Conditions: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV 2 Infection) COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2285
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate whether bemnifosbuvir (BEM) is effective and safe in adults with COVID-19 who do not need to be in the hospital but who are at high risk for progression to severe disease. Eligible subjects will be randomly assigned (by chance) to receive BEM or matching placebo orally for 5 days. Co-administration of locally available standard of care (SOC) is allowed. The total duration of the study is 60 days.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Bemnifosbuvir (BEM) intervention 2: Placebo
Intervention descriptions: intervention 1: BEM tablets administered orally every 12 hours (twice a day) for a total of 5 days intervention 2: Placebo tablets administered orally every 12 hours (twice a day) for a total of 5 days

Protocol document:
Prot_000.pdf: 
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A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19 
 
 
Sponsor Protocol Number: 
AT-03A-017 
EU CT Number: 
2023-504540-33-00 
Investigational Product(s): 
Bemnifosbuvir Hemisulfate  
(BEM; AT-527) 
Sponsor: 
Atea Pharmaceuticals, Inc. 
225 Franklin Street 
Suite 2100 
Boston, MA 02110 USA 
+1 (857) 284-8891 
 
COMPLIANCE 
The study will be conducted in accordance with this protocol, the ethical principles in the latest 
version of the Declaration of Helsinki, and standards of Good Clinical Practice, as defined by the 
International Conference on Harmonisation and all applicable federal and local regulations. 
Protocol Version 
Date 
2.0 
FINAL 
15Jun2023 
1.0 
FINAL 
08Sept2022 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from the Sponsor. 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................6 
LIST OF ABBREVIATIONS ........................................................................................................17 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background on COVID-19 .........................................................................................21 
1.2. 
Background on Bemnifosbuvir ...................................................................................23 
1.2.1. 
Summary of Results from the Phase 2 and Phase 3 COVID-19 Studies ....................23 
1.2.2. 
Supportive Results from Clinical Pharmacology and Non-Clinical Studies ..............26 
1.3. 
Rationale for the Dose Selection ................................................................................26 
1.4. 
Rationale for Study Population ...................................................................................27 
1.5. 
Rationale for Study Design and Allowance of Standard of Care ...............................28 
1.6. 
Rationale for Primary Endpoint ..................................................................................29 
1.7. 
Benefit-Risk Assessment ............................................................................................30 
2. 
STUDY OBJECTIVES ..............................................................................................31 
3. 
STUDY DESIGN .......................................................................................................32 
3.1. 
General Study Design .................................................................................................32 
4. 
SUBJECT SELECTION .............................................................................................34 
4.1. 
Study Population .........................................................................................................34 
4.2. 
Inclusion Criteria ........................................................................................................34 
4.3. 
Exclusion Criteria .......................................................................................................36 
5. 
STUDY TREATMENTS............................................................................................38 
5.1. 
Description and Handling of Study Treatments .........................................................38 
5.1.1. 
Test Product ................................................................................................................38 
5.1.2. 
Control Product ...........................................................................................................38 
5.1.3. 
Packaging and Labeling ..............................................................................................38 
5.1.4. 
Storage and Handling .................................................................................................38 
5.1.5. 
Background Standard of Care .....................................................................................38 
5.2. 
Method of Assigning Subjects to Treatment Groups .................................................39 
5.3. 
Blinding ......................................................................................................................39 
5.4. 
Dosing and Administration .........................................................................................39 
5.4.1. 
Dispensing ..................................................................................................................39 


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5.4.2. 
Administration Instructions ........................................................................................39 
5.4.3. 
Treatment Compliance ................................................................................................40 
5.5. 
Study Drug Accountability .........................................................................................40 
5.6. 
Premature Treatment or Study Discontinuation .........................................................40 
5.7. 
Prior Therapy, Concomitant Therapy, Permitted Therapy, Cautionary 
Therapy, and Prohibited Therapy ...............................................................................42 
5.7.1. 
Prior Therapy ..............................................................................................................42 
5.7.2. 
Concomitant Therapy .................................................................................................42 
5.7.3. 
Permitted Therapy ......................................................................................................42 
5.7.4. 
Cautionary Therapy ....................................................................................................43 
5.7.4.1. 
Herbal Therapies .........................................................................................................43 
5.7.4.2. 
Mitigation of Other Potential DDI ..............................................................................43 
5.7.5. 
Prohibited Therapy .....................................................................................................44 
5.8. 
Contraception Requirements ......................................................................................44 
6. 
STUDY PROCEDURES AND GUIDELINES..........................................................46 
6.1. 
Schedule of Assessments ............................................................................................46 
6.2. 
Medical History ..........................................................................................................49 
6.3. 
Physical Examination .................................................................................................49 
6.4. 
Vital Signs ..................................................................................................................49 
6.5. 
Safety Laboratory Evaluations ...................................................................................49 
6.6. 
Other Laboratory Evaluations .....................................................................................50 
6.6.1. 
Sparse PK Sampling ...................................................................................................50 
6.6.2. 
Bioanalytical Methods for PK Samples ......................................................................50 
6.7. 
COVID-19 Symptom Assessment ..............................................................................50 
6.7.1. 
Data Collection Methods for the PRO ........................................................................51 
6.8. 
COVID-19-Related Medically Attended Visit(s) Assessment ...................................52 
7. 
ADVERSE EVENTS..................................................................................................54 
7.1. 
Definitions ..................................................................................................................54 
7.1.1. 
Intensity Assessment ..................................................................................................55 
7.1.2. 
Causality Assessment .................................................................................................55 
7.2. 
Routine Reporting .......................................................................................................56 
7.3. 
Serious Adverse Event Reporting ...............................................................................56 


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7.4. 
Pregnancy Reporting ..................................................................................................57 
8. 
STATISTICAL ANALYSES .....................................................................................59 
8.1. 
Analysis Populations ..................................................................................................59 
8.1.1. 
Safety Population ........................................................................................................59 
8.1.2. 
Intention to Treat Population ......................................................................................59 
8.1.3. 
Modified Intent-to-Treat Population ...........................................................................59 
8.1.4. 
PK Population .............................................................................................................59 
8.2. 
Endpoints ....................................................................................................................59 
8.3. 
Statistical Methods ......................................................................................................61 
8.3.1. 
Primary Efficacy Analysis ..........................................................................................62 
8.3.2. 
Secondary Efficacy Analyses .....................................................................................62 
8.3.3. 
Exploratory Analyses ..................................................................................................62 
8.3.4. 
Safety Analyses ..........................................................................................................63 
8.3.5. 
PK Analyses ................................................................................................................63 
8.4. 
Interim Analyses .........................................................................................................63 
8.5. 
Sample Size ................................................................................................................64 
9. 
ETHICS ......................................................................................................................65 
9.1. 
Institutional Review Board/Independent Ethics Committee ......................................65 
9.2. 
Ethical Conduct of the Study ......................................................................................65 
9.3. 
Participant Information and Consent ..........................................................................65 
9.4. 
Subject Confidentiality and Personal Data Protection ................................................65 
10. 
DATA COLLECTION, RETENTION, AND MONITORING .................................67 
10.1. 
Data Safety Monitoring Board ....................................................................................67 
10.2. 
Case Report Forms .....................................................................................................67 
10.3. 
Data Management and Processing ..............................................................................67 
10.4. 
Quality Assurance .......................................................................................................67 
10.5. 
Record Retention ........................................................................................................67 
10.6. 
Monitoring of the Study..............................................................................................68 
11. 
ADMINISTRATIVE PROCEDURES .......................................................................69 
11.1. 
Adherence to Protocol ................................................................................................69 
11.2. 
Investigator Responsibilities and Delegation of Investigator Duties .........................69 
11.3. 
Premature Termination or Suspension of a Study ......................................................69 


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11.4. 
Publication Policy .......................................................................................................69 
12. 
REFERENCES ...........................................................................................................70 
13. 
APPENDICES ............................................................................................................72 
13.1. 
Appendix 1: COVID-19 Symptom Diary ...................................................................72 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................47 
Table 2: 
Adverse Event Relationship to Study Drug ................................................................55 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................33 
 
 


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SYNOPSIS 
Protocol Title: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19 
Protocol Number: 
AT-03A-017 
Clinical Phase: 
3 
Primary Objective: To evaluate the efficacy of bemnifosbuvir (BEM) compared with placebo in 
reducing all-cause hospitalization or all-cause death in COVID-19 outpatients 
receiving only supportive care. 
Secondary 
Objectives: 
To evaluate the efficacy of BEM compared with placebo on: 
• 
COVID-19 related hospitalization or all-cause death through Day 29 
• 
All-cause death through Day 29 and Day 60 
• 
COVID-19-related complications (eg, death, hospitalization, 
radiologically confirmed pneumonia, acute respiratory failure, sepsis, 
coagulopathy, pericarditis/myocarditis, cardiac failure) through 
Day 29 
• 
COVID-19-related medically attended visits (hospitalization, 
emergency room (ER) visit, urgent care visit, physician’s office visit, 
or telemedicine visit) or all-cause death through Day 29 and Day 60 
• 
COVID-19 symptom relapse 
To evaluate the antiviral activity of BEM compared with placebo on viral load 
rebound 
To evaluate the safety of BEM compared with placebo 
Exploratory 
Objectives: 
To evaluate the efficacy of BEM compared with placebo on: 
• 
Alleviation or improvement of individual COVID-19 symptoms 
• 
Return to usual (pre-COVID-19) health 
• 
Requirement for post-randomization rescue therapy 
• 
The antiviral activity of BEM compared with placebo 
To assess plasma concentrations of AT-511 (free base form of AT-527 [BEM]) 
and its metabolites  
Study Design: 
• Randomized, double-blind, placebo-controlled study 
• BEM or matching placebo will be administered twice daily (BID) for 5 days 
(10 doses) 


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• Locally available standard of care (SOC) treatment should be initiated in 
parallel in addition to study drug (add-on). SOC treatments with direct 
antiviral activity against SARS-CoV-2 are allowed but should be initiated 
during screening and/or within 24 hours prior to or after randomization.  
• Subjects will be randomized 1:1 (active:placebo) to one of the following 
arms: 
− 
550 mg BEM (2 x 275-mg tablets) BID for 5 days 
− 
Placebo (2 tablets) BID for 5 days 
Note: Each dose consists of 2 tablets. On each dosing day, 2 tablets will be 
taken for the morning dose and 2 tablets will be taken for the evening dose. 
The total treatment course consists of 10 doses over 5 days (20 tablets 
total).  
• Randomization will be stratified by geographic region (North America, 
Europe, Asia, and rest of world [ROW]), age (< 65 years old vs ≥ 65 years 
old) and by the type of SOC which the investigator plans to administer in 
parallel at time of study drug initiation. The type of SOC received will be 
used to classify subjects into two categories: 
a. Combination antiviral stratum (subsequently referred to as the 
combination antiviral population): In addition to study drug, the 
subject will be initiated on a local SOC regimen which includes a 
treatment with direct SARS-CoV-2 antiviral activity. Examples 
include nirmatrelvir/ritonavir, molnupiravir, favipiravir, monoclonal 
antibodies (mAbs). 
b. Supportive-care-only stratum (subsequently referred to as the 
supportive-care-only population): the SOC regimen the subject will 
receive does not include any treatment with direct SARS-CoV-2 
antiviral activity. 
 
Note: Although randomization is stratified by whether COVID-19 drugs with 
antiviral effects are administered, both strata allow local SOC therapies 
without direct antiviral effects (ie, corticosteroids).  
Note: Patients who require SOC treatment with a non-compatible antiviral 
treatment, defined as those with a potential drug-drug interaction (DDI) 
with BEM (eg, remdesivir), are excluded. 
Note:  As ritonavir is a major P-gp inhibitor, subjects enrolled in the 
combination antiviral group who are taking nirmatrelvir/ritonavir should 
not take nirmatrelvir/ritonavir until at least 2 hours after taking study 
drug  
Study Population 
• High-risk outpatients with mild or moderate COVID-19 
− 
Age and comorbidities will determine risk and eligibility (see 
inclusion criteria) 


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• Onset of COVID-19 symptoms will have occurred ≤ 5 days before 
randomization 
Duration of Study: 
• The primary study period is up to 30 days, including up to 1 day for 
screening and 29 days from randomization 
• Extended follow-up data will be collected through Day 60 for mortality and 
medically attended visit assessment.  The Day 60 follow-up contact marks 
the end of study participation for each subject and the study ends when the 
last subject completes the Day 60 follow-up contact. 
Number of Subjects: 
• Approximately 2510 eligible subjects with COVID-19 will be enrolled 
− 
2210 subjects are expected to comprise the supportive-care-only 
population 
− 
Up to 300 subjects are expected to comprise the combination 
antiviral population 
Inclusion Criteria: 
1. Willing and able to provide informed consent. 
2. Positive SARS-CoV-2 diagnostic test (reverse transcription polymerase 
chain reaction [RT-PCR] or validated rapid antigen test) conducted 
≤ 5 days prior to randomization. Note:  The test may be obtained locally. 
A documented historical record of positive result (RT-PCR or validated 
rapid antigen test) from a test conducted ≤ 5 days prior to randomization 
is acceptable. 
3. Mild or moderate COVID-19 with symptom onset ≤ 5 days before 
randomization and at least one COVID-19 related symptom present at 
time of screening: 
• 
Mild COVID-19: 
− 
Symptoms of mild illness with COVID-19, which could include 
fever, cough, sore throat, malaise, headache, muscle pain, nausea, 
vomiting, diarrhea, and loss of taste or smell, without shortness of 
breath or dyspnea 
− 
No clinical signs indicative of moderate, severe, or critical illness 
severity 
• 
Moderate COVID-19: 
− 
Symptoms of moderate illness with COVID-19, which could 
include any symptom of mild illness or shortness of breath with 
exertion 
− 
Clinical signs suggestive of moderate illness with COVID-19, 
such as respiratory rate ≥ 20 breaths per minute, heart rate 


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≥ 90 beats per minute; with saturation of oxygen (SpO2) > 93% 
on room air 
− 
No clinical signs indicative of severe or critical illness severity 
4. For females of childbearing potential: agreement to remain abstinent 
(refrain from heterosexual intercourse) or use adequate contraception 
during the treatment period and for 30 days after the final dose of study 
drug. 
5. Females of childbearing potential must have a negative pregnancy test 
prior to initiation of study drug.  
6. Subject must be able to take oral tablet medications. 
7. Subject is, in the opinion of the investigator, willing and able to comply 
with the study drug regimen and all other study requirements. 
8. Subject must be high risk, defined below. 
• 
Age ≥70 years OR 
• 
Age ≥55 years with one of the following risk factors: 
− 
Obesity (body mass index [BMI] ≥30 kg/m2) 
− 
Diabetes mellitus 
− 
Cardiovascular disease (including congenital heart disease) or 
hypertension (with at least one medication recommended or 
prescribed) 
− 
Chronic lung disease requiring routine therapy (eg, chronic 
obstructive pulmonary disease [COPD], moderate-to-severe 
asthma, interstitial lung disease, cystic fibrosis, pulmonary 
hypertension)   
OR 
• 
Age 50 to 54 inclusive with two of the following risk factors: 
− 
Obesity (body mass index [BMI] ≥30 kg/m2) 
− 
Diabetes mellitus 
− 
Cardiovascular disease (including congenital heart disease) or 
hypertension (with at least one medication recommended or 
prescribed) 
− 
Chronic lung disease requiring routine therapy (eg, chronic 
obstructive pulmonary disease [COPD], moderate-to-severe 
asthma, interstitial lung disease, cystic fibrosis, pulmonary 
hypertension)   
OR 


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• 
Age ≥18 years with one of the following: 
− 
Down syndrome 
− 
Sickle cell disease 
− 
Dementia 
− 
Parkinson’s disease 
− 
Care home residents 
− 
One of the following immunocompromising conditions or 
immunosuppressive treatments: 
o On immunosuppressive regimens including chemotherapy, 
for the treatment of cancer 
o Hematologic malignancy associated with poor response to 
COVID-19 vaccines (eg, CLL, non-Hodgkin lymphoma, 
multiple myeloma, acute leukemia) 
o Being within 2 years of a hematopoietic stem cell transplant 
o Receipt of a solid-organ transplant and on 
immunosuppressive therapy 
o Human immunodeficiency virus (HIV) infection (untreated) 
or with CD4+ T lymphocyte count <350 cells per cubic 
millimeter (mm3)  
o Moderate or severe primary immunodeficiency  
o Active treatment with an immunosuppressive medication 
regimen (eg, high-dose corticosteroids [ie, 20 mg of 
prednisone daily or equivalent for ≥2 weeks], alkylating 
agents, antimetabolites, transplant-related 
immunosuppressive drugs, cancer chemotherapeutic agents 
that are severely immunosuppressive, tumor necrosis factor 
[TNF] blockers, biologics that are immunosuppressive) 
• 
Enrollment of 24 high-risk adolescents (≥ 12 years to 17 years) will 
be allowed after the planned, pre-specified interim analysis for which 
65% of the supportive-care-only strata completed the follow-up 
period (Day 29). A DSMB recommendation that the study continue at 
this interim analysis point will trigger enrollment of adolescents. The 
Sponsor will notify sites when enrollment of adolescent subjects is 
permitted.   
Note: “High-risk” subjects in this age group are identical to high-risk 
subjects ≥ 18 years. 
Exclusion Criteria: 
1. Female subject is pregnant or breastfeeding. 


