 ADMINISTRATIVE PROCEDURES AND ETHICAL CONSIDERATIONS
10.1 Subject Information and Informed Consent
The Investigator will ensure that the subject/LAR fully understands study participation 
requirements including possible risks and benefits. Subjects must also be notified that they are free 
to withdraw from the study at any time. During the informed consent process, the subject should 
be given the opportunity to ask questions and allowed time to consider the information provided. 
The subjects’ informed consent must be obtained before conducting any study-specific procedures.  
10.2 In person consent
When participants are recruited from one of the primary MedStar research sites and consented 
while on site a standard consent process will be used in accordance with institutional policy and 
procedures. (MG.O-004.01)
10.3 Remote Consent
Remote consent may be used for participants that are identified as potentially eligible for the 
study but are no longer present at one of the primary MedStar Research sites or received 
treatment at another MedStar Emergency Department or Urgent Care facility. In all cases remote 
consent will be conduced in accordance with MedStar policies and procedures (MG.O-004.06).
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10.4 Documentation of Consent
In all cases consent will be documented before research procedures begin. Standard documentation 
of consent may be used including presentation of a paper consent for to a potential participant for 
signature. This form of documentation of consent may be used for either with an in person or 
remote consent process. In all cases documentation of consent will be obtained in accordance with 
institutional policy and procedures (MG.O-004.01, MG.O-004.06). 
Electronic Consent
Electronic consent (eConsent) may be used for documentation of consent for both participants 
that are consented in person and those that are consented via a remote process. In all cases 
eConsent will be conducted in accordance with institutional policies and procedures (MG.O-
004.07).
10.5 Study Monitoring
During the study, a dedicated Clinical Research Associate (CRA) will have regular contacts with 
the investigational site, for the following:

Provide information and support to the Investigator,

Confirm that facilities remain acceptable,

Confirm that the investigational team is adhering to the protocol, that data is being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed,

Perform source data verification. This includes a comparison of the data in the eCRFs with 
the subjects’ medical records, and other records relevant to the study. This will require 
access to all original records for each subject (e.g., clinic charts) as described in the study 
monitoring plan.

Record and report any protocol deviations not previously sent to MedStar Health.

Confirm adverse events and serious adverse events have been properly documented on 
eCRFs and confirm any serious adverse events have been forwarded to MedStar Health, 
and those serious adverse events that met criteria for reporting have been reported to the 
IRB.
The CRA will be available over the course of the study if the Investigator or other staff needs 
information or advice. Remote visits will be conducted until it is possible to perform on-site visits.
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10.6 Audits and Inspections
Authorized representatives of the FDA, or the Institutional Review Board (IRB) may visit the site 
to perform audits or inspections, including source data verification. The purpose of any inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
International Conference on Harmonization (ICH), and FDA regulations. The Investigator / 
Sponsor should contact the site immediately if contacted by a regulatory agency about an 
inspection.
10.7 Ethics Committee Review
The final study protocol, including the final version of the Informed Consent Form, must be 
approved by the MedStar Health Research Institute IRB.
The Sponsor is responsible for submitting any modifications to the Protocol to the IRB and 
obtaining approval in advance of implementing these modifications. In addition, the IRB must 
approve all advertising used to recruit subjects for the study. The study must also be renewed 
annually with the IRB as long as study conduct is occurring.
The Investigator / Sponsor are also responsible for providing the IRB with reports of any reportable 
new information (RNI) including any serious adverse drug reactions from any other study 
conducted with the investigational product.  
10.8 Standards
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory requirements.
10.9 Confidentiality
Any research information obtained specific to subjects enrolled into this study will be kept 
confidential. A subject will not be identified by name, only by a unique study number. The 
subject’s name or any identifying information will not appear in any reports published as a result 
of this study.
However, information obtained from individual subjects’ participation in the study may be 
disclosed with his/her consent to the healthcare providers for the purpose of obtaining appropriate 
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medical care. The subject’s medical records/charts, tests with his/her name on them may be made 
available to the appropriate contract research organization (CRO), MedStar Health, IRB, and the 
FDA. This is for the purpose of verifying information obtained for this study.
A subject’s name will not be given to anyone except the researchers conducting the study, who 
have pledged an oath of confidentiality. All identifying information will be kept behind locked 
doors, under the supervision of the Investigator and will not be transferred outside of WHC / 
MedStar as applicable.
A subject may take away his/her permission to collect, use and share information about him/her at 
any time. If this situation occurs, the subject will not be able to remain in the study. No new 
information that identifies the subject will be gathered after that date. However, the data about the 
subject that has already been collected may still be used and given to others as described above in 
order to preserve the scientific integrity and quality of the study.
10.10 Protocol Adherence
The records of study treatment delivered to subjects and IP inventory will be maintained at WHC 
/ MedStar; the administration to each subject; and storage or disposal of any unused IP. These 
records should include dates, quantities, batch/serial numbers, expiration dates, IDS temperature 
log, and unique code numbers assigned to the product and study subjects.
The Investigator will maintain records that document adequately that the subjects were provided 
with the correct study drug and will maintain IP accountability and tracking records.
10.11 Amendments to the Protocol
Modifications to the protocol are only possible by approved protocol amendments authorized by 
the Sponsor, approved by the IRB, and deemed as not-objectionable by the FDA. The Investigator 
must not implement any deviations from, or changes to the protocol, except where it is necessary 
to eliminate an immediate hazard to the study subject.
10.12 Protocol Deviations
The protocol must be conducted compliantly, significant deviations from the protocol will be 
reported to the FDA and/or IRB per policy.
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10.13 Study Termination
This study may be prematurely terminated, if in the opinion of the Investigator or MedStar Health 
there is sufficient reasonable cause. Circumstances that may warrant termination include, but are 
not limited to:

Determination of unexpected, significant, or unacceptable risk to subjects.

Failure to enroll subjects at an acceptable rate.

Insufficient adherence to protocol requirements.

Insufficient complete and/or evaluable data.

Plans to modify, suspend, or discontinue the development of belnacasan (VX-765/RVT-
201/MST-001).
10.14 Inspection of Records
MedStar Health will be allowed to audit data for the purpose of monitoring any aspect of the study 
they deem necessary, pursuant to local restrictions on monitoring due to health concerns. The 
Investigator agrees to allow the IRB and regulatory authorities to inspect the drug storage area, 
study drug stocks, drug accountability records, subject charts and study source documents, and 
other records relative to study conduct.  Remote access can be granted in the event the pandemic 
prevents on-site monitoring.
10.15 Data Management
All data relating to study procedures will be entered onto the eCRF (OnCore platform). CRF 
completion guidelines will be developed to assure the required data is appropriately captured.  
eCRFs will be completed for each subject. It is the Investigator’s responsibility to ensure the 
accuracy, completeness, and timeliness of the data entered in each subject’s eCRF. Source 
documentation supporting the eCRF data should indicate the subject’s participation in the study 
and document the dates and details of study procedures, adverse events, and subject status.
The Investigator, or designee, should complete the eCRF as soon as possible after data is collected, 
preferably on the same day that a subject is seen for an examination, treatment, or any other study 
procedure. Any outstanding entries must be entered immediately after the final examination.  An 
explanation should be given for all late or missing data.
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10.16 Liability and Insurance
Subject Injury: Sponsor will not provide reimbursement if any subject suffers an adverse reaction, 
illness, or injury, which is determined to have been caused directly by the subject’s participation 
in the study.  
Insurance: Sponsor shall, at its sole cost and expense, maintain a policy or program of insurance 
or self-insurance in compliance with applicable law in amounts sufficient to cover Sponsor’s 
liabilities and obligations in connection with the study.
10.17 Retention of Records
Investigators shall retain study records and source documents for a period of 2 years following the 
date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified and / or the 
period required by local, state, and federal laws, regulations and FDA Guidance.
The Investigator agrees to comply with all applicable federal, state, and local laws and regulations 
relating to the privacy of protected health information, including, but not limited to, the Standards 
for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the Health Insurance 
Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The Investigator shall 
ensure that study subjects authorize the use and disclosure of protected health information in 
accordance with HIPAA Privacy Regulation.
10.18 Data Quality Assurance
WHC / MedStar and all relevant subject study and medical records may be subject to a quality 
assurance audit during the course of the study. In addition, inspections may be conducted by the 
FDA at their discretion.
If sites receive a request for an inspection or written or oral inquiries regarding any aspect of 
institution’s or Investigator’s activities related to this study from a regulatory authority, the 
Investigator must immediately notify MedStar Health of the request. Following this inspection 
and/or audit, the Investigator must notify MedStar Health of any violation or deficiency noted by 
the regulatory authority.
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11 USE OF INFORMATION
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will be 
agreed between the Institution and MedStar Health or their designee. With respect to such rights, 
MedStar Health or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by Investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, Investigators will be required to assign all such inventions directly to MedStar Health 
or its designee, as will be set forth in the clinical study agreement.
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12 APPENDIX
12.1 Labs and Tests
Hematology
Serum Chemistry
Albumin
Alanine Aminotransferase (ALT)
Alkaline Phosphatase (ALP)
Aspartate Aminotransferase (AST)
Blood Urea Nitrogen (BUN)
Calcium
Carbon Dioxide 
Chloride 
Creatinine 
Glucose 
Lipase
Magnesium
Potassium 
Sodium 
Total Bilirubin
Total Protein 
Lactate Dehydrogenase (LDH)
Creatine Kinase, Total
CRP
Ferritin
D-Dimer
HbA1c
Troponin I, High Sensitivity (hs-