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2. Clinical signs or symptoms indicative of severe or critical COVID-19 
illness, including any of the following:  shortness of breath at rest, 
respiratory rate ≥ 30 breaths per minute, heart rate ≥ 125 beats per minute, 
SpO2 ≤ 93% on room air, partial pressure of oxygen/fraction of inspired 
oxygen (PaO2/FiO2) <300, shock (defined by systolic blood pressure 
<90 mm Hg or diastolic blood pressure < 60 mm Hg or requiring 
vasopressors), multi-organ dysfunction/failure, respiratory distress, 
respiratory failure; requirement of endotracheal intubation, mechanical 
ventilation, oxygen delivered by high-flow nasal cannula, noninvasive 
positive pressure ventilation, extracorporeal membrane oxygenation 
(ECMO). 
Note: Subjects receiving chronic supplemental oxygen by nasal cannula 
are eligible for the study if there has been no increase in baseline oxygen 
requirement/settings. 
3. Admitted to a hospital within 90 days prior to randomization due to 
COVID-19 or is hospitalized (inpatient) for any reason at randomization. 
Note:  If local policy requires COVID-19 isolation or internment in a 
hospital or similar facility, but subjects otherwise meet inclusion criteria, 
this exclusion may not apply. However, subjects under clinical 
observation at a clinic/study site or hospital with plans to remain in that 
setting overnight are not study eligible. 
4. In the opinion of the investigator, is likely to experience imminent 
deterioration and require hospitalization within 24 hours. 
5. Use of other investigational drugs within 30 days prior to planned dosing, 
or plans to enroll in another clinical trial of an investigational agent while 
participating in the present study, except for unblinded protocols that 
don’t include direct acting antivirals for COVID-19 (eg, open-label 
oncological regimen variations or biologic studies). Note:  Prior to 
enrolling subjects that are on other open-label studies, it is the site’s 
responsibility to ensure that the study criteria for that study allow for 
enrollment into this study. 
6. Initiation or planned initiation of remdesivir for treatment of the current 
SARS-CoV-2 infection. 
7. Requirement of any prohibited medications, as described in Section 5.7, 
including either hydroxychloroquine or amiodarone within 3 months prior 
to screening. (see rationale in Section 5.7.5) 
 Note: Subjects who had already initiated any COVID-19 drug with 
antiviral effects intended to treat symptomatic SARS-CoV-2 infection 
(≥24 hours prior to randomization) will be excluded. During screening 
(or within 24 hours prior to or after randomization), locally available 
COVID-19 drugs with antiviral effects (including but not limited to 
nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs) will be permitted. 


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8. Other known active viral or bacterial infection at the time of screening, 
such as influenza (ie, as verified by a locally available rapid flu test at 
screening) and respiratory syncytial virus (RSV).  
Note:  This exclusion does not apply to subjects with stable chronic viral 
infections, such as chronic hepatitis C virus (HCV) or HIV providing 
other eligibility criteria are met. 
9. Receiving dialysis or have known severe renal impairment (ie estimated 
glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 within 6 months of 
the screening visit, using the serum creatinine-based CKD-EPI formula). 
Note: If the investigator suspects the subject may have eGFR 
<30 mL/min/1.73 m2, a confirmatory test should be performed at 
screening to confirm eligibility before the first dose of study drug. 
10. History of severe hepatic impairment (Child-Pugh Class C)  
11. Known allergy or hypersensitivity to components of study drug.  
12. Malabsorption syndrome or other condition that would interfere with 
enteral absorption. 
13. Any clinically significant medical condition or known laboratory 
abnormality that, in the opinion of the investigator, could jeopardize the 
safety of the subject or impact subject compliance or safety/efficacy 
observations in the study. 
Test Product: 
• BEM will be provided as 275 mg tablets (designated as formulation 
A2-275 mg) 
• Matching BEM-placebo tablets will also be provided. 
Dose and Mode of 
Administration: 
• BEM and placebo to be administered orally 
• Doses and frequency as described in the protocol 
Data Safety 
Monitoring Board 
(DSMB) 
• An independent DSMB will evaluate safety, efficacy, and futility, as 
described in the DSMB charter 
Study Endpoints 
The primary efficacy endpoint is the proportion of subjects in the supportive-
care-only population who are hospitalized for any cause or died due to any 
cause through Day 29. 
Secondary endpoints are: 
Efficacy: 
• 
Proportion of subjects with COVID-19-related hospitalization or who 
died due to any cause through Day 29 


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• 
Proportion of subjects who died due to any cause through Day 29 and 
Day 60 
• 
Proportion of subjects with COVID-19-related complications (eg, 
death, hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, 
cardiac failure) through Day 29 
• 
Proportion of subjects with COVID-19-related medically attended 
visits (hospitalization, emergency room (ER) visit, urgent care visit, 
physician’s office visit, or telemedicine visit) or who died due to any 
cause through Day 29 and Day 60 
• 
Proportion of subjects with COVID-19 symptom relapse through Day 
29  
• 
Proportion of subjects with viral load rebound (term to be defined in 
the Statistical Analysis Plan [SAP]) through Day 29 
Safety: 
• 
The incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs) 
Exploratory endpoints are: 
Efficacy: 
• 
Time to alleviation or improvement of individual COVID-19 
symptoms 
• 
Time to self-reported return to usual (pre-COVID-19) health 
• 
Proportion of subjects requiring post-randomization rescue therapy 
Note:  For subjects randomized into the combination antiviral 
population, antiviral medications administered post-baseline within 
24 hours of first study drug, as part of the combination regimen, are 
not considered rescue medication. 
Note:  Rescue therapy for the purpose of the endpoint includes only 
treatments with direct activity against SARS-CoV-2; and that is 
administered for COVID-19-related clinical decline. 
• 
Duration and severity of COVID-19 symptom relapse 
• 
Proportion of subjects with both COVID-19 symptom relapse and viral 
load rebound 
• 
Change from baseline in amount of severe acute respiratory syndrome 
coronavirus-2 (SARS-CoV-2) viral RNA as measured by reverse 
transcription quantitative polymerase chain reaction (RT-qPCR) over 
time 


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• 
Time to cessation of SARS-CoV-2 viral shedding by RT-qPCR  
• 
Proportion of subjects negative for SARS-CoV-2 viral RNA by RT-
qPCR over time 
• 
Area under the curve (AUC) in the amount of SARS-CoV-2 viral 
RNA as measured by RT-qPCR  
• 
Proportion of subjects with treatment-emergent mutations in SARS-
CoV-2 viral genes 
• 
 
 
Pharmacokinetics: 
• 
Plasma concentrations of AT-511 (free base form of AT-527 [BEM]) 
and its metabolites  
The primary efficacy endpoint will also be assessed in the combination antiviral 
population as a secondary endpoint. All secondary 
 endpoints 
will be assessed in both the supportive-care-only population, and the 
combination antiviral population 
Statistical Methods: The primary efficacy analysis will be conducted using the modified intent-to-treat-
S (mITT-S) population, which is defined as all randomized subjects who received 
≥ 1 dose of study drug, have ≥ 1 positive SARS-CoV-2 result through Day 5 
(from nasopharyngeal [NP] swab samples), and who are stratified into the 
supportive-care-only population.  
The primary efficacy objective of this study is to evaluate the efficacy of BEM 
based on the proportion of patients who are hospitalized for any cause or who died 
due to any cause through Day 29 in the supportive-care-only population. This 
proportion of patients will be compared between the BEM and placebo arms using 
a Cochran-Mantel-Haenszel (CMH) test adjusted for the stratification factors of 
age and region. The CMH p-value and estimated common risk difference, odds 
ratio and relative risk, along with the corresponding 95% confidence intervals 
(CIs) for these estimates, will be presented. 
The primary estimand will be the difference in the proportion of all-cause 
hospitalization and all-cause mortality between BEM-treated and placebo-treated 
subjects, regardless of adherence to study drug and subsequent interventions, in 
non-hospitalized COVID-19 patients whose initial course of treatment was 
supportive care only. Intercurrent events are those that occur after treatment 
initiation and either preclude observation of the variable or affect its 
interpretation. For the intercurrent events of rescue (eg intervention with 
remdesivir) and concomitant COVID-19 medications, a treatment policy approach 
will be taken, whereby use of rescue and concomitant medications will be ignored, 
and observations collected after they are administered to the patient will be used. 
In addition, patients will be followed, assessed, and analyzed irrespective of their 
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completion of the course of the study treatment. The analysis will be performed 
based on observed data, and the following measures will be used to reduce 
missing hospitalization/death data: electronic Case Report Forms (eCRFs) 
capturing clinical information that may be indicative of hospitalization will be 
reviewed to mitigate the risk of unreported hospitalizations, and study staff may 
use a public information source to obtain information about survival status if a 
patient withdraws from the study. 
The primary efficacy endpoint will also be assessed in the combination antiviral 
population as a secondary endpoint. . Other secondary efficacy endpoints will be 
analyzed using methods similar to those specified for the primary efficacy 
endpoint.  Data handling, analysis populations, and specification of statistical 
testing for secondary efficacy endpoints, with methods used to control overall type 
I error, will be detailed in the SAP. Statistical analyses of exploratory efficacy 
endpoints, and any exploratory subgroup analyses will be detailed in the SAP 
An interim futility analysis and an interim efficacy/futility analysis are planned 
after 30% and 65% of subjects in the supportive-care-only population respectively 
are enrolled and have completed the follow-up period (Day 29). Testing will 
employ alpha spending and non-binding beta spending, both according to Lan-
Demets approximation of O’Brien Fleming method.  
The study is powered to detect a true 60% reduction in the hospitalization and all-
cause mortality rate with BEM as compared to placebo. With 2100 evaluable 
supportive-care-only subjects and interim analyses at 30% and 65%, there is 90% 
power if the true rate in the placebo arm is 4% (corresponding to an absolute 
difference of 2.4% in rate) and at least 80% power if the true rate in the placebo 
arm is 3% (corresponding to an absolute difference of 1.8%).  Sample size was 
calculated using SAS (version 9.4) for a 2-sample proportion Chi-square test. 
Considering a group sequential design with 2 interim analyses and O’Brien-
Fleming spending for both alpha (0.025) and beta (0.1), the total sample size was 
inflated by a multiplier of 1.055 to arrive at a target sample size of 2100 subjects 
in the supportive-care-only population.  Assuming ~95% of randomized subjects 
in the supportive-care-only population will meet the criteria for inclusion in the 
mITT-S population , the study targets total enrollment of 2210 subjects in the 
supportive-care-only population. Planned enrollment in the combination antiviral 
arm will be up to 300 subjects. Therefore, the total planned sample size will be 
2510 subjects. 
Treatment comparisons and summaries for frequency/proportion secondary 
endpoints will be similar to those specified for the primary endpoint. Specification 
of statistical testing for secondary endpoints, with methods used to control overall 
type I error, will be specified in the SAP. 
Time-to-event endpoints will be analyzed using Kaplan-Meier methods for 
estimation and log-rank test for treatment comparison. 


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LIST OF ABBREVIATIONS 
 
Term 
Definition 
AE(s) 
Adverse event(s) 
AIDS 
Acquired immunodeficiency syndrome 
ALT 
Alanine aminotransferase 
AUC 
Area under the curve 
AST 
Aspartate aminotransferase 
AT-527 
Bemnifosbuvir hemisulfate; BEM 
BAL 
Bronchoalveolar lavage fluid 
BEM 
Bemnifosbuvir hemisulfate 
BID 
Bis in die; twice daily 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CK 
Creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CoV 
Coronaviruses 
CRO 
Contract research organization 
DAIDS 
Division of AIDS 
DDI 
Drug-drug interactions 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EC90 
90% effective concentration 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic Data Capture 
ER 
Emergency room 
ET 
Early termination 
EU 
European Union 
EUA 
Emergency use authorization 
EUL 
Emergency use listing procedure 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practices 


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GI 
Gastrointestinal 
HCV 
Hepatitis C virus 
HAE 
Human airway epithelia 
HBV 
Hepatitis B virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IV 
Intravenous 
mAb 
Monoclonal Antibody (ies) 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MERS 
Middle East Respiratory Syndrome 
mITT 
Modified intention to treat 
mITTi 
Modified intention to treat infected 
mITT-S 
Modified intention to treat safety 
NiRAN 
Nidovirus-RdRP-associated nucleotidyl transferase 
NP 
Nasopharyngeal 
NSAID 
Non-steroidal anti-inflammatory drug 
Nsp12 
Non-structural protein 12 
P-gp 
P-glycoprotein 
PaO2 
Partial pressure of oxygen 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
qPCR 
Quantitative polymerase chain reaction 
RdRp 
RNA-dependent RNA polymerase 
RNA 
Ribonucleic acid 
ROW 
Rest of world 
RSV 
Respiratory syncytial virus 
RT-PCR 
Reverse transcription polymerase chain reaction 
RT-qPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2 


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SOC 
System organ class 
SOP 
Standard Operating Procedure 
SpO2 
Blood oxygen saturation 
TNR 
Tumor necrosis factor 
ULN 
Upper limit normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 


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Principal Investigator PROTOCOL APPROVAL 
Protocol Number: AT-03A-017 
 
TITLE:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19 
I have read this study protocol and agree that it contains all necessary information required to 
conduct this study. I agree to conduct the study according to this protocol and in accordance with 
Good Clinical Practices and the applicable regulatory requirements: 
 
 
 
_____________________________ 
____________________ 
Signature 
Date (dd-mmm-yyyy) 
Principal Investigator 
 
 
 
_____________________________ 
 
Printed Name  
Principal Investigator 


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1. 
INTRODUCTION 
1.1. 
Background on COVID-19 
Coronaviruses (CoV) are positive-sense, single-stranded RNA viruses, named for the crown-like 
appearance of their spike glycoproteins on the virus envelope. They are a family of viruses that 
cause illnesses ranging from the common cold to more severe diseases such as Middle East 
Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). An epidemic 
of cases with unexplained lower respiratory tract infections was first detected in Wuhan, the 
largest metropolitan area in China’s Hubei province, and was reported to the World Health 
Organization (WHO) Country Office in China on 31-Dec-2019. This coronavirus disease 2019 
(COVID-19) is caused by a novel coronavirus strain called SARS coronavirus-2 (SARS-CoV-2). 
The WHO subsequently declared a pandemic on 11-Mar-2020. As of May 20, 2022, over 
526 million cases of COVID-19 were reported worldwide, with over 6 million deaths; as of 07 
June 2023, over 767 million cases were reported worldwide with over 6.9 million deaths 
(WHO Dashboard).   
Infection with SARS-CoV-2 may be asymptomatic or it may cause a wide spectrum of illnesses, 
ranging from a mild upper respiratory tract infection to severe life-threatening sepsis and 
multiorgan failure (Wiersinga et al. 2020). Commonly reported symptoms include fever, cough, 
shortness of breath, loss of taste or smell, sore throat, fatigue, headaches, muscle aches, and 
gastrointestinal disturbance. Symptoms are typically thought to last 2 to 3 weeks, but many 
patients continue to experience symptoms for many weeks or develop new symptoms, which is 
now recognized as the post-acute COVID-19 syndrome, also called Long COVID (NIHR 2020). 
COVID-19 affects people of all age; however, people who are elderly or have certain underlying 
medical conditions (eg obesity, diabetes, chronic heart, lung and kidney disease, and cancer; and 
the immunocompromised) are at increased risk of mortality and poor outcomes  
(Carfi et al. 2020; CDC 2022; ) and therefore have the greatest unmet need. 
Prevention and control of the disease have focused on public health measures to slow 
transmission, such as social distancing, the use of face masks, national or regional lockdowns, 
and vaccination. The first of several effective COVID-19 vaccines was authorized in December 
2020. However, despite large multi-national vaccination campaigns, as of July 2022, 63% of the 
global population have been fully vaccinated with rates <40% in many low-income countries; as 
of March 2023, 67% of the global population have been fully vaccinated with vaccination rates 
in low-income countries still <40% (New York Times Vaccination Tracker). Furthermore, the 
durability of response after vaccination is not well understood, and there are known  
breakthrough infections, including among fully vaccinated individuals, partly driven by the 
emergence of SARS-CoV-2 variants (Hacisuleyman et al. 2021). COVID-19 vaccines may 
provide insufficient or incomplete protection due to waning antibody responses post-vaccination. 
Coupled with the on-going risk of emerging viral variants, the need for additional treatment 
options is paramount. Additionally, there remains a subset of the population who may not 
respond to or are ineligible for the available vaccines, have a contraindication to vaccination, or 
refuse to be vaccinated. 
Although access and approvals vary by region, there are a number of therapeutic treatment 
options for non-hospitalized COVID-19 patients with mild to moderate disease who are at high 


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risk of disease progression. Depending on the country, Emergency Use Authorization (EUA) or 
approvals may be available for some of these options, including nirmatrelvir/ritonavir, 
remdesivir, and molnupiravir. However, there are limitations with all of these compounds, 
highlighting the need for the continued development of additional novel therapeutics to add to 
the COVID-19 therapeutic arsenal.  
While the efficacy rates for nirmatrelvir/ritonavir are high in high-risk unvaccinated patients 
(86% reduction in hospitalization/death [Paxlovid. Prescribing Information 2023]), the 
nirmatrelvir component of nirmatrelvir/ritonavir requires boosting with ritonavir, resulting in 
significant drug-drug interactions (DDIs). As high-risk patients are likely to be on multiple 
concomitant medications, this DDI liability has the potential to significantly limit or at least 
complicate nirmatrelvir/ritonavir’s use in the very population for which it is indicated. Before 
prescribing ritonavir-boosted nirmatrelvir, concomitant medications need to be closely reviewed 
and potentially managed to prevent serious or life-threatening drug toxicities. Prescribers need to 
also consider expert consultation, especially for patients receiving highly specialized therapies or 
drugs prone to concentration-dependent toxicities, such as certain anticonvulsant, anticoagulant, 
antiarrhythmic, chemotherapeutic, neuropsychiatric, and immunosuppressant drugs. Cases of 
relapse of symptomatic SARS-CoV-2 infection following suppression with nirmatrelvir and 
ritonavir have also been reported (Charness et al case report 2022). As more data are gathered in 
larger populations of patients, it will be important to understand the true incidence and etiology 
of these relapses in the real-world setting.  In addition, the efficacy of nirmatrelvir/ritonavir is 
decreased in high-risk vaccinated patients (57% reduction in hospitalization/death) as well as 
standard risk patients (51% reduction in hospitalization/death) [Pfizer press release 2022]). 
Similar high efficacy rates were observed with remdesivir (87% reduction in 
hospitalization/death in high-risk unvaccinated patients). However, remdesivir must be 
administered intravenously (IV), making it logistically complicated to treat large populations of 
outpatients who may not have immediate access to dedicated specialized health care facilities 
with trained health care providers prepared to administer parenteral medications. 
Molnupiravir is an orally administered nucleoside analog but has lower efficacy than the 
preferred treatment options (30% reduction in hospitalization/death in high-risk unvaccinated 
patients). As a mutagenic ribonucleoside agent, there is a theoretical risk that molnupiravir will 
be metabolized by the human host cell and incorporated into the host DNA, leading to mutations. 
Molnupiravir is not recommended for use in pregnant patients because fetal toxicity has been 
reported in animal studies. Also, effective contraception must be used during and following 
treatment with molnupiravir. In addition, there have been concerns about the potential effects of 
molnupiravir on SARS-CoV-2 mutation rates. As a result of the above, its use is restricted to 
only when alternative treatment options are not accessible or clinically appropriate  
(Lagevrio EUA 2022).    
As the effectiveness of the anti-SARS-CoV-2 monoclonal antibody (mAb) therapies varies 
significantly depending on the circulating variant, the role of each anti-SARS-CoV-2 mAb in the 
treatment of COVID-19 is dynamic and constantly changing. The use of mAbs is currently 
limited as the high frequency of circulating SARS-CoV-2 variants are not susceptible to the 
available mAbs. Like remdesivir, mAbs must also be administered intravenously, making it 
logistically complicated to treat large populations of outpatients who may not have immediate 