TnI)
Screening Tests
Complete Blood Count:
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin (Hb)
Hematocrit (Hct)
Mean Corpuscular Volume (MCV)
Red Blood Cell Distribution Width (RDW)
Platelet Count 
Differential - absolute and percent of:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Coagulation Tests:
Partial Thromboplastin Time (PTT)
Prothrombin Time (PT)
Immune Cell Counts – absolute and percent of:
CD3+ T cells1
Serum and Plasma Levels of Cytokines and 
Inflammasome Markers2: 
IL-18
IL-1β
IL-1 receptor antagonist
IL-6
Gasdermin D
G-CSF
TNF-α
Caspase-1
HIV
Hepatitis B
Hepatitis C
Pregnancy (serum pregnancy test for 
women of child-bearing potential 
per MedStar definition at enrollment 
and once during IP course)
1 CD3+ counts/cell isolation/storage for future research samples will be sent to for resulting/storage:
Cell Therapy Manufacturing Facility
MedStar Georgetown University Hospital
3800 Reservoir Rd NW, Room M1334
Washington, DC 20007
2 Cytokines and inflammasome markers will be sent/resulted to/from:
University of Maryland Cytokine Core Laboratory
655 West Baltimore Street, Bressler Research Bldg, 7th Floor, Room 07010
Baltimore, MD  21201
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12.2 Illustrative Subject Diary Excerpts 
Subject Diary – Overview of Study Events
Week 1
1
2
3
4
5
6
7
Week 2
8
9
10
11
12
13
14
Week 3
15
16
17
18
19
20
21
Week 4
22
23
24
25
26
27
28
Week 5
29
30
31
32
33
34
35
Week 6
36
37
38
39
40
41
42
Week 7
43
44
45
46
47
48
49
Week 8
50
51
52
53
54
55
56
Week 9
57
58
59
60
Days
Legend
Days 1-28: Three times per day: take the study drug;
Once every morning: rate your symptoms and overall health
and record your temperature and oxygen saturation levels
Days 1, 4, 10, 42, 60: Receive phone calls from Study Team
Days 7, 14, 21, 28: Visit Study Center in person
Days 7, 14, 21, 28: Give Study Team last 7 days of Diary pages
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Subject Diary – Sample Daily Log – Page 1
Date:
Subject Number:
Common COVID-19 Symptoms
None
Mild
Moderate
Severe
Stuffy or runny nose
Sore throat
Shortness of breath at rest
Shortness of breath with exertion
Cough
Low energy or tiredness
Muscle or body aches
Headache
Chills or shivering
Feeling hot or feverish
Nausea
What was the SEVERITY of these symptoms at their worst in the last 24 hours? Place anX
Time you are filling
this out today:
0
times
1-2
times
3-4
times
5 or more
times
Vomit (throw up)
Diarrhea (loose or watery stools)
In the last 24 hours, how often did you have these ISSUES? Place anX
SAME
as usual
LESS
than usual
I have
NO sense
Sense of smell
Sense of taste
In the last 24 hours, how would you rate your SENSES? Place anX
Over the last 24 hours, if there were any other symptoms beyond the ones listed above
that you experienced, please describe them here:
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Subject Diary – Sample Daily Log – Page 2
Morning
Mid-Day
Evening
am
_m
pm
Place anX to note that you have taken
3 tablets of the STUDY DRUG and note
the time you took them; remember you
will take 9 tablets total each day
Medication
Temperature
Time
oF
am
Record your temperature from the thermometer and note
the time you took the measurement; if your temperature
is higher than 100.4 F, please call your Study Nurse
Temperature
Date:
Subject Number:
Note any OTHER medications, vitamins,
or supplements you took, other than
those you told us at enrollment that you
take on a regular basis; use the back of
this page if you need more space
Name
Dose
Time
Global Health Impression
None
Mild
Moderate
Severe
In the past 24 hours, what was the
severity of your OVERALL COVID-19-
related symptoms at their worst?
Yes
No
In the past 24 hours, have you returned to your
usual HEALTH (before your COVID-19 illness)?
In the past 24 hours, have you returned to your
usual ACTIVITIES (before your COVID-19 illness)?
Place an X
Time you are filling
this out today:
O2 Saturation
Time
%SpO2
am
Record your oxygen saturation from the pulse oximeter and
note the time you took the measurement; if your oxygen
saturation is lower than 93%, please call your Study Nurse
Oxygen (O2) Saturation
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12.3 Illustrative Randomization Table
A randomization table such as the one below will be used to allocate subjects to belnacasan or 
placebo group (N=20 each). Assignment of A or B to treatment or placebo blinded to subjects 
and investigators.
Sequential subject
Group assignment
Sequential subject
Group assignment
1
A
21
B
2
B
22
A
3
B
23
A
4
A
24
B
5
A
25
A
6
B
26
B
7
A
27
A
8
B
28
B
9
A
29
A
10
A
30
A
11
B
31
B
12
B
32
B
13
B
33
B
14
A
34
B
15
A
35
A
16
B
36
A
17
B
37
B
18
A
38
A
19
B
39
B
20
A
40
A
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