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access to dedicated specialized health care facilities with trained health care providers prepared 
to administer parenteral medications and monitor for infusion reactions.   
Additional well-tolerated, highly efficacious, more convenient oral, non-mutagenic direct-acting 
antivirals with a low DDI potential are urgently needed in high-risk patients. 
1.2. 
Background on Bemnifosbuvir  
Bemnifosbuvir (AT-527; BEM) is a unique, 6-modified purine nucleotide prodrug discovered by 
Atea Pharmaceuticals Inc. and does not have a marketing authorization.  In laboratory studies, 
BEM potently inhibits the RNA-polymerase of several single-stranded RNA viruses. BEM is 
converted to its active intracellular triphosphate form (AT-9010) through a series of intermediate 
metabolites. AT-9010 binds to the active sites of both RNA-dependent RNA polymerase (RdRp) 
and nidovirus RdRp-associated nucleotidyl transferase (NiRAN) domains of non-structural 
protein 12 (nsp12), blocking their respective activities and potently inhibiting SARS-CoV-2 
replication via a unique dual mode of action. BEM has demonstrated sub-micromolar potency 
against a range of coronaviruses, including SARS-CoV-2 (mean 90% effective concentration 
[EC90] = 0.5 µM). BEM maintains potency in vitro against all tested SARS-CoV-2 variants of 
concern, including Omicron (BA.1, BA.2, BA.4, BA.5 and XBB). 
Prior to COVID-19, clinical development for BEM was first initiated for the treatment of chronic 
hepatitis C virus (HCV) infection. Safety and pharmacokinetic (PK) data (at doses up to 550 mg 
once daily for up to 12 weeks) from two completed studies within the HCV program (AT-01B-
001 and AT-01B-002) supported the clinical evaluation of BEM for COVID-19 at the outset of 
the pandemic. 
As part of an accelerated global clinical development plan in COVID-19, the Phase 2 virology 
study (WV43042 [MOONSONG]) and the Phase 3 study (CV43043 [MORNINGSKY]) were 
started in parallel at the end of 2020/beginning of 2021. The CV43043 study was initiated with a 
550 mg twice daily (BID) dose of BEM, which was predicted to be the effective dose based on 
available in vitro antiviral activity data, tissue distribution data in animals, and human PK data 
from healthy subjects and the HCV clinical program. The Phase 2 virology study WV43042 
being conducted in parallel was intended to be supportive of the selected dose in CV43043. The 
initial Phase 3 program objective was to demonstrate alleviation/improvement of COVID-19 
symptoms in broad outpatient populations that included both high-risk patients and standard-risk 
patients (without risk factors). Hospitalization and death were secondary endpoints in CV43043. 
Of note, the CV43043 study was terminated due to program and operational decisions but there 
were no safety concerns at the time of discontinuation.  
Data from the CV43043 study are available. The encouraging results (described below) support 
the current Phase 3 study (AT-03A-017). 
1.2.1. 
Summary of Results from the Phase 2 and Phase 3 COVID-19 Studies 
The Phase 3 study (CV43043, MORNINGSKY) was a randomized, placebo-controlled study in 
non-hospitalized adult and adolescent patients with mild or moderate COVID-19 who were at 
high risk or standard risk for disease progression. The study also allowed vaccinated patients to 
be enrolled. Patients were randomized (2:1) to receive 550 mg BEM or placebo BID for 5 days. 
The primary endpoint was time to alleviation/improvement of COVID-19 symptoms. Secondary 


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endpoints included hospitalization, all-cause mortality and change in viral load. At the time of 
discontinuation, 216 patients had been randomized (2:1; active:placebo), with 207 patients 
included in the efficacy evaluable population. The study enrolled a broad outpatient population, 
with 47% who were high risk, 28% who were vaccinated, and 56% who were seropositive at 
baseline. Because the study was prematurely discontinued, no formal statistical comparisons 
were made and results are presented descriptively. Although the primary endpoint of symptoms 
alleviation or improvement was not met, a lower proportion of patients required hospitalization 
for COVID-19 (secondary endpoint) in the BEM arm (2.9%; 4/137 patients) compared to the 
placebo arm (10%; 7/70 patients). This represents a 71% reduction in hospitalization in patients 
who received BEM. This clinical observation favoring the BEM arm was consistent for the 
clinical outcome secondary efficacy endpoints, including COVID-19 related medically attended 
visits (10.2% vs 14.3%; BEM vs placebo), COVID-19 related complications (4.4% vs 10.0%) 
and post-treatment infections (9.5% vs 14.3%). There were no deaths in the study. There was no 
meaningful difference in the change from baseline in viral load between the BEM arm and the 
placebo arm. In addition, the safety and tolerability of the 550 mg BID dose was generally 
comparable to placebo. There were no drug-related serious adverse events (SAEs) reported, and 
proportions of patients with adverse events (AEs) leading to study drug discontinuation were low 
(2.8% in the BEM arm vs 7.0% in the placebo arm). Overall, gastrointestinal (GI) AEs were 
11.3% in the BEM arm vs. 9.9% in the placebo arm. There were more drug-related GI AEs 
(nausea, diarrhea, abdominal discomfort/pain) in the BEM arm (9.2%) compared to placebo 
(1.4%), but all were low grade (mild/moderate) and none resulted in treatment discontinuation. 
There was no reported vomiting in the BEM arm.   
Although CV43043 was prematurely discontinued and did not meet the primary endpoint of 
symptom alleviation, the positive signal observed in hospitalization/deaths is the most clinically 
important and relevant finding to support the Phase 3 AT-03A-017 study. Considering the 71% 
reduction in hospitalization with BEM was observed in a broad patient population that included 
vaccinated and standard risk patients, this outcome compares favorably to the rates reported in 
Phase 3 studies with other oral direct acting antivirals. These other studies enrolled mainly high 
risk, unvaccinated patients (molnupiravir with a 30% risk reduction; nirmatrelvir/ritonavir with a 
86% risk reduction [Paxlovid. Prescribing Information 2023, Lagevrio EUA 2022]). Efficacy 
with nirmatrelvir/ritonavir was lower in high-risk vaccinated patients (57% risk reduction) and 
standard risk patients (51% risk reduction) [Pfizer press release 2022].  Although selected as the 
primary endpoint for the CV43043 study, symptom-based endpoints for COVID-19 will be 
difficult to achieve considering the variability of presentation across patients, impact of differing 
and evolving SARS-CoV-2 variants on symptoms, and the lack of validated tools to measure 
symptoms.   
Across the BEM program there have been inconsistent trends with virology data. Despite the 
observed clinical benefit favoring the BEM arm in the CV43043 study, there was no meaningful 
difference in nasopharyngeal viral load between the BEM arm and the placebo arm in this study. 
This lack of correlation is not well understood but is not unique to BEM. Similar findings have 
been well documented in studies with remdesivir, a United States Food and Drug Administration 
(US FDA)-approved intravenously administered nucleoside analogue. In the Phase 2 Pinetree 
study, an 87% reduction in hospitalization/death was observed in high-risk outpatients receiving 
remdesivir with no impact on viral load (Gottlieb et al 2022)
 
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In addition to CV43043, two Phase 2 treatment studies have been conducted, one in an outpatient 
population (WV43042, MOONSONG) and one in hospitalized patients with moderate 
COVID-19 (AT-03A-001).   
WV43042 was a Phase 2 virology dose-ranging study designed to evaluate the antiviral activity, 
safety, PK, and efficacy of BEM in non-hospitalized adult patients with mild or moderate 
COVID-19 who were at high risk or standard risk. The doses evaluated were 550 mg BID and 
1100 mg BID for 5 days. The study did not meet its primary virology endpoint of reduction in 
the amount of SARS-CoV-2 virus RNA by reverse transcriptase polymerase chain reaction (RT-
PCR) in the full study population which included a heterogeneous group of low-risk patients who 
were vaccinated or seropositive at baseline, similar to the CV43043 study population. 
Nevertheless, there were positive virology trends observed in exploratory subgroups of patients 
at high risk (SARS-CoV-2 virus RNA reductions by RT-PCR of ~0.5 log10 at Day 7 with BEM 
[550 mg BID and 1100 mg BID] compared to placebo). The differences in viral load decline in 
the high-risk cohort were also observed in the infectious virus titer assay. The safety and 
tolerability of the 550 mg BID dose of BEM was generally comparable to placebo. However, 
mild to moderate nausea or vomiting led to study drug discontinuation in 16.7% of patients (5 of 
30 patients) in the 1100 mg BID arm compared to 0% in the 550 mg BID arm and 2.5% of 
patients (1 of 40 patients) in the placebo arm. 
AT-03A-001 was a prematurely discontinued Phase 2 study designed to evaluate the safety, 
antiviral activity, and efficacy of BEM in high-risk adult hospitalized patients with moderate 
COVID-19. Part A of the study evaluated a dose of 550 mg BID for 5 days. Part B was intended 
to evaluate a dose of 1100 mg BID for 5 days. As with CV43043, this study was also 
prematurely discontinued due to the changing COVID-19 landscape as management and 
standard of care for hospitalized COVID-19 patients had adapted making continued enrollment 
in a placebo-controlled trial no longer feasible in a hospitalized population. Only 2 subjects had 
been enrolled in Part B and both received placebo. Although low background disease-
progression rates precluded achievement of the primary clinical endpoint (protocol-defined 
progressive respiratory insufficiency), there were numerical trends which directionally favored 
the BEM 550 mg BID arm. In Part A, the rates of progressive respiratory insufficiency were 
7.3% with BEM 550 mg BID (3 of 41 subjects) compared to 10% on placebo (4 of 40 subjects). 
In addition, the rates of all-cause mortality were 0% with BEM 550 mg BID (0 of 41 subjects) 
compared to 5% on placebo (2 of 40 subjects). In Part B, a third death occurred in a subject 
receiving placebo. For the virology endpoints, there were encouraging and consistent trends, 
similar to those observed in the high-risk subset in the Phase 2 outpatient study. At Day 2, 
patients receiving BEM 550 mg BID experienced a 0.6 log10 greater mean reduction from 
baseline viral load as compared to placebo, and a sustained difference in viral load reduction was 
maintained through Day 8. The safety and tolerability of the 550 mg BID dose of BEM was 
generally comparable to placebo.   
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1.2.2. 
Supportive Results from Clinical Pharmacology and Non-Clinical Studies 
Supporting data from a bronchoalveolar lavage (BAL) study in healthy subjects (AT-03A-007) 
provided confidence that BEM is being efficiently delivered to the lungs (epithelial lining fluid), 
the primary site of SARS-CoV-2 infection. In this study, it was confirmed that mean levels of 
BEM above the EC90 are achieved in the lungs at 4 hours after dosing with BEM 550 mg BID, 
with levels of AT-273 that approximate the EC90 at 12 hours. 
Additionally, the clinical pharmacology of BEM has been investigated in multiple dedicated 
Phase 1 clinical pharmacology studies. The DDI studies conducted confirm BEM’s minimal 
potential for drug interactions. At doses higher than 550 mg BID, including 825 mg BID and 
1100 mg BID, mild to moderate GI-related AEs, specifically nausea and vomiting, and 
abdominal pain were more frequently reported in healthy subjects (consistent with data from the 
1100 mg BID arm of the Phase 2 WV43042 study).   
In support of the clinical program, the nonclinical safety profile of BEM was assessed in a 
comprehensive non-clinical safety program consistent with the requirements set out in the 
International Conference on Harmonisation (ICH) M3 (R2) guideline and the ICHM3(R2) Q&A 
(R2) document (ICH 2009; ICH 2012). The intended clinical route of administration (ie oral 
administration) was used. Rats and monkeys were the selected species for the toxicology and 
safety pharmacology studies. Both species, as well as the rabbit used in reproductive toxicity 
studies, convert the prodrug to the active metabolite similarly to humans. Additionally, all 
metabolites observed in humans were also observed in the preclinical species. BEM is non-
mutagenic, has no effect on reproductive performance and is non-teratogenic. 
Additional details can be found in the BEM Investigator’s Brochure.  
1.3. 
Rationale for the Dose Selection 
The dose regimen selected for the current Phase 3 study is 550 mg (2 x275 mg tablets) BID for 5 
days, as this dose has shown clinical benefit in CV43043. This dose and duration were well 
tolerated and resulted in a 71% reduction in hospitalization in the prematurely discontinued 
Phase 3 study CV43043 in a broad outpatient population, including standard risk and vaccinated 
patients. Available PK data from this study showed a mean trough of 149.8 ng/mL, right at the 
targeted 150 ng/mL (based on in vitro EC90).   
Conceptually, higher doses are expected to achieve higher drug exposure and therefore better 
clinical outcomes. For BEM, doses beyond 550 mg BID were evaluated in healthy subjects and 
patients with COVID-19. While, as expected, these studies demonstrated higher AT-273 trough 
levels of approximately 200 ng/mL with 825 mg BID and 1100 mg BID, these doses were also 
associated with increased incidences of GI related AEs including vomiting that were not 
observed in patients with the 550 mg BID regimen. A large phase 1 study (AT-03A-015) was 
conducted to further investigate the GI AEs for the 825 mg BID regimen. GI AEs including 
vomiting, while occurring at a lower rate compared with the 1100 mg BID dose (AT-03A-002 
cohorts 4 and 5, WV43042 Part B), were still present 
 relative to 
placebo regardless of meal status. 
The 550 mg BID dose was also the initial dose regimen selected for the COVID-19 program 
based on in vitro data, tissue distribution data in non-human primates, and modeling data from 
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the completed studies in the HCV program. The 550 mg BID regimen was predicted, using 
plasma AT-273 as a surrogate, to rapidly achieve and maintain a mean intracellular level of the 
active triphosphate metabolite AT-9010 above the in vitro EC90 (0.5 uM or 150 ng/mL of AT-
273 eq.) of the drug in inhibiting SARS-CoV-2 replication in human airway epithelial (HAE) 
cells. 
Preliminary PK results from the BAL study (AT-03A-007) in healthy subjects demonstrated that 
antiviral concentrations of AT-273 with the 550 mg BID regimen of BEM were achieved in 
epithelial lining fluid ELF in the human lung, the primary target of the SARS-CoV-2 virus.  
Cumulative PK results from studies in healthy subjects (AT-03A-002) and patients with 
COVID-19 (AT-03A-001 and WV43042 Part A) have subsequently confirmed that mean plasma 
concentrations of AT-273 exceeded shortly after dose initiation and maintained mostly above the 
target of 150 ng/mL during the dosing period of 5 days for the 550 mg BID regimen. 
At the 550 mg BID dose, the safety and tolerability of BEM has been generally comparable to 
placebo. There have been no drug-related SAEs in the program and non-serious AEs have been 
generally mild to moderate in intensity. No GI-related premature treatment discontinuations have 
occurred at this dose level in either of the Phase 2 or Phase 3 studies. Overall, over 600 human 
subjects have been exposed to BEM across both COVID-19 and HCV development programs. 
Of these, over 350 human subjects have received BEM at or above the selected dose and 
duration for the Phase 3 study. 
1.4. 
Rationale for Study Population 
The COVID-19 landscape is constantly changing and unpredictable, making design of clinical 
studies challenging. Emerging and evolving SARS-COV-2 variants, waxing and waning of 
vaccine efficacy over time, differing rates of vaccine booster uptake across populations, differing 
levels of population immunity, and differing standards of care across geographies are only a few 
factors that will impact study endpoints and baseline rates of hospitalization and death. Thus, this 
protocol targets a Phase 3 study population of subjects who are at the highest risk of clinical 
progression. Age is the strongest risk factor for severe COVID-19 outcomes. As of May 2023, 
75% of deaths in the US ( >970,000 deaths) occurred in patients  ≥65 years of age  
(CDC Demographic Trends 2023). A consistent trend was observed with BEM in the CV43043 
study, in that the hospitalization rates were higher in older patients.  In the control arm, the 
hospitalization rate for subjects > 40 years old was 15.4%, compared to 3.2% for those 
≤ 40 years. Further, there was an 82% reduction in risk of hospitalization in the subgroup of 
patients ≥40 years treated with BEM 550 mg BID. Because age is such a strong risk factor, 
differing age thresholds are defined in the current protocol, depending on whether patients have 
concurrent comorbid conditions. The Phase 3 population for this study will include older patients 
(≥ 70 years or ≥ 55 years with one risk factor or 50 to 54 years with two risk factors) or those 
≥ 18 years with other comorbidities (immunocompromised, Down syndrome, sickle cell disease, 
dementia, Parkinson’s disease, or care home residents), regardless of vaccination status. This 
represents a population of high-risk patients who are in most need of effective COVID-19 
treatment options and also are at increased risk of hospitalization/death. Eligibility criteria are 
generally consistent with the priority list of patients who are at the highest risk of clinical 
progression according to the NIH COVID-19 Treatment Guidelines as well as those listed by the 
CDC (NIH 2023, CDC Hospitalization and Death by Age 2023).  Studying this enriched high-


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risk population is necessary given the relatively low hospitalization/death rate with the current 
circulating variants. 
Enrollment of 24 high-risk adolescents (≥ 12 years to 17 years) will be allowed after the planned 
interim analysis for which 65% of the supportive-care-only stratum completed the follow-up 
period (Day 29). A DSMB recommendation that the study continue at this interim analysis point 
will trigger enrollment of adolescents.  Similar safety and PK characteristics are expected for 
adolescents compared with adults.  
 
1.5. 
Rationale for Study Design and Allowance of Standard of Care 
With the rising COVID-19 cases due to the Omicron variant, more COVID-19 therapies will be 
required, either as monotherapy or potentially as combination therapy, if resistance and relapse 
become an issue with current therapies. In the targeted Phase 3 patient population of high-risk 
patients, SOC for COVID-19 greatly varies globally. While access to antiviral therapies may not 
be an issue in some countries, their use or access may be limited in other countries. Patients 
enrolled in the trial will be stratified by SOC type at the time of randomization resulting in two 
separate strata: those receiving antivirals in addition to study drug (referred to as the 
“combination antiviral stratum”) and those receiving supportive-care-only (no treatments with 
activity against SARS-CoV-2 except study drug, referred to as the “supportive-care-only 
stratum”). Functionally, this will result in two distinct populations, one which will allow 
assessment of BEM as a monotherapy and another that will allow assessment of BEM in 
combination with other compatible antivirals. It is estimated that the supportive-care-only 
population will comprise > 88% of the patients enrolled in this global trial. Thus, the primary 
endpoint, proportion of subjects in the supportive-care-only population who are hospitalized for 
any cause or who died due to any cause through Day 29, would support a BEM monotherapy 
indication in this population.  
While the primary objective of the study is to demonstrate efficacy in the supportive-care-only 
stratum (BEM monotherapy), the “combination antiviral stratum” could result in valuable 
supporting data on the efficacy, antiviral activity, and safety of BEM used in combination with 
other antiviral drugs. With an expected ~12% of the patients expected to enroll in this stratum, 
these data collected in parallel could provide the necessary proof-of-concept, hypothesis-
generating data to support further evaluations of direct-acting antiviral combination therapy in 
the targeted population. Considering the speed with which novel SARS-CoV-2 variants are 
arising and the lack of ability to predict whether currently available therapies will continue to 
remain effective or whether resistance will develop over time, the study design proactively 
allows the evaluation of combination therapy
 
 
 
  
This study was designed based on the clinical landscape of COVID-19; no patient groups were 
consulted in the design of this study.   
CCI


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1.6. 
Rationale for Primary Endpoint 
Rates of hospitalization/death remain the most clinically important and objective endpoints for 
COVID-19 in the high-risk patient population. One of the most critical goals for the treatment of 
COVID-19 with a direct-acting antiviral is to reduce the rate of hospitalization or death 
associated with disease progression via inhibition of SARS-CoV-2 viral replication at the 
primary site of infection, presumably, the lung. Viral load reduction in nasopharyngeal (NP) 
swab by reverse transcription quantitative polymerase chain reaction (RT-qPCR) is commonly 
regarded as a measure of clinical antiviral activity, which is thought to translate into the 
aforementioned clinical benefits. While this concept has been successful in some cases including 
the protease inhibitors nirmatrelvir/ritonavir and ensitrelvir, it has not been the case for the 
nucleotide drug remdesivir. In non-hospitalized patients with COVID-19, remdesivir was able to 
reduce the risk for hospitalization or death by 87% while showing no difference in viral load 
reduction compared with placebo (Gottlieb et al., 2022). While the reason for the discordance 
between clinical antiviral activity measured in NP swab and clinical efficacy/benefits remains to 
be elucidated, it raises the question on the reliability of using changes in NP swab viral load as a 
measure of clinical antiviral activity during clinical development of a nucleotide antiviral for 
SARS-CoV-2. Furthermore, the US FDA Guidance for Industry COVID-19: Developing Drugs 
and Biological Products for Treatment or Prevention (February 2021) acknowledges the lack of 
established predictive relationship between the magnitude and timing of viral load reductions and 
the extent of clinical benefit.  
The clinical development of BEM for COVID-19, a nucleotide analog belonging to the same 
class as remdesivir, has largely been focused on demonstrating NP swab viral load reduction. 
However, virology results have been variable. In the AT-03A-001 phase 2 study in hospitalized 
patients with moderate COVID-19 and risk factors for poor outcomes, BEM 550 mg BID x 
5 days rapidly reduced SARS-CoV-2 viral load with a 0.6 log10 greater mean reduction from 
baseline as compared to placebo on day 2. A difference in viral load reduction was maintained 
through Day 8. In the WV43042 phase 2 study in non-hospitalized patients with mild or 
moderate COVID-19, in the general population overall, BEM 550 mg BID and 1100 mg BID x 
5 days did not achieve a statistically significant difference in NP swab viral load reduction from 
baseline as compared with placebo, although subgroup analyses showed a numerically larger 
viral load reduction in BEM treated patients with risk factors compared with placebo. Recent 
data from the prematurely discontinued CV43043 study in patients with mild or moderate 
COVID-19 seemed partially in agreement with WV43042 in that, in the overall population, BEM 
550 BID did not show any difference in NP swab viral load reduction from baseline as compared 
with placebo. Unlike WV43042, CV43043 did not achieve numerically better viral response in 
patients with risk factors either. Importantly, BEM 550 mg BID x 5 days substantially reduced 
the risk of hospitalization by 71% as compared with placebo, in patients without or with risk 
factors. These analyses support further clinical evaluation of the efficacy of BEM in reducing the 
rate of hospitalization or death in patients with COVID-19 with virologic responses as 
secondary/supportive endpoints.  
The primary endpoint will be assessed in the supportive-care-only population as the clinical 
efficacy of BEM can only be evaluated in this population without the interference of the 
potential clinical benefit provided by the combination with other antivirals. The 
hospitalization/death endpoint is proposed based on US FDA and other international health 


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authorities’ recommendations and it is most appropriate for a high-risk population such as the 
one included in this study. It has been the basis for evidence for other authorized and approved 
therapies in similar populations. As cases continue to rise very rapidly as a result of the current 
Omicron surge, it remains the most clinically important endpoint for patients, overburdened 
health care infrastructure, and public health.   
1.7. 
Benefit-Risk Assessment 
Overall, BEM was well tolerated across the entire development program. At 550 mg BID in the 
Phase 2 and CV43043 studies, the safety profile was comparable to placebo. AEs reported were 
generally mild to moderate in severity and self-limiting. Available data from the BEM clinical 
pharmacology program suggest a low DDI potential. At dose levels ≥825 mg BID, an increase in 
GI-related AEs (mostly nausea and vomiting) was observed, which were mild to moderate in 
severity. GI AEs were more frequent at the 1100 mg BID dose and resulted in early treatment 
discontinuation. SAEs were only reported in the COVID-19 Phase 2 and Phase 3 studies (none in 
Phase 1 healthy volunteer studies), assessed as not related to study treatment, and tended to 
describe progression or complications of COVID-19; SAEs resulting in death have only been 
reported in subjects receiving placebo. The clinical efficacy data at 550 mg BID from the 
truncated study CV43043 indicate a benefit in reduction of hospitalizations (71%), COVID-19 
complications, and medically attended visits. This clinical benefit was observed consistently 
across sub-analyses in several populations within the study.  
Furthermore, the nonclinical safety profile of BEM was similarly favorable, as assessed in a 
comprehensive non-clinical safety program. There were no target organs identified in 2- and 
13-week toxicity studies. BEM is non-mutagenic, has no effect on reproductive performance and 
is non-teratogenic. 
Based on the totality of the data, BEM at 550 mg BID has demonstrated a favorable benefit-risk 
profile for evaluation in patients with COVID-19. 


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2. STUDY OBJECTIVES  
The primary objective is: 
• To evaluate the efficacy of BEM compared with placebo in reducing all-cause 
hospitalization or all-cause death in COVID-19 outpatients receiving only supportive 
care. 
The secondary objectives are: 
• To evaluate the efficacy of BEM compared with placebo on: 
− COVID-19 related hospitalization or all-cause death through Day 29 
− All-cause death through Day 29 and Day 60 
− COVID-19-related complications (eg., death, hospitalization, radiologically confirmed 
pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, 
cardiac failure) through Day 29 
− COVID-19-related medically attended visits (hospitalization, emergency room (ER) visit, 
urgent care visit, physician’s office visit, or telemedicine visit) or all-cause death through 
Day 29 and Day 60 
− COVID-19 symptom relapse 
• To evaluate the antiviral activity of BEM compared with placebo on viral load rebound 
• To evaluate the safety of BEM compared with placebo 
The exploratory objectives are  
• To evaluate the efficacy of BEM compared with placebo on: 
− Alleviation or improvement of individual COVID-19 symptoms 
− Return to usual (pre-COVID-19) health 
− Requirement for post-randomization rescue therapy 
− The antiviral activity of BEM compared with placebo 
• To assess plasma concentrations of AT-511 (free base form of AT-527 [BEM]) and its 
metabolites from sparse PK sampling at steady-state  
 


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3. STUDY DESIGN 
3.1. 
General Study Design 
This Phase 3 randomized, double-blind, placebo-controlled study will be conducted in 
non-hospitalized adult subjects (≥18 years of age) with mild or moderate COVID-19 (as defined 
in inclusion criterion 3, Section 4.2) and risk factors for severe COVID-19 (as defined in 
inclusion criterion 8, Section 4.2).  
Age and comorbidities will determine a patient’s risk and eligibility (see inclusion criterion 8, 
Section 4.2). Onset of COVID-19 symptoms will have occurred ≤5 days before randomization. 
BEM 550 mg or matching placebo will be administered BID for 5 days (10 doses, with each dose 
including 2 tablets).  
Locally available SOC treatment should be initiated in parallel in addition to study drug (add-
on). SOC treatments with direct antiviral activity against SARS-CoV-2 are allowed, but should 
be initiated during screening and/or within 24 hours prior to or after randomization.  
Subjects will be randomized 1:1 (active:placebo) to one of the following arms: 
• 550 mg BEM (2 x 275-mg tablets) BID for 5 days 
• Placebo (2 tablets) BID for 5 days 
Randomization will be stratified by geographic region (North America, Europe, Asia, and rest of 
world [ROW]), age (< 65 years old vs ≥ 65 years old) and by the type of SOC which the 
investigator plans to administer in parallel at time of study drug initiation. The type of SOC 
received will be used to classify subjects into two categories: 
a. Combination antiviral stratum (subsequently referred to as the combination antiviral 
population): In addition to study drug, the subject will be initiated on a local SOC regimen 
which includes a treatment with direct SARS-CoV-2 antiviral activity. Examples include 
nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs,  
b. Supportive-care-only stratum (subsequently referred to as the supportive-care-only 
population): the SOC regimen the subject will receive does not include any treatment with 
direct SARS-CoV-2 antiviral activity. 
Although randomization is stratified by whether COVID-19 drugs with antiviral effects are 
administered, both strata allow local SOC therapies without direct antiviral effects (ie 
corticosteroids).  
Patients who require SOC treatment with a non-compatible antiviral treatment, defined as those 
with a potential DDI with BEM (eg, remdesivir), are excluded. 
For subjects who deteriorate on-study, any rescue therapy which is SOC for progression to 
severe COVID-19 is permitted. As noted in Section 5.7.5, if rescue therapy will be remdesivir, 
study drug should be discontinued before initiation of remdesivir. 
Approximately 2510 eligible subjects with COVID-19 will be enrolled, with a target of 
2210 subjects in the supportive-care-only population and up to 300 subjects in the combination 
antiviral population. The primary study endpoint (hospitalization/death) will be evaluated in the 
supportive-care-only population. 


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The primary study period is up to 30 days, including up to 1 day for screening and 29 days from 
randomization. Extended follow-up data will be collected through Day 60 for mortality and 
medically attended visit assessment. The Day 60 follow-up contact marks the end of study 
participation for each subject and the study ends when the last subject completes the Day 60 
follow-up contact. 
A schematic of the study design is presented in Figure 1. 
Figure 1: Study Design 
 
This is a global clinical trial that complies with the European Union Clinical Trial Regulations 
(EU CTR).  Results will be released to a publicly accessible web site (eg, Clinical Trial 
Information System [CTIS]) after the last European subject’s completion of the study. However, 
if the study is ongoing outside the EU as of that date, results will be released after the last 
subject’s completion date.  
 


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4. SUBJECT SELECTION 
4.1. Study Population 
Subjects must meet all the inclusion criteria and none of the exclusion criteria to be eligible for 
participation in this study. 
4.2. Inclusion Criteria 
1. Willing and able to provide informed consent.   
2. Positive SARS-CoV-2 diagnostic test (RT-PCR or validated rapid antigen test) conducted 
≤ 5 days prior to randomization. Note:  The test may be obtained locally. A documented 
historical record of positive result (RT-PCR or validated rapid antigen test) from test 
conducted ≤ 5 days prior to randomization is acceptable.   
3. Mild or moderate COVID-19 with symptom onset ≤ 5 days before randomization and at 
least one COVID-19 related symptom present at time of screening:  
• Mild COVID-19:   
− 
Symptoms of mild illness with COVID-19, which could include fever, cough, 
sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss 
of taste or smell, without shortness of breath or dyspnea   
− 
No clinical signs indicative of moderate, severe, or critical illness severity  
• Moderate COVID-19:   
− 
Symptoms of moderate illness with COVID-19, which could include any 
symptom of mild illness or shortness of breath with exertion  
− 
Clinical signs suggestive of moderate illness with COVID-19, such as respiratory 
rate ≥ 20 breaths per minute, heart rate ≥ 90 beats per minute; with saturation of 
oxygen (SpO2) > 93% on room air   
− 
No clinical signs indicative of severe or critical illness severity 
4. For females of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraception during the treatment period and 
for 30 days after the final dose of study drug.  
5. Females of childbearing potential must have a negative pregnancy test prior to initiation 
of study drug.  
6. Subject must be able to take oral tablet medications.  
7. Subject is, in the opinion of the investigator, willing and able to comply with the study 
drug regimen and all other study requirements.  
8. Subject must be high risk, defined below. 
• Age ≥70 years OR  
• Age ≥55 years with one of the following risk factors:  


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− 
Obesity (body mass index [BMI] ≥30 kg/m2)  
− 
Diabetes mellitus  
− 
Cardiovascular disease (including congenital heart disease) or hypertension (with 
at least one medication recommended or prescribed)  
− 
Chronic lung disease requiring routine therapy (eg, chronic obstructive 
pulmonary disease [COPD], moderate-to-severe asthma, interstitial lung disease, 
cystic fibrosis, pulmonary hypertension)  
OR 
• Age 50 to 54 inclusive with two of the following risk factors: 
− Obesity (body mass index [BMI] ≥30 kg/m2) 
− Diabetes mellitus 
− Cardiovascular disease (including congenital heart disease) or hypertension (with 
at least one medication recommended or prescribed) 
− Chronic lung disease requiring routine therapy (eg, chronic obstructive pulmonary 
disease [COPD], moderate-to-severe asthma, interstitial lung disease, cystic 
fibrosis, pulmonary hypertension)   
OR  
• Age ≥18 years with one of the following: 
− 
Down syndrome 
− 
Sickle cell disease 
− 
Dementia 
− 
Parkinson’s disease 
− 
Care home residents  
− 
One of the following immunocompromising conditions or immunosuppressive 
treatments:  
o On immunosuppressive regimens including chemotherapy for the treatment of 
cancer  
o Hematologic malignancy associated with poor response to COVID-19 vaccines 
(eg, CLL, non-Hodgkin lymphoma, multiple myeloma, acute leukemia) 
o Being within 2 years of a hematopoietic stem cell transplant  
o Receipt of a solid-organ transplant and on immunosuppressive therapy 
o Human immunodeficiency virus (HIV) infection (untreated) or with CD4+ T 
lymphocyte count <350 cells per cubic millimeter (mm3)  
o Moderate or severe primary immunodeficiency disorder  


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o Active treatment with an immunosuppressive medication regimen (eg, high-dose 
corticosteroids [ie, 20 mg of prednisone daily or equivalent for ≥2 weeks], 
alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, 
cancer chemotherapeutic agents that are severely immunosuppressive, anti-tumor 
necrosis factor (TNF) blockers, biologics that are immunosuppressive)  
• Enrollment of 24 high-risk adolescents (≥ 12 years to 17 years) will be allowed after 
the planned interim analysis for which 65% of the supportive-care-only stratum 
completed the follow-up period (Day 29). A DSMB recommendation that the study 
continue at this interim analysis point will trigger enrollment of adolescents.  The 
Sponsor will notify sites when enrollment of adolescent subjects is permitted. 
Note: “High-risk” subjects in this age group are identical to high-risk subjects  
≥ 18 years. 
4.3. Exclusion Criteria 
1. Female subject is pregnant or breastfeeding.  
2. Clinical signs or symptoms indicative of severe or critical COVID-19 illness, including 
any of the following:  shortness of breath at rest, respiratory rate ≥ 30 breaths per minute, 
heart rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air , partial pressure of oxygen/ 
fraction of inspired oxygen (PaO2/FiO2) <300, shock (defined by systolic blood pressure 
< 90 mm Hg or diastolic blood pressure < 60 mm Hg or requiring vasopressors), multi-
organ dysfunction/failure, respiratory distress, respiratory failure; requirement of 
endotracheal intubation, mechanical ventilation, oxygen delivered by high-flow nasal 
cannula, noninvasive positive pressure ventilation, extracorporeal membrane oxygenation 
(ECMO).   
Note: Subjects receiving chronic supplemental oxygen by nasal cannula are eligible for 
the study if there has been no increase in baseline oxygen requirement/settings. 
3. Admitted to a hospital within 90 days prior to randomization due to COVID-19 or is 
hospitalized (inpatient) for any reason at randomization.  
Note:  If local policy requires COVID-19 isolation or internment in a hospital or similar 
facility, but subjects otherwise meet criteria, this exclusion may not apply. However, 
subjects under clinical observation at a clinic/study site or hospital with plans to remain 
in that setting overnight are not study eligible. 
4. In the opinion of the investigator, is likely to experience imminent deterioration and 
require hospitalization within 24 hours. 
5. Use of other investigational drugs within 30 days prior to planned dosing, or plans to 
enroll in another clinical trial of an investigational agent while participating in the present 
study, except for unblinded protocols that don’t include direct acting antivirals for 
COVID-19 (eg, open-label oncological regimen variations or biologic studies). Note:  
Prior to enrolling subjects that are on other open-label studies, it is the site’s 
responsibility to ensure that the study criteria for that study allow for enrollment into this 
study.  


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6. Initiation or planned initiation of remdesivir for treatment of the current SARS-CoV-2 
infection. 
7. Requirement of any prohibited medications, as described in Section 5.7, including either 
hydroxychloroquine or amiodarone within 3 months prior to screening. (see rationale in 
Section 5.7.5) 
Note: Subjects who had already initiated any COVID-19 drug with antiviral effects 
intended to treat symptomatic SARS-CoV-2 infection (≥ 24 hours prior to randomization) 
will be excluded. During screening (or within 24 hours prior to or after randomization), 
locally available COVID-19 drugs with antiviral effects (including but not limited to 
nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs) will be permitted, as long as 
there are no concerns for DDIs (eg, remdesivir would not be permitted).  
8. Other known active viral or bacterial infection at the time of screening, such as influenza 
(ie, as verified by a locally available rapid flu test at screening) or respiratory syncytial 
virus (RSV).  
Note:  This exclusion does not apply to subjects with stable chronic viral infections, such 
as chronic HCV or HIV providing other eligibility criteria are met. 
9. Receiving dialysis or have severe renal impairment [ie estimated glomerular filtration 
rate (eGFR) <30 mL/min/1.73 m2 within 6 months of the screening visit, using the serum 
creatinine-based CKD-EPI formula]. Note: If the investigator suspects the subject may 
have eGFR <30 mL/min/1.73 m2, a confirmatory test should be performed at screening to 
confirm eligibility before the first dose of study drug. 
10. History of severe hepatic impairment (Child-Pugh Class C)  
11. Known allergy or hypersensitivity to components of study drug.  
12. Malabsorption syndrome or other condition that would interfere with enteral absorption.  
13. Any clinically significant medical condition or known laboratory abnormality that, in the 
opinion of the investigator, could jeopardize the safety of the subject or impact subject 
compliance or safety/efficacy observations in the study. 
One-time retests of individual screening laboratory parameters or assessments may be permitted 
in certain scenarios. Such scenarios may include lab processing error, results inconsistent with 
subject’s historical values/medical history, or other extenuating circumstances such as a recent or 
intercurrent illness potentially affecting screening laboratory results.  


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5. 
STUDY TREATMENTS 
5.1. 
Description and Handling of Study Treatments 
5.1.1. 
Test Product 
BEM will be provided by the Sponsor as 275 mg tablets (designated as formulation A2-275 mg). 
5.1.2. 
Control Product 
Matching placebo tablets for BEM will be provided by the Sponsor. 
5.1.3. 
Packaging and Labeling 
The Sponsor will be responsible for ensuring that study drugs (active and placebo) are 
manufactured in accordance with applicable Good Manufacturing Practice regulations and 
requirements. The labels for the study drug(s) will meet applicable local regulatory requirements. 
5.1.4. 
Storage and Handling 
Study drugs should be stored under the conditions described on the label. 
5.1.5. 
Background Standard of Care 
Study drug (BEM or placebo) should be administered as an “add-on” therapy to locally available 
SOC. Depending on the region, SOC may either include compatible antiviral treatments (such as 
nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs or other COVID-19 drugs with antiviral 
effects) or alternatively be deemed ‘supportive care only’ (and not include treatment with 
COVID-19 drugs with antiviral effects). Standard of care is administered at the discretion of the 
investigator, based on local practice, and includes therapies or treatments that are locally 
available to the investigator/site. SOC is not a study drug and is therefore not provided by the 
Sponsor. However, the type of background SOC that is administered must be documented and 
captured in the electronic case report form (eCRF).  
Patients who require SOC treatment with a non-compatible antiviral treatment, defined as those 
with a potential DDI with BEM (eg, remdesivir), are excluded. 
Auxiliary Medicinal Products (for EU sites) 
Compatible antiviral treatments as SOC, such as direct acting antivirals and mAbs, are 
considered auxiliary medicinal products in this study as per EU regulation No 536/2014 Article 2 
(8) and should be used in accordance with the terms of their marketing authorization. 
Nirmatrelvir/ritonavir is an example of an authorized auxiliary medicinal product. Some 
compatible antiviral treatments utilized as SOC in the combination antiviral arm of this trial 
outside of the EU may not be available in the EU; all antivirals will be administered in 
accordance with their approved local usage.   
 


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5.2. 
Method of Assigning Subjects to Treatment Groups 
A unique subject number will be assigned to each subject at screening. Once assigned, it will not 
be reassigned to another subject. Once eligibility is confirmed, subjects will then be randomly 
assigned to a treatment group (active vs. placebo) according to a randomization list, generated by 
the designated independent biostatistician. This will be through a centralized randomization 
process and eligible subjects may also receive a unique randomization number linked to a 
treatment assignment. Randomization will be stratified by geographic region (North America, 
Europe, Asia, and ROW), age (< 65 years old vs ≥ 65 years old) and by the type of SOC which 
the investigator plans to administer in parallel at time of study drug initiation (combination 
antiviral vs supportive-care-only). The primary stratification factor is the type of background 
SOC that the investigator plans to administer as this determines whether the subject is in the 
supportive-care only group (ie may be included in the primary analysis population) or the 
combination antiviral group. Within each of the primary strata, randomization is further stratified 
by geographic region (North America, Europe, Asia, and ROW) and age (<65 and ≥65). 
5.3. 
Blinding 
Study site personnel and subjects will be blinded to treatment assignment during the study. The 
Sponsor and its agents will also be blinded to treatment assignment, with the exception of 
individuals who require access to treatment assignments to fulfill their job roles during a clinical 
trial. These roles include clinical supply chain managers, any laboratory responsible for 
performing study drug PK, IxRS service provider, and Data Safety Monitoring Board (DSMB) 
members. 
Unless efficacy is demonstrated at an interim analysis, the study blind will not be broken until 
after all subjects complete the primary study period (through Day 29). 
During the study, the blind may be broken for an individual subject by the investigator only in 
emergencies or when knowledge of a subject’s treatment group is necessary for further subject 
management. Although not necessary in the case of an emergency, the investigator should 
discuss the specific case with the Sponsor prior to unblinding. The date and reason for breaking 
the blind must be recorded. 
5.4. 
Dosing and Administration 
5.4.1. 
Dispensing 
Designated site staff will dispense the blinded study drugs (active or placebo) to each subject at 
the Day 1 visit. 
5.4.2. 
Administration Instructions 
Study drug dosing should occur on the same day as randomization.  Subjects will self-administer 
BEM 550 mg (2 x 275 mg tablets) or matching placebo (2 tablets) orally BID on Days 1-5. Each 
dose consists of 2 tablets. On each dosing day, 2 tablets will be taken for the morning dose and 2 
tablets will be taken for the evening dose. The total treatment course consists for a total of 
10 doses over 5 days (20 tablets total).  


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BEM (or matching placebo) should be taken orally approximately 12 hours apart, with a 
minimum of 6 hours apart. If the first study dose is taken prior to 16:00 on Day 1, the next dose 
should be taken in the evening of the same day (ie prior to midnight on the same calendar day 
with a minimum of 6 hours between doses). For these subjects, the final (tenth) dose will be 
taken in the evening of Day 5. However, if the first study dose is taken after 16:00 on Day 1, the 
next dose should be taken in the morning of Day 2. For these subjects, the final (tenth) dose will 
be taken on the morning of Day 6. 
BEM (or placebo) tablets should be swallowed whole with a glass of water and should not be 
chewed, cut, crushed, or dissolved. 
If a dose of BEM (or placebo) is missed (ie, not taken within 6 hours after the scheduled dosing 
time), the subject should resume dosing with the next scheduled dose. Subjects should never 
double the next dose after a missed dose. In this scenario where a dose is missed, the subject 
should still complete the full course of 10 doses, making up for the missed dose at the end of the 
dosing period (as opposed to only taking 9 doses). If a subject vomits after taking a dose, a 
replacement tablet should not be taken, and dosing should resume with the next scheduled dose. 
Subjects will be instructed to bring their bottles of study drug to each study visit. 
BEM can be taken with or without food. 
5.4.3. 
Treatment Compliance 
Subjects will be provided with a dosing diary, to record the times at which they self-administer 
study drug. The dosing diary will be used to assess treatment compliance.  Subjects who have 
difficulty in using the diary (eg, blind, illiterate, physical limitations, unfamiliar with technology) 
can obtain assistance from close contacts (eg family members or friends) in recording responses 
but should not obtain advice or help from others with constructing responses. 
5.5. 
Study Drug Accountability 
Complete and accurate records of all study drugs must be kept. These include acknowledgment 
of receipt of each shipment of study product, subject dispensing records, and records of returned 
or destroyed study product. 
At the end of the study, all unused study drugs and containers will be returned to the Sponsor (or 
designee) or destroyed, per the instruction of the Sponsor. Documentation confirming drug 
accountability will be reviewed over the course of the trial. 
5.6. 
Premature Treatment or Study Discontinuation 
Subjects may voluntarily discontinue treatment or withdraw from the study at any time. They 
may also be removed from the study at the discretion of the investigator or Sponsor at any time. 
The investigator may withdraw a subject at any time if it is determined that continuing the study 
would result in a significant safety risk to the subject. 
Premature treatment or study discontinuation may occur for any of the following reasons: 
• Persistent noncompliance with the protocol requirements 


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• AE 
• Death 
• Subject request (withdrawal of consent) 
• Investigator request 
• Sponsor request 
• Loss to follow-up 
• Pregnancy 
Individual Study Drug Stopping Rules  
Study drug treatment will be immediately discontinued in any individual subject who 
experiences: 
• Any treatment-emergent SAE, or AE of grade 3 severity or higher (including confirmed 
laboratory abnormalities of grade 3 severity or higher reported as AEs) considered by the 
investigator to be related to study drug 
• Confirmed estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 
• For subjects with liver function testing within normal limits on the Day 1 lab draw: 
o Confirmed treatment-emergent elevation of alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) > 3 x ULN with total bilirubin (TB) > 2 x upper 
limit of normal (ULN) not due to hemolysis, and without evident alternative cause 
for these elevations 
• For subjects with ALT or AST levels above the upper limit of normal on the Day 1 lab 
draw: 
o Confirmed treatment-emergent elevation of ALT or AST > 3 x baseline with TB 
> 2 x ULN not due to hemolysis, and without evident alternative cause for these 
elevations 
• For subjects with TB level above the upper limit of normal on the Day 1 lab draw: 
o Confirmed treatment-emergent elevation of ALT or AST > 3 x ULN with 
TB >2x baseline level (and not due to hemolysis), and without evident alternative 
cause for these elevations 
•  Initiation or planned initiation of remdesivir 
• Pregnancy 
Hospitalization for the acute management of COVID-19 or other medical conditions does not 
require discontinuation of study drug; however on-going study drug management will be at the 
discretion of the PI and treating physicians. 
Subjects who prematurely discontinue study drug treatment should be encouraged to remain in 
the study and maintain the same protocol schedule and assessments as described in Table 1. This 
will allow for continued subject follow-up for key outcome data. Subjects who prematurely 


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discontinue the study [prior to Day 29 (primary study period)] and are unable to maintain the 
same protocol schedule should complete early termination (ET) assessments at the time of study 
discontinuation, as described in Table 1. Nevertheless, all attempts should be made to contact the 
subject at Day 29 (telephone contact is acceptable) to confirm key study endpoints, including 
hospitalization and survival. 
The primary study period is through Day 29. The end of the study for any individual subject will 
be defined as the 60-day follow-up contact. 
5.7. 
Prior Therapy, Concomitant Therapy, Permitted Therapy, 
Cautionary Therapy, and Prohibited Therapy 
5.7.1. 
Prior Therapy 
Restrictions on prior therapies are described in exclusion criteria (Section 4.3). Subjects who 
have used other investigational drugs within 30 days prior to planned dosing (except for 
exclusions referenced in exclusion criterion #5) or initiated any COVID-19 drug with antiviral 
effects intended to treat symptomatic SARS-CoV-2 infection ≥ 24 hours prior to randomization 
will be excluded. Of note, subjects who have received mAb(s) taken as pre- or post-exposure 
prophylaxis (including if received ≥ 24 hours prior to randomization) will be allowed into the 
study but they will be considered as part of the combination antiviral cohort. 
In addition, hydroxychloroquine or amiodarone within 3 months prior to screening is not allowed 
for the reasons described in Section 5.7.5. 
Subjects may be included regardless of COVID-19 vaccination status. However, information will 
be collected on timing and type of prior COVID-19 vaccination as well as timing of any prior 
SARS-CoV-2 infection. 
5.7.2. 
Concomitant Therapy 
Concomitant therapy consists of any medication (eg prescription drugs, over the counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a subject in addition 
to study drug treatment. All such medications should be reported to the investigator and recorded 
on the Concomitant Medications eCRF. 
5.7.3. 
Permitted Therapy 
Locally available SOC treatment should be initiated in parallel in addition to study drug (add-
on). If SOC includes treatment that has direct antiviral activity against SARS-CoV-2 
(combination antiviral cohort), such drug should be initiated during screening or within 24 hours 
prior to or after randomization. Allowed SARS-CoV-2 antiviral treatments could include, but are 
not limited to nirmatrelvir/ritonavir, molnupiravir, favipiravir, and mAbs. SARS-CoV-2 
treatments with concerns for DDIs (remdesivir) with BEM are not permitted. 
Subjects are also permitted to use the following therapies during the study: 
• Acetaminophen (paracetamol) 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 


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• Anti-emetics to manage any nausea or vomiting observed on the study (such as 
dopamine antagonists, serotonin 5-HT3 receptor antagonists, and antihistamines) 
• Prophylactic anticoagulation with low-dose aspirin, direct factor Xa inhibitors, or 
direct thrombin inhibitors 
• Prescribed medications for concomitant conditions as per medical history, such as 
chronic supplementary oxygen, antihypertensives, antidiabetic medications, 
rheumatologic medications, or respiratory medications (eg, chronic 
inhaled/intranasal/oral steroids) 
• Hormonal contraceptives (see Section 5.8) 
• Hormone replacement therapy 
• Corticosteroids 
• Convalescent plasma (For purposes of stratification, those receiving convalescent 
plasma would be included in the supportive-care-only cohort). 
• For subjects who deteriorate on-study, any rescue therapy which is SOC for severe 
COVID-19 is permitted (see Section 5.7.5 for details about remdesivir). 
5.7.4. 
Cautionary Therapy 
5.7.4.1. 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their PK, safety profiles, and 
potential DDI are generally unknown. 
5.7.4.2. 
Mitigation of Other Potential DDI 
For more details regarding potential DDI, refer to the BEM Investigator’s Brochure. 
5.7.4.2.1. P-glycoprotein (P-gp)-Based Inhibition 
Concomitant use of P-gp inhibitors is permitted but must be taken at least 2 hours after 
administration of study drug. Common examples of P-gp inhibitors include cyclosporine, 
carvedilol, imidazoles, macrolides, ritonavir, and verapamil.  
For a full list of P-gp inhibitors, refer to:  https://go.drugbank.com/categories/DBCAT002667. 
Note:  As ritonavir is a major P-gp inhibitor, subjects enrolled in the combination antiviral 
group who are taking nirmatrelvir/ritonavir should not take nirmatrelvir/ritonavir until at least 
2 hours after taking study drug. 
Subjects taking tacrolimus, sirolimus, or everolimus should do so at least 2 hours after study 
drug (BEM/placebo). 
Subjects taking digoxin must do so at least 2 hours after taking study drug. 


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5.7.4.2.2. Gastrointestinal Acid Reduction Based Interaction 
Gastrointestinal acid reducing agents such as proton-pump inhibitors, H2 blockers and antacids 
may reduce the solubility of BEM. Subjects taking these agents will do so at least 2 hours after 
taking study drug. 
5.7.4.2.3. Tenofovir Alafenamide 
Tenofovir alafenamide and BEM may compete for activation enzymes.  Subjects with HIV 
and/or hepatitis B virus (HBV), who are taking tenofovir alafenamide should do so at least 
2 hours after administration of study drug.   
5.7.5. 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited from Day 1 until Day 29 (the primary 
study period) or early termination, except as otherwise indicated, as described below: 
• Investigational therapy (other than protocol-mandated study treatment), except for 
unblinded protocols that don’t include direct acting antivirals for COVID-19  
(eg, open-label oncological regimen variations or biologic studies)  
Note:  Prior to enrolling subjects that are on other open-label studies, it is the site’s 
responsibility to ensure that the study criteria for that study allow for enrollment into 
this study. 
• SARS-CoV-2 treatments with concerns for DDIs:  remdesivir 
Note:  As BEM and remdesivir share a common target and metabolic activation 
pathway, there is a potential for PK or pharmacodynamic (PD) drug interactions 
between the two, during concomitant administration of both drugs. Study drug should 
be discontinued before initiation of remdesivir. 
• Sofosbuvir-containing regimens for subjects with active HCV, as BEM has potent 
inhibitory activity against HCV, which will cause pharmacodynamic interactions 
• Abacavir for subjects with HIV, as abacavir and BEM share a common activation 
pathway 
• Hydroxychloroquine or amiodarone 
Note:  There is a known DDI between amiodarone and sofosbuvir (bradycardia). The 
phosphoramidate moiety of the BEM structure is identical to that of sofosbuvir 
(SOF). As it is unclear if the phosphoramidate moiety of sofosbuvir is contributory to 
the DDI, amiodarone use is prohibited to ensure subject safety. 
Coadministration of hydroxychloroquine and remdesivir can result in reduced 
remdesivir antiviral activity. While remdesivir is not a study drug in this study, it 
remains a viable rescue therapy that subjects may be given if clinically warranted. 
Therefore, hydroxychloroquine is prohibited during the study. 
5.8. 
Contraception Requirements 
A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a 
postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than 


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menopause), and is not permanently infertile due to surgery (ie, removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator (eg, Müllerian agenesis). 
The definition of childbearing potential may be adapted for alignment with local guidelines or 
regulations. Women of childbearing potential must be established on their chosen method of 
contraception at screening. 
The following are examples of adequate contraceptive methods:   
• Bilateral tubal ligation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Hormonal contraceptives 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide. 
• Vasectomized partner 
• Sexual abstinence 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not adequate methods 
of contraception. If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will be described in 
the local Informed Consent Form (ICF). 
Should acceptable methods of contraception be more restrictive than the methods listed above 
per local regulations, guidance, investigator practice, or based on SOC administered (eg, 
molnupiravir), a more restrictive list may be included within the site/country-specific 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF. 


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6. 
STUDY PROCEDURES AND GUIDELINES 
Study-specific assessments and the study schedule are summarized in Table 1. An “X” indicates 
when the assessments are to be performed.   
When feasible, visits may be conducted remotely (eg, via telephone or telemedicine), in clinic, or 
at home. 
If possible, screening and Day 1 will occur on the same day, as soon as eligibility is confirmed. 
Assessments need not be conducted twice if screening/Day 1 occur on the same day. 
Screening/Day 1 assessments should occur prior to first dose of study drug. Dosing should occur 
within 24 hours of screening. 
The Day 60 visit can be a telephone contact. 
All subjects who prematurely discontinue study treatment should be encouraged to remain in the 
study and maintain the same protocol schedule and assessments as described in Table 1. This 
will allow for continued subject follow-up for key outcome data. Subjects who prematurely 
discontinue the study [prior to Day 29 (primary study period)] and are unable to maintain the 
same protocol schedule should complete early termination (ET) assessments at the time of study 
discontinuation. 
6.1. 
Schedule of Assessments 
The schedule of assessments is provided in Table 1. 
 
 


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Table 1: 
Schedule of Assessments 
 
                                                                                             Day:  
Screening 
Treatment 
Follow-up (FU) 
Extended FU ET 
Within 24 
hours  
of dosing 
1 
3 
(± 1 day) 
5 
(± 1 day) 
7 
(± 1 day) 
14  
(± 1 day) 
29  
(± 1 day) 
60a 
(± 7 days) 
ELIGIBILITY 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history and baseline conditions 
X 
 
 
 
 
 
 
 
 
Pre-existing symptom assessment 
X 
 
 
 
 
 
 
 
 
Rapid test for influenzab 
X 
PHYSICAL EXAMINATION AND VITAL SIGNS  
Vital signs, including temperature and SpO2 
X 
X 
X 
X 
X 
X 
X 
Height and weight 
X 
Complete physical examination 
X 
Symptom-targeted physical examination 
 
As clinically indicated 
 
Xc 
Assessment of medically attended visit(s)  
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
Central safety labd  
X 
X 
X 
X 
Pregnancy test (females of childbearing potential) 
X 
SARS-CoV-2 diagnostic test, RT-PCR or validated rapid 
antigen test (obtained locally if needed to confirm eligibility)e 
X 
Nasopharyngeal (NP) swab (central lab)f 
X 
X 
X 
X 
X 
X 
X 
Blood samples for biomarkers
 
 (central lab) 
X 
X 
X 
X 
PHARMACOKINETICS 
Plasma sample for sparse PK (central lab) 
X 
X 
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                                                                                             Day:  
Screening 
Treatment 
Follow-up (FU) 
Extended FU ET 
Within 24 
hours  
of dosing 
1 
3 
(± 1 day) 
5 
(± 1 day) 
7 
(± 1 day) 
14  
(± 1 day) 
29  
(± 1 day) 
60a 
(± 7 days) 
 
STUDY INTERVENTION 
Randomization 
Xh 
 
 
 
 
 
 
 
Study drug dosing (w/completion of dosing diary) 
 
Days 1–5 (10 doses) 
 
 
 
 
 
STUDY ASSESSMENTS 
COVID-19 Symptom Diary 
Daily on Days 1–29 
ADVERSE EVENT AND CONCOMITANT MEDICATION MONITORING 
Adverse events (AEs) and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
SAEs Only 
X 
 
aDay 60 can be a telephone contact: assessment of mortality and COVID-19 related medically attended visits as defined in Section 6.9  
b Can be a locally available test and must be negative for the subject to enroll. 
c As clinically indicated 
d Safety laboratory tests may be performed at local laboratories if deemed medically necessary by the investigator or Sponsor. In these cases, the site should 
collect a matching sample and ship it to the central laboratory. 
eA documented historical positive result from a test conducted ≤ 5 days prior to randomization is acceptable. 
fNasopharyngeal swabs should be taken at each visit. Should the subject decline a nasopharyngeal swab, a nasal swab may be collected instead.  Collection 
instructions will be provided by the central lab.  In addition to SARS-CoV-2 RT-qPCR and resistance, aliquots may be analyzed for viral titer and other 
respiratory pathogens such as influenza and RSV to rule out co-infection. For subjects with COVID-19 symptom relapse, NP swabs should also be collected at 
the time of relapse (see Section 6.6) 
gBlood samples will be collected. 
; others will be kept for future use to potentially 
analyze disease-related biomarkers or other immune markers to inform the course of the disease. 
 hStudy drug dosing should occur on the same day as randomization. 
Screening/Day 1 assessments should occur prior to first dose of study drug. 
ET = early termination; PK = pharmacokinetics; RT-PCR = reverse transcription polymerase chain reaction  
 
 
 
 
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6.2. 
Medical History 
Complete medical history will be obtained at screening. Information about COVID-19 disease 
history and prior infections, including the onset date of symptoms, and risk factors will be 
collected. Subjects may be questioned about alcohol and drug use, and information about prior or 
concomitant medications will also be collected. Information will also be collected on prior 
COVID-19 vaccine history. 
6.3. 
Physical Examination 
A complete physical examination will be performed by a medically qualified individual as 
scheduled in Table 1. The complete physical examination will include a review of the following: 
head and neck, ears/nose/throat, lymph nodes, heart, lungs, abdomen, musculoskeletal, 
neurological, skin, and general appearance.   
Demographic data (age, gender, ethnicity/race, body weight, height, BMI) will be recorded.   
After screening, a symptom-targeted physical exam should be done as clinically indicated. 
6.4. 
Vital Signs 
Vital sign measurements (body temperature, pulse rate, respiratory rate, and blood pressure) and 
SpO2 should be captured as specified in Table 1. Vital signs and SpO2 should be assessed while 
the subject is in a seated position. 
6.5. 
Safety Laboratory Evaluations 
Safety laboratory evaluations will be performed as scheduled in Table 1. The investigator or 
designee will assess each abnormal value to determine if it is clinically significant.  
• Chemistry: Sodium, calcium, potassium, chloride, bicarbonate or total carbon dioxide 
(either is acceptable), glucose, blood urea nitrogen (BUN) or urea, creatinine, eGFR 
(CKD-EPI formula), total protein, total bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, albumin, creatine kinase (CK), triglycerides, cholesterol, 
amylase, and lipase 
• Hematology: White blood cell (WBC) count with differential, red blood cell count, 
hemoglobin, hematocrit, and platelet count 
• Coagulation: Prothrombin time (PT) and International Normalized Ratio (INR) 
Note: Depending on logistics, the laboratory may use the PT to calculate INR and 
only report the INR to the clinical sites. 
• Pregnancy tests (serum or urine) will be performed on female subjects of childbearing 
potential at screening, as specified in Table 1  
Note, the pregnancy test can be done at Day 1, as long as results are confirmed prior 
to dosing with study drug. 
The total volume of blood withdrawn during the study should not exceed 500 mL. However, it is 
possible that the total blood donation may be higher if repeat blood samples are required for 
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6.6. 
Other Laboratory Evaluations 
At screening, a RT-PCR or validated rapid antigen SARS-CoV-2 diagnostic test will be 
performed locally to confirm eligibility (Table 1). A documented historical positive result from a 
test conducted ≤ 5 days prior to randomization is acceptable for confirming eligibility. 
Samples for the following will be sent to designated central laboratories or Sponsor designee for 
analysis, on the schedule outlined in Table 1: 
• Nasopharyngeal (NP) swab samples for SARS-CoV-2 RT-qPCR; an aliquot will be 
dedicated for resistance analyses which will be described in a separate resistance 
monitoring plan. Aliquots may also be analyzed for viral titer and other respiratory 
pathogens such as influenza and RSV to rule out co-infection 
• Blood samples will be collected for potential future biomarker analyses
 
 others will be kept for future use to potentially 
analyze disease-related biomarkers or other immune markers to inform the course of 
the disease. 
• Plasma samples for sparse PK analysis 
All samples will be processed, stored, and shipped according to the sample processing 
instructions supplied by the Sponsor or receiving laboratory.   
For any subject who experiences a COVID-19 symptom relapse, an NP swab should be collected 
as soon as possible at the time of symptom relapse.  If symptom relapse occurs outside of the 
planned visit schedule in Table 1, an unscheduled visit should occur to collect the NP swab.  
Subjects will be instructed to contact their site if they feel their COVID-19 symptom(s) have 
returned or worsened, after experiencing alleviation or improvement.  
6.6.1. 
Sparse PK Sampling 
PK samples will be collected on Day 5, as specified in Table 1, at the same time a blood sample 
is drawn for safety laboratory analysis. It is important that the date and time of the PK sampling 
is recorded as well as the date and time of the most recent study drug administration. 
6.6.2. 
Bioanalytical Methods for PK Samples 
Plasma concentrations of BEM and metabolites (as appropriate) will be measured according to 
validated bioanalytical methods.  
Samples from all subjects who received at least one dose of BEM will be analyzed. Samples 
from subjects who received placebo will not be analyzed. 
Bioanalytical laboratory personnel will have access to the randomization assignment. 
6.7. 
COVID-19 Symptom Assessment  
A COVID-19 symptom diary will be completed daily until Day 29 (Table 1). The symptom diary 
is provided in Appendix 1 (Section 13.1). This diary will be used to characterize key symptoms 
recognized as part of COVID-19 illness based on FDA guidance (FDA 2020). The COVID-19 
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Symptom Diary is composed of individual symptom item questions, each with a 2- or 4- point 
Likert response option. In addition to symptoms, subjects will be asked for a self-assessment as 
to whether they have returned to their usual (pre-COVID-19) health status, as well as their 
assessment of COVID-19 symptom relapse. 
On Day 1, a baseline diary questionnaire should be completed at the clinic, prior to the first dose 
of study drug. Thereafter, the COVID-19 Symptom Diary will be completed in its entirety by the 
subject once daily at the same time each evening through Day 29. 
6.7.1. 
Data Collection Methods for the PRO 
The COVID-19 Symptom Diary is a patient-reported outcome (PRO) measure that will be self-
administered at the clinic (Day 1) and/or at home (see schedule in Table 1). At the clinic on Day 
1, instruments will be administered before the subject receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of study 
treatment. 
The PRO instrument, translated into the local language as appropriate, will be completed either 
through use of an electronic application on the subject’s own electronic device, through use of a 
device provided by the Sponsor, or as paper dairy. Subjects should be given the following 
instructions for completing the PRO at home:  
• The assessment should be completed at the same time each day (before bed each 
evening), and the recall period (in the last 24 hours) should be specified clearly. 
• Subjects should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
• Subjects should answer questions to the best of their ability; there are no right or 
wrong answers. 
• Subjects who have difficulty in using the diary (eg, blind, illiterate, physical 
limitations, unfamiliar with technology) can obtain assistance from close contacts (eg 
family members or friends) in recording responses, but should not obtain advice or 
help from others with constructing responses. 
During the study visit on Day 1, the PRO instruments should be administered as outlined below: 
• Subjects’ health status should not be discussed prior to administration of the 
instruments 
• Sites must administer the official version of each instrument, as provided by the 
Sponsor. Instruments must not be copied from the protocol. 
• Sites should allow sufficient time for subjects to complete the instruments 
• Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
• Subjects should be instructed to answer questions to the best of their ability; there are 
no right or wrong answers. 


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• Site staff should not interpret or explain questions but may read questions verbatim 
upon request. 
• Subjects who have difficulty in using the diary (eg, blind, illiterate, physical 
limitations, unfamiliar with technology) can obtain assistance from close contacts (eg 
family members or friends) in recording responses but should not obtain advice or 
help from others with constructing  responses. 
6.8. 
Hospitalization 
Hospitalization is defined as >24 hours of acute care, in a hospital or similar acute care facility, 
including Emergency Rooms or temporary facilities instituted to address medical needs of those 
with severe COVID-19 . This includes specialized acute medical care unit within an assisted 
living facility or nursing home. This does not include hospitalization for the purposes of public 
health and/or clinical trial execution.  Furthermore, scheduled hospitalization for a pre-planned 
procedure (including chemotherapy) to treat a pre-existing condition that has not worsened is not 
an SAE, and would not be considered a hospitalization for the purposes of the efficacy analyses. 
A pre-existing condition is a clinical condition that is diagnosed prior to the use of study drug 
and is documented in the subject’s medical history. 
6.9. 
COVID-19-Related Medically Attended Visit(s) Assessment 
A COVID-19-related medically-attended visit will be defined as follows: hospitalization, 
(Section 6.8) ER visit, urgent care visit, physician’s office visit, or telemedicine visit, with the 
primary reason for the visit being COVID-19.  
Only medically-attended visits related to COVID-19, as determined by the investigator, will be 
recorded in the eCRF. Details will include at minimum: 
• Type of visit (hospitalization, ER, urgent care, physician’s office visit, telemedicine) 
• Date of visit 
• Primary reason for COVID-19 related medically-attended visit  
• Treatments given for COVID-19 (including, but not limited to, concomitant 
medications and supplemental oxygen)  
• If hospitalization was required, site personnel will record length of visit, whether 
intensive care unit (ICU) care was given, or whether mechanical ventilation was 
required. If additional infectious work-up was performed, the results should be 
included in the hospitalization narrative. 
 
Any AEs or concomitant therapies reported to the investigator should be recorded on the 
respective AE eCRF or Concomitant Medications eCRF.  
For countries that have local COVID--19 isolation policies, the condition of a medically-attended 
visit (including hospitalizations) in subjects hospitalized for isolation purposes only would be 
met either for worsening of disease (such as: AE, treatment, intervention, transfer to higher level 
of care or as per standard of care would not be an appropriate treatment for an ambulatory 


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patient) OR subject spontaneously asks for medical advice about their current condition (and 
confirming the need for advice was important enough that if they were in their home setting, they 
still would have also sought advice for the same event/concern). 


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7. 
ADVERSE EVENTS 
7.1. 
Definitions 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product(s) and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product(s), whether or not considered related to this medicinal product(s). 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug(s) caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug(s) and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a 
drug(s). 
An AE may be: 
• A new illness 
• Worsening of a previous chronic illness or a concomitant illness 
• An apparent adverse effect of the study medication(s) on safety-related laboratory 
tests. This observation could include a clinically-significant abnormal laboratory 
value or a significant shift from baseline (though still within normal range) which the 
clinical investigator or qualified designate considers to be clinically significant 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned (elective) surgical measures and the conditions(s) 
leading to these measures are not AEs, if the condition(s) was (were) known before the start of 
study treatment. In the latter case, the condition should be reported as medical history. 
An SAE or reaction is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above (according to medical 
judgment of the qualified investigator) 
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities that require medical or surgical intervention or lead to study 
drug interruption, modification, or discontinuation must be recorded as an AE, as well as an 


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SAE, if they meet the definition above. In addition, laboratory or other abnormal assessments 
(eg, electrocardiogram [ECG], x-rays, vital signs) that are associated with signs and/or symptoms 
must be recorded as an AE or SAE if they meet the definition of an AE or SAE as described 
above. If the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (eg, 
anemia), not the laboratory result (ie, decreased hemoglobin). Laboratory abnormalities that do 
not require medical intervention or action are generally not considered AEs. 
Severity should be recorded and graded according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017, as 
described below. If a value falls within the local laboratory normal range, then it will not be 
graded. For AEs associated with laboratory abnormalities, the event should be graded on the 
basis of the clinical severity in the context of the underlying conditions; this may or may not be 
in agreement with the grading of the laboratory abnormality. 
7.1.1. 
Intensity Assessment 
The investigator or the designated person will provide an assessment of the severity of each AE 
by recording a severity rating on the appropriate AE reporting page of the subject’s eCRF. In 
classification of AEs, the term “severe” is not the same as “serious”. Severity is a description of 
the intensity of a specific event (as in mild, moderate, or severe chest pain). The term “serious” 
relates to a participant/event outcome or action criteria, usually associated with events that pose 
an immediate threat to a participant’s life or functioning, and meet one or more of the SAE 
criteria described above. 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 
will be used for assessing AEs (DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Version 2.1. [July 2017]). All AEs will be graded as grade 1 (mild), grade 2 
(moderate), grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) according 
to the definitions described in the DAIDS Table. Every effort will be made to obtain an adequate 
evaluation of the severity. 
7.1.2. 
Causality Assessment 
The qualified investigator or a medically qualified designate will determine the relationship of 
any AE to study drugs using the following guidelines in Table 2. 
Table 2: 
Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
There is evidence to suggest a causal relationship between the drug(s) 
and the AE (eg, AE is uncommon and known to be strongly associated 
with drug exposure or is uncommon in the study population, but not 
commonly associated with drug exposure). 
No Reasonable Possibility 
There is no evidence to suggest a causal relationship between the 
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7.2. 
Routine Reporting 
For the purposes of this study, non-serious AEs and SAEs will be recorded in the eCRF from the 
time of informed consent through Day 29 (the primary study period). SAEs will be recorded 
through Day 60. 
During these periods, all AEs spontaneously reported by the subject, observed by the clinical 
staff, or elicited by general questioning will be recorded and reported in the eCRF. 
Any AE which remains unresolved as of the last visit will require follow-up until the AE has 
been resolved, a reasonable explanation for its persistence found, or is deemed chronic or stable 
by the investigator. It is the investigator’s responsibility to ensure subjects experiencing AEs 
receive appropriate follow-up, treatment where required, and that every action is well 
documented. 
Classification will be performed by System Organ Class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of events) 
should be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as an SAE or AE in the eCRF. However, 
medically significant AEs occurring secondary to an initiating event that are separated in time 
should be recorded as independent events on the eCRF. 
7.3. 
Serious Adverse Event Reporting 
Clinical sites must notify 
 of any SAE, without regard to causality, within 
24 hours after becoming aware of its occurrence. Any non-serious AE which worsens and 
eventually meets the criteria for an SAE must also be reported as a new SAE. 
Information regarding SAEs will be transmitted to 
 using the Serious Adverse 
Event form in the electronic data collection tool, which must be completed by a member of the 
investigational site staff within 24 hours. This form should include a clearly written narrative 
describing diagnostic terms, signs, symptoms, and treatment of the event; diagnostic procedures; 
as well as any relevant laboratory data and an assessment of the potential causal relationship 
between the event and the investigational product(s). Information not available at the time of the 
initial report (eg an end date for the AE, laboratory values received after the report, or hospital 
discharge summary) must be documented. All follow-up information must be reported as soon as 
the relevant information is available.  
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
and transmit to 
 within 24 hours by one of the following methods: 
 
Email: 
 
 
Fax:
 
The site will enter the SAE data into the electronic system as soon as it becomes available.  
Contact information for the Sponsor’s physician is also listed below, should the sites need to 
contact the Sponsor to discuss any medical, safety related questions, or SAEs:   
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Atea Pharmaceuticals, Inc. 
Telephone
 
Email: 
 
An unlisted (unexpected) SAE is one in which the nature or severity is not consistent with the 
applicable product reference safety information (RSI). For investigational product(s), the 
expectedness of an SAE will be determined by whether or not it is listed in the RSI within the 
Investigator’s Brochure(s). Investigators will be notified, and the Investigator’s Brochure will be 
updated, if any new pattern of AEs or laboratory abnormalities is found to be related to BEM 
dosing. 
The start date of an SAE reported on the Serious Adverse Event form must be the same as the 
start date of the corresponding AE documented on the eCRF. If a change in severity is noted for 
the existing AE, it must be recorded. If a worsened AE meets the criteria for an SAE, the start 
date of the SAE must be the same as the start date of the worsened AE. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value is available 
• The event can be attributed to agents other than the study drugs or to factors unrelated 
to study conduct 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
Any SAE reports will be reported by the investigators (or designee) to their local IRB/IEC in 
accordance with local reporting requirements and reporting timelines. 
Similarly, the Sponsor (or designee) will determine whether an SAE must be reported in an 
expedited manner to regulatory authorities, in accordance with regulatory requirements, 
including auxiliary medicinal products to Eudravigilance per Directive 2001/83/EC where 
appropriate. If so, the Sponsor (or designee) will report the event to the regulatory authorities in 
accord with applicable reporting timelines.  
7.4. 
Pregnancy Reporting 
All initial reports of pregnancy in female subjects  during the study (until 30 days after the last 
dose of study drug) or female partners of male subjects, where locally required, must be reported 
to 
 (see Section 7.3 for contact information) by the investigational staff within 
24 hours of their knowledge of the event  by completing the “Pregnancy Notification” section of 
the designated form. All pregnancies will be followed-up to determine the outcome including 
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spontaneous or voluntary termination, details of birth, presence or absence of any birth defects, 
congenital anomalies, maternal and/or newborn complications, or longer where locally required. 
After the expected pregnancy end date, the site will complete the “Pregnancy Outcome” section 
of the designated form and provide to the 
. Abnormal pregnancy outcomes are 
considered SAEs and must be reported using the electronic Serious Adverse Event form. Any 
subject who becomes pregnant during treatment must immediately discontinue study drug. 
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8. 
STATISTICAL ANALYSES 
This section summarizes the statistical analyses pertinent to the assessments in this study. A 
statistical analysis plan (SAP) describing the detailed statistical methods will be developed and 
finalized before any analyses are performed.  
8.1. 
Analysis Populations 
8.1.1. 
Safety Population 
The safety population will include all subjects who received at least one dose of the study drug 
(BEM or placebo). The study population will be analyzed as treated. 
8.1.2. 
Intention to Treat Population 
The intention to treat (ITT) population will include all randomized subjects and will be analyzed 
as randomized. 
8.1.3. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population includes all randomized subjects who received  
≥1 dose of study drug and have ≥ 1 positive SARS-CoV-2 result (from NP swab samples via 
central testing) through Day 5. The majority of subjects are expected to have the positive SARS-
CoV-2 qualifying sample at baseline, but the window is extended to allow the inclusion of 
subjects who may have a baseline false negative or missing sample at baseline. 
The modified intent-to-treat-S (mITT-S) population includes all randomized subjects who 
received ≥ 1 dose of study drug, have ≥ 1 positive SARS-CoV-2 result (from NP swab samples 
via central testing) through Day 5, and who are stratified into the supportive-care-only 
population.   
The modified intent-to-treat-C (mITT-C) population will include all randomized subjects who 
received ≥ 1 dose of study drug, have ≥ 1 positive SARS-CoV-2 result (from NP swab samples 
via central testing) through Day 5, and who are stratified into the combination antiviral 
population.  
For analyses and displays based on mITT-S and mITT-C analysis sets, subjects will be classified 
according to randomized treatment.  
8.1.4. 
PK Population 
The PK population will include all subjects who received at least one dose of BEM and for 
whom evaluable plasma concentration data are available. Subjects who received placebo will not 
be included in the PK population. 
8.2. 
Endpoints 
The primary efficacy endpoint is the proportion of subjects in the supportive-care-only 
population who are hospitalized for any cause or who died due to any cause through Day 29. 


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The secondary endpoints are: 
Efficacy: 
• Proportion of subjects with COVID-19-related hospitalization or who died due to any 
cause through Day 29 
• Proportion of subjects who died due to any cause through Day 29 and Day 60 
• Proportion of subjects with COVID-19-related complications (eg., death, 
hospitalization, radiologically confirmed pneumonia, acute respiratory failure, sepsis, 
coagulopathy, pericarditis/myocarditis, cardiac failure) through Day 29 
• Proportion of subjects with COVID-19-related medically attended visits 
(hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, 
or telemedicine visit) or who died due to any cause through Day 29 and Day 60 
• Proportion of subjects with COVID-19 symptom relapse (term to be defined in the 
SAP) through Day 29 
• Proportion of subjects with viral load rebound (term to be defined in the SAP) 
through Day 29 
 
Safety: 
• The incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs) 
The exploratory endpoints are: 
Efficacy: 
• Time to alleviation or improvement of individual COVID-19 symptoms  
• Time to self-reported return to usual (pre-COVID-19) health  
• Proportion of subjects requiring post-randomization rescue therapy 
Note:  For subjects randomized into the combination antiviral population, antiviral 
medications administered post-baseline within 24 hours of first study drug, as part of 
the combination regimen, are not considered rescue medication. 
Note:  Rescue therapy for the purpose of the endpoint includes only treatments with 
direct activity against SARS-CoV-2; and that is administered for COVID-19-related 
clinical decline. 
• Duration and severity of COVID-19 symptom relapse 
• Proportion of subjects with both COVID-19 symptom relapse and viral rebound  
• Change from baseline in amount of SARS-CoV-2 viral RNA as measured by RT-
qPCR over time   
• Time to cessation of SARS-CoV-2 viral shedding by RT-qPCR 


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• Proportion of subjects negative for SARS-CoV-2 viral RNA by RT-qPCR over time  
• Area under the curve (AUC) in the amount of SARS-CoV-2 viral RNA as measured 
by RT-qPCR 
• Proportion of subjects with treatment-emergent mutations in SARS-CoV-2 viral 
genes  
• 
 
 
Pharmacokinetics: 
• Plasma concentrations of AT-511 (free base form of AT-527 [BEM]) and its 
metabolites  
The primary efficacy endpoint will also be assessed in the combination antiviral population as a 
secondary endpoint.  All secondary 
 endpoints will be assessed in both the 
supportive-care-only population, and the combination antiviral population. 
8.3. 
Statistical Methods 
The primary and secondary efficacy analyses will be conducted using the mITT-S population. 
Efficacy analyses will be repeated using the mITT-C population.  
Safety analyses will be performed on the safety population, which consists of all subjects who 
received at least one dose of study drug. In all safety analyses, subjects will be grouped 
according to the treatment that the subjects actually received rather than the treatment assigned at 
randomization. Here, treatment will be considered as BEM monotherapy and placebo for 
subjects in the supportive-care-only population and as BEM combination and compatible 
antiviral in the combination antiviral population. 
Demographics and baseline characteristics will be summarized by treatment group and overall 
for each analysis population. Disposition, with respect to both treatment and study completion, 
will be summarized by treatment group and overall with reasons for discontinuation tabulated.  
For continuous variables, descriptive statistics will include the following information: the 
number of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, 
minimum, and maximum. For categorical or ordinal data, frequencies and percentages will be 
displayed for each category. 
Time-to-event endpoints will be analyzed using Kaplan-Meier methods for estimation and log-
rank test for treatment comparison. 
Data handling for quantitative data that are reported as less than the lower limit of quantification, 
as well as values reported greater than the upper limit of quantification, will be described in the 
SAP.  
In general, data will be considered as observed, ie, values for missing data will not be imputed.  
The primary analysis will occur when all randomized subjects have had sufficient follow-up time 
to complete the Day 29 visit. Data collected during the extended FU period will be summarized 
separately, after the primary study analysis.  
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8.3.1. 
Primary Efficacy Analysis 
The primary efficacy objective of this study is to evaluate the efficacy of BEM based on the 
proportion of patients who are hospitalized for any cause or who died due to any cause through 
Day 29 in the supportive-care-only population. The primary estimand is the difference in the 
proportion of patients who are hospitalized for any cause or who died due to any cause through 
Day 29 in the supportive-care-only population, and the primary treatment effect comparison will 
be between the BEM arm and the placebo arm. This proportion will be compared between the 
BEM and placebo arms using a Cochran-Mantel-Haenszel (CMH) test adjusted for the 
stratification factors of age and region. The CMH p-value and estimated common risk difference, 
odds ratio and relative risk, along with the corresponding 95% confidence intervals (CIs) for 
these estimates, will be presented.   
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the variable or affect its interpretation. For the intercurrent events of rescue (eg intervention 
with remdesivir) and concomitant COVID-19 medications, a treatment policy approach will be 
taken, whereby use of rescue and concomitant medications will be ignored and observations 
collected after they are administered to the patient will be used. In addition, patients will be 
followed, assessed, and analyzed irrespective of their completion of the course of the study 
treatment. The analysis will be performed based on observed data, and the following measures 
will be used to reduce missing hospitalization/death data: eCRFs capturing clinical information 
that may be indicative of hospitalization will be reviewed to mitigate the risk of unreported 
hospitalizations, and study staff may use a public information source to obtain information about 
survival status if a patient withdraws from the study.  
8.3.2. 
Secondary Efficacy Analyses 
Analysis of the primary efficacy endpoint will be conducted for the combination antiviral 
population as a secondary endpoint. Presentation and analysis of other secondary efficacy 
endpoints will be carried out using methods similar to those specified for the primary efficacy 
endpoint.  Data handling, analysis populations, and specification of statistical testing for 
secondary efficacy endpoints, with methods used to control overall type I error, will be detailed 
in the SAP. 
8.3.3. 
Exploratory Analyses 
Additional efficacy and antiviral endpoints will be summarized descriptively. Any exploratory 
statistical analysis to be conducted on these endpoints will be documented in the SAP.   
Resistance analyses, including assessment of treatment-emergent mutations in SARS-CoV-2 
viral genes, will be documented in a separate resistance monitoring plan. 
 
   
Exploratory sub-group analyses may also be conducted; these will be detailed in the SAP.   
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8.5. 
Sample Size 
The study is powered to detect a true 60% reduction in the hospitalization and all-cause mortality 
rate with BEM as compared to placebo. With total N=2100 and the interim analysis plan as 
defined in Section 8.4, there is 90% power if the true rate in the placebo arm is 4% 
(corresponding to an absolute difference of 2.4% in rate) and at least 80% power if the true rate 
in the placebo arm is 3% (corresponding to an absolute difference of 1.8%). Sample size was 
calculated using SAS (version 9.4) for a 2-sample proportion Chi-square test. Considering a 
group sequential design with 2 interim analyses using both alpha and beta spending according to 
Lan-Demets approximation of O’Brien Fleming method (see Section 8.4), the total sample size 
was inflated by a multiplier of 1.055 to arrive at a target sample size of 2100 participants in the 
supportive-care-only population. 
Assuming ~95% of randomized subjects who receive only supportive care as SOC will meet the 
mITT-S population criteria, the study targets total enrollment of 2210 subjects in the supportive-
care-only population. Planned enrollment in the antiviral combination arm is up to 300 subjects. 


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9. 
ETHICS 
9.1. 
Institutional Review Board/Independent Ethics Committee 
This protocol and the ICF will be submitted to an IRB or IEC prior to initiation of the study and 
the study will not start until the IRB or IEC, as applicable, has approved the documents. 
9.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles in the 
latest version of the Declaration of Helsinki, the ICH Guideline E6 for Good Clinical Practices 
(GCP) and local regulations.  
9.3. 
Participant Information and Consent 
Before inclusion in the study, each prospective subject will be given a full explanation of the 
purpose of the study, the procedures to be carried out and the potential hazards. Once this 
essential information is provided to the subject, the subjects will be required to read, sign and 
date an informed consent form prior to enrollment. Subjects will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. They will be given 
a copy of their ICF. 
If an amended or revised ICF is introduced during the study, each subject’s further consent must 
be obtained. 
9.4. 
Subject Confidentiality and Personal Data Protection 
The investigators and the Sponsor (and organizations processing data on its behalf [Processers]) 
will preserve the confidentiality of all subjects taking part in the study, in accordance with GCP 
and local regulations. Subjects should be identified by a unique subject identifier on all study 
documents provided to the Sponsor (and Processors). In compliance with local regulations/ICH 
GCP Guidelines, it is required that the investigator and institution permit authorized 
representatives of the Sponsor, of the regulatory agency(s), and IRB/IEC access to review the 
subject’s original medical records for verification of study-related procedures and data. 
Supplemental Information for Participating Sites Located in the European Union (EU), as 
applicable 
The collection of data from European patients in the study constitutes a processing of personal 
data within the meaning of Article 4 of the General Data Protection Regulation (EU) 2016/679 of 
the European Parliament and of the Council of 27 April 2016 (GDPR).  
At an organizational level, to meet European requirements the Sponsor has appointed a certified 
Data Protection Officer (DPO) in charge of ensuring compliance with data protection 
regulations. The DPO oversees the conduct of the required Data Protection Impact Assessment 
(DPIA) to assess and protect rights and freedoms of data subjects regarding processing 
operations. All Processors are bound by a data protection agreement (DPA). If personal data are 
transferred to a third country within the meaning of the General Data Protection Regulation 
(GDPR), the DPA contains the Standard Contractual Clauses established by the European 


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Commission. The DPO is also in charge of any data subject request and can be contacted directly 
by the data subject through the email provided in the patient information sheet. 
The subjects and healthcare professionals involved in this study will be informed on the type of 
data collected and processed about them, for which objective and on which legal basis; they will 
also be informed about their rights on their personal data, and how to exercise their rights. 
At a technical level, the Sponsor has implemented and maintains, and requires that Processors 
have implemented and maintain, measures such that personal data are stored in a secured 
environment, encrypted, and partitioned from other data. Access to personal data is limited to 
relevant staff through access policies. All persons accessing data are bound by a confidential 
clause or professional secrecy. 
Subjects will be assigned a unique identifier (data pseudonymization) and will not be identified 
by name in eCRFs, study databases, study-related forms, study reports, or any related 
publications. The key to identify subjects is stored in a secure manner by each study site.  
The Sponsor will regularly review its technical and organizational security measures and update 
them to take into account any evolution on technological developments. The Sponsor may apply 
additional specific statutory requirements, where applicable in the national laws. 
Besides technical and organizational measures, the Sponsor, by means of internal measures and 
imposed contractual clauses to Processors, further maintains the confidentiality of records and 
personal data of subjects. 
The Sponsor has put in place a functional process of reporting of any data breach occurring at the 
Sponsor’s or Processor’s facilities and premises which involve personal data of subjects in the 
clinical study.  In case of the occurrence of any data breach, the Sponsor, in consultation with its 
DPO, will immediately apply relevant measures to mitigate the risks to data subjects as 
appropriate in relation to the specific context of the data breach, taking into account its source, 
underlying intentions, possibilities of recovery, etc. Any data breach presenting risks to the rights 
and freedoms of data subjects will be reported to the relevant supervisory data protection 
authority within 72 hours of the Sponsor becoming aware of the data breach. In addition, in case 
of occurrence of a high-risk breach, subjects will be informed by the Sponsor (via clinical study 
site). 
 


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10. 
DATA COLLECTION, RETENTION, AND MONITORING 
10.1. 
Data Safety Monitoring Board  
An independent DSMB will evaluate safety periodically and review unblinded data from interim 
analyses (Section 8.4), providing any recommendations for early termination or study design 
adaptations.  Timing of additional reviews will be detailed in the DSMB charter.  
10.2. 
Case Report Forms 
Designated site staff will use source document entries to enter the data required by the protocol 
into the eCRFs. Representatives of the Sponsor, the CRO or their designee(s) will train 
designated site staff on accessing and using a web-based Electronic Data Capture (EDC) system. 
Investigational site staff will not be given access to the EDC system until the required training is 
completed and documented. One eCRF will be completed for each subject enrolled in the study. 
All eCRFs will be reviewed, evaluated, and approved/signed by the investigator (or designee), as 
required. 
The original source documents and a copy of the corresponding eCRFs will be retained by the 
investigator. Copies of the eCRFs will be provided to the Sponsor (or designee). 
10.3. 
Data Management and Processing 
Data from eCRFs and other external data (eg, laboratory data) will be entered into the eCRF or 
merged with a clinical database as specified in the data management plan. Quality control and 
data validation procedures will be applied to ensure the validity and accuracy of the clinical 
database. 
In accordance with the vendor’s applicable data management procedures, the clinical database 
will be reviewed and checked for omissions, apparent errors, and values requiring further 
clarification using computerized and manual checks and listings. Data queries requiring 
clarification will be issued in the eCRF and sent to the study site for resolution. Only authorized 
personnel will make corrections to the clinical data in the eCRF, and all corrections will be 
documented in an audit trail. 
10.4. 
Quality Assurance 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
CRO(s) that will conduct the study. These SOPs are designed to ensure adherence to ICH 
Guideline E6 for GCP.   
All vendors and clinical sites will be subject to inspection by the Sponsor (or designee) to ensure 
that the data are generated, documented, and reported in compliance with the study plan and 
applicable local regulatory requirements. 
10.5. 
Record Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 


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clinical development of the investigational product or at least 25 years after the end of the trial, 
whichever is longer. However, these documents should be retained for a longer period if required 
by the applicable regulatory requirement(s) or if needed by the Sponsor. 
10.6. 
Monitoring of the Study 
Due to the COVID-19 situation, any training or monitoring described in this section may be 
conducted remotely or via telephone or video. Depending on the situation over time at each site, 
it is possible that trainers or monitors may be on-site. 
Before study initiation, representatives of the Sponsor or its designee(s) will review the protocol 
and eCRF with the investigators and their staff and perform study-specific training.  
During the study, the study monitor and CRO will check documentation, either remotely or on-
site, to ensure completeness of records, accuracy of entries on the eCRFs, adherence to the 
protocol and to GCP, progress of enrollment, and confirmation study drug supply/logistics. Key 
study personnel must be available to assist the study monitor during remote or on-site visits. 
The investigator must maintain source documents for each subject in the study, which may 
consist of case and visit notes (hospital or clinic medical records). All information on eCRFs 
must be traceable to these source documents in the subject's file. For any on-site visits, the 
investigator must give the study monitor access to any relevant source documents to confirm 
their consistency with the eCRF entries. The investigator must also keep records documenting 
the informed consent process. Information in source documents that could identify the subjects 
(such as the subjects’ names) will not be forwarded to the Sponsor (or its designee(s)). 
Depending on COVID-19 restrictions, the Sponsor or its representative(s) may visit the study 
facilities in order to maintain current knowledge of the study through review of the records, 
comparison with source documents, observation and discussion of the conduct and progress of 
the study. The clinical site will then permit any trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents. 


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11. 
ADMINISTRATIVE PROCEDURES 
11.1. 
Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, 
safety, and well-being of the study subjects, the study will be conducted as described in the 
approved protocol and performed according to ICH/GCP and local regulatory guidelines.  
If amendments to the protocol and/or amendments or revisions to the ICF are required, the 
modifications will be documented and submitted to an IRB/IEC for approval. 
11.2. 
Investigator Responsibilities and Delegation of Investigator Duties 
The investigator will ensure that all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
The investigator will maintain a list of sub-investigators and other appropriately qualified 
persons to whom he/she delegates significant trial-related duties. 
11.3. 
Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the investigator (or designee) 
should promptly inform the trial subjects, should assure appropriate follow-up for the subjects, 
and should inform the regulatory authority(ies)/IRB/IEC, when required. 
11.4. 
Publication Policy 
This is a multicenter clinical trial sponsored by Atea Pharmaceuticals. Any formal presentation 
or publication of data collected for this study will be considered as a joint presentation or 
publication by the clinical investigator(s) and the Sponsor. As is customary for multicenter trials, 
publication or presentation of data from individual study centers will not be allowed prior to the 
publication of the principal study abstract(s) and manuscript(s), without the explicit written 
permission of Atea Pharmaceuticals. Subsequent publications or presentations of data from the 
study must receive review and approval from Atea Pharmaceuticals before submission.  
Any publication of data generated from this study will adhere to the guidelines delineated in the 
Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3 
(Battisti WP et al 2015).  In addition, Atea Pharmaceuticals will determine authorship of the 
principal study manuscript(s) in accordance with guidance provided by the 2022 ICMJE 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals (ICMJE). The publication or presentation of any study results shall comply 
with all applicable privacy laws. 
 
 


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12. 
REFERENCES 
[WHO Dashboard] World Health Organization Coronavirus (COVID-19) Dashboard, [resource 
on the internet] . [Accessed 12 June 2023]. Available from: https://covid19.who.int/ 
[Wiersinga et al 2020] Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, 
transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. 
JAMA 2020;324:782-93. 
[NIHR 2020] National Institute for Health Research. Living with Covid19 [resource on the 
Internet]. 2020 [published 15 October 2020; cited 11 May 2022]. Available from: 
https://evidence.nihr.ac.uk/themedreview/living-with-covid19/. 
[Carfi et al 2020] Carfi A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute 
COVID 19. JAMA 2020;324:603-5. 
[CDC 2022] Centers for Disease Control and Prevention. People with certain medical conditions 
[resource on the internet]. 2022 [updated 11 May 2023; cited 02 June 2023]. Available from: 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html 
[New York Times Vaccination Tracker] Available from: 
https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html.[archived 13 
March 2023; last accessed 26 April 2023] 
[Hacisuleyman et al 2021] Hacisuleyman E, Hale C, Saito Y, et al. Vaccine breakthrough 
infections with SARS-CoV-2 variants. N Eng J of Med 2021;384:2212-18. 
[Paxlovid. Prescribing Information] Pfizer; 2023.  Accessed June 1, 2023.  . 
https://labeling.pfizer.com/ShowLabeling.aspx?id=19599 
[Charness et al case report 2022] Charness M, Gupta K, Stack G, et al. Rapid Relapse of 
Symptomatic Omicron SARS-CoV-2 Infection Following Early Suppression with 
Nirmatrelvir/Ritonavir. 23 May 2022 Version 3. https://doi.org/10.21203/rs.3.rs-1588371/v1 
[Pfizer press release 2022] Pfizer Reports Additional Data on PAXLOVID™ Supporting 
Upcoming New Drug Application Submission to U.S. FDA. 14 June 2022. 
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-
paxlovidtm-supporting 
[Lagevrio EUA 2022] US FDA Emergency Use Authorization for Lagevrio, Revised 
Authorization 23 Mar 2022. https://www.fda.gov/media/157300/download. 
[CDC Demographic Trends 2023] Centers for Disease Control and Prevention COVID Data 
Tracker, Demographic Trends of COVID -19 cases and deaths in the US reported to CDC. 
[Updated 31 May 2023, Accessed 02 June 2023]. https://covid.cdc.gov/covid-data-
tracker/#demographics. 
[NIH 2023] NIH COVID-19 Treatment Guidelines- Therapeutic Management of Non-
hospitalized Adults with COVID-19. [Updated 20 Apr 2023, Accessed 02 June 2023]. 
https://www.covid19treatmentguidelines.nih.gov/management/clinical-
management/nonhospitalized-adults--therapeutic-management/ 


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[CDC Hospitalization and Death by Age 2023] Centers for Disease Control and Prevention Risk 
for COVID-19 Infection, Hospitalization, and Death by Age Group. [Updated 25 Apr 2023, 
Accessed 18 May 2023]. 
[Gottlieb et al 2022] Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent 
progression to severe Covid-19 in outpatients. N Engl J Med 2022;386:305-15. 
[ICH 2009] International Conference on Harmonization. Guidance on Non-clinical Safety 
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals M3 (R2). Step 4, dated 11 June 2009.   
[ICH 2012] International Conference on Harmonization. Guidance on Non-clinical Safety 
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals Questions and Answers (R2), dated 05 March 2012.   
[DAIDS 2017] U.S. Department of Health and Human Services, National Institutes of Health, 
National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. 
Available from:  https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
[Battisti WP et al. 2015] Good Publication Practice for Communicating Company-Sponsored 
Medical Research: GPP3. Ann Intern Med. 2015;163:461-464. doi:10.7326/M15-0288 
[ICMJE]  Uniform Requirements for Manuscripts.  https://www.icmje.org/icmje-
recommendations.pdf.  


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13. 
APPENDICES 
13.1. 
Appendix 1: COVID-19 Symptom Diary 
 


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COVID-19 Symptom Diary 
Do not reproduce or distribute.  The Sponsor will provide sites 
with all instruments to be completed in this study. 
Note that the following is a sample. 
 
Date of completion:_____________ 
Time of completion:_______________ 
 
SYMPTOMS 
 
1. Please choose the response below that best describes the worst severity of your COVID-19   
symptoms over the past 24 hours. 
 
 
No symptoms 
 
Mild 
 
Moderate 
 
Severe 
 
2. Please choose the response below that best describes your general physical health over the 
past 24 hours. 
 
 
Excellent 
 
Very good 
 
Good 
 
Fair 
 
Poor 
 
3. Have you returned to your usual (pre-COVID) health?  
 
     Yes 
 
No 
 
Indicate the worst severity of your symptoms DURING THE PAST 24 HOURS 
 
Symptoms 
Absent 
Mild 
Moderate 
Severe 
Cough 
 
 
 
 
Shortness of breath or difficulty breathing  
 
 
 
 
Feeling feverish 
 
 
 
 
Chills 
 
 
 
 
Fatigue (low energy) 
 
 
 
 
Body pain or muscle pain or aches 
 
 
 
 
Diarrhea (loose or watery or more frequent stools) 
 
 
 
 
Nausea (feeling like you want to throw up) 
 
 
 
 
Vomiting (throwing up) 
 
 
 
 
Headache 
 
 
 
 
Sore throat 
 
 
 
 
Nasal obstruction or congestion (stuffy nose) 
 
 
 
 
Nasal discharge (runny nose) 
 
 
 
 
 
 
 
 


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Indicate if you have had the following during the past 24 hours: 
 
 
Yes 
No 
Loss of taste 
 
 
Loss of smell 
 
 
 
 
 
4.  Symptom Relapse:  Have your COVID-19 symptoms returned after previously improving? 
 
     Yes 
 
No 
 
Not applicable (symptoms have not yet improved) 
 


Signature Page for VV-CLIN-000033 v3.0
Signature Page for VV-CLIN-000033 v3.0
Approval Task Task
Verdict: Approved
25-Jun-2023 20:35:35 GMT+0000
PPD

SAP_001.pdf: 
Atea Pharmaceuticals, Inc.   
 
Version 5 
Statistical Analysis Plan – AT-03A-017 
 
June 24, 2024 
 
1 
 
 
  
 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
 
VERSION: 5 
DATE OF PLAN: 
24-JUN-2024 
 
BASED ON: 
AT-03A-017 Protocol Version 2.0, 15-Jun-2023 
 
STUDY DRUG: 
Bemnifosbuvir Hemisulfate (BEM; AT-527) 
PROTOCOL NUMBER: 
AT-03A-017 
STUDY TITLE: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19 
 
SPONSOR: 
Atea Pharmaceuticals, Inc. 
225 Franklin Street 
Suite 2100 
Boston, MA 02110 USA 
+1 (857) 284-8891 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 
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SIGNATURE PAGE 
 
 
This document has been prepared and reviewed by: 
 
 
 
 
 
 
 
 
This document has been reviewed and accepted by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
INTRODUCTION ........................................................................................................9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
3.1. 
Study Objectives .........................................................................................................10 
3.1.1. 
Primary Objective .......................................................................................................10 
3.1.2. 
Secondary Objectives .................................................................................................10 
3.1.3. 
Exploratory Objectives ...............................................................................................10 
3.2. 
Study Endpoints ..........................................................................................................11 
3.2.1. 
Primary Endpoints ......................................................................................................11 
3.2.2. 
Secondary Endpoints ..................................................................................................11 
3.2.3. 
Exploratory Endpoints ................................................................................................11 
4. 
STUDY DESIGN .......................................................................................................18 
4.1. 
Summary of Study Design ..........................................................................................18 
4.2. 
Definition of Study Drugs ..........................................................................................19 
4.3. 
Sample Size Considerations .......................................................................................19 
4.3.1. 
Sample Size Justifications ..........................................................................................19 
4.4. 
Randomization ............................................................................................................20 
4.5. 
Clinical Assessments ..................................................................................................20 
5. 
PLANNED ANALYSES ............................................................................................22 
5.1. 
Interim Analyses .........................................................................................................22 
5.2. 
Final Analyses ............................................................................................................22 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................23 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........23 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................23 
6.3. 
Data Management .......................................................................................................23 
6.4. 
Data Presentation Conventions ...................................................................................24 
6.5. 
Analysis Populations ..................................................................................................24 
6.5.1. 
Screen Failures ............................................................................................................24 
6.5.2. 
Safety Population ........................................................................................................24 
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6.5.3. 
ITT Population ............................................................................................................24 
6.5.4. 
mITT Population .........................................................................................................24 
6.5.5. 
Per Protocol Population ..............................................................................................25 
6.5.6. 
Completers ..................................................................................................................25 
6.6. 
Baseline Definition .....................................................................................................25 
6.7. 
Derived and Transformed Data ..................................................................................25 
6.7.1. 
Baseline Age ...............................................................................................................25 
6.7.2. 
Study Day ...................................................................................................................26 
6.7.3. 
Change from Baseline .................................................................................................26 
6.7.4. 
Visit Windows ............................................................................................................26 
6.7.5. 
Multiple Assessments .................................................................................................27 
6.8. 
Handling of Missing Data ...........................................................................................27 
6.8.1. 
Missing Efficacy Endpoints ........................................................................................27 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................27 
6.8.3. 
Missing Start and Stop Dates for Adverse Events ......................................................27 
7. 
STUDY POPULATION .............................................................................................29 
7.1. 
Subjects Disposition ...................................................................................................29 
7.2. 
Screen Failures ............................................................................................................29 
7.3. 
Protocol Deviations ....................................................................................................29 
7.4. 
Demographic and Baseline Characteristics ................................................................30 
7.5. 
Medical History and Medical Conditions Present at Entry ........................................30 
7.6. 
Prior Medication History and Medications Present at Entry ......................................31 
8. 
EFFICACY .................................................................................................................32 
8.1. 
General Considerations ...............................................................................................32 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline .......................32 
8.3. 
Statement of the Null and Alternate Hypotheses ........................................................32 
8.4. 
Subgroup Analyses .....................................................................................................32 
8.5. 
Multiple Comparisons and Multiplicity......................................................................33 
8.6. 
Analysis of the Primary Efficacy Endpoint ................................................................34 
8.6.1. 
Primary Efficacy Analysis ..........................................................................................34 
8.6.2. 
Sensitivity Analyses of the Primary Efficacy Results ................................................36 
8.7. 
Analysis of the Secondary Efficacy Endpoints ..........................................................36 
8.8. 
Analysis of Exploratory Efficacy Endpoints ..............................................................37 
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8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses .......................................................................................................39 
9. 
SAFETY AND TOLERABILITY ..............................................................................40 
9.1. 
Overall Summary of Tolerability ................................................................................40 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............40 
9.3. 
Exposure .....................................................................................................................41 
9.4. 
Concomitant and Other Medications ..........................................................................41 
9.5. 
Routine Laboratory Data ............................................................................................41 
9.6. 
Vital Signs ..................................................................................................................42 
9.7. 
Physical Examination .................................................................................................42 
9.8. 
Pharmacokinetics ........................................................................................................42 
10. 
REFERENCES ...........................................................................................................44 
11. 
APPENDICES ............................................................................................................45 
11.1. 
COVID-19 Symptom Diary ........................................................................................45 
11.2. 
Sample Size Calculation Details .................................................................................46 
 
 
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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Estimand Definitions for Primary and Key Secondary Endpoints .............................13 
Table 3: 
Visit Windows (Days) ................................................................................................26 
Table 4: 
Summary of Analyses Related to the Primary Efficacy Endpoint .............................34 
Table 5: 
Criteria for Markedly Abnormal Changes in Vital Signs ...........................................42 
 
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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BEM 
Bemnifosbuvir 
BID 
Two times a day 
BMI 
Body mass index 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
DAIDS 
Division of AIDS 
DDI 
Drug-drug interaction 
DSMB 
Data and Safety Monitoring Board 
EFU 
Extended follow-up 
EOT 
End-of-Treatment 
EUA 
Emergency use authorization 
FDA 
United States Food and Drug Administration 
FDD 
First dosing date of study drug 
I/E 
Inclusion/exclusion 
ITT 
Intent-to-Treat Population 
LOD 
Limit of Detection 
LLoQ 
Lower Limit of Quantification 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MedDRASOC 
System organ class 
mITT 
Modified intent-to-treat 
mITT-C 
Modified intent-to-treat for combination antiviral stratum 
mITT-S 
Modified intent-to-treat for supportive care stratum 
NP 
Nasopharyngeal 
 
 
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Abbreviation 
Term 
PK 
Pharmacokinetics 
PT 
Preferred term 
RNA 
Ribonucleic acid 
PP 
Per-Protocol Population 
ROW 
Rest of world 
RT-qPCR 
Reverse transcription quantitative real-time polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System  
SD 
Standard deviation 
SOC 
Standard of care 
SOP 
Standard operating procedure 
ULN 
Upper Limit of Normal 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of the normal range 
WHODRUG 
World Health Organization Drug Dictionary 
 
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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol AT-03A-017. 
Protocol Revision Chronology: 
Protocol 
08-SEP-2022 
Original (Version 1.0) 
Protocol Amendment 
15-JUN-2023 
Amendment (Version 2.0) 
 
The SAP is based on:  
x Protocol No. AT-03A-017 Amendment, Version 2.0, dated June 15, 2023 
x IND 149508 FDA End of Phase 2 Meeting Minutes, issued 18 AUG 2022 
x ICH E9: Statistical Principles for Clinical Trials1.  
The purpose of this document is to provide details on study populations and on how the variables 
will be derived, how missing data will be handled as well as details on statistical methods to be 
used to analyze the safety and efficacy data in Study AT-03A-017.  
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests.  However, the final SAP will be finalized, approved by the 
Sponsor, and placed on file before unblinding of study data. Deviations from the final approved 
plan will be noted in the clinical study report. 
Study AT-03A-017 will have evaluations of efficacy and safety in 2 strata: a supportive-care 
only group that will receive either bemnifosbuvir (BEM) or placebo without any additional 
COVID-19 antiviral drugs and a combination antiviral group that will receive either BEM or 
placebo in addition to an antiviral COVID-19 therapy. The primary analysis is based on subjects 
in the supportive-care only stratum and this stratum will comprise the majority of subjects 
enrolled into the study.
 
 
Unless otherwise specified, all analyses will be carried out on each stratum. Further information 
can be found in the protocol. 
SAP version 5 includes additional subgroup analysis, and clarifications from previous SAP 
versions for programming. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of bemnifosbuvir (BEM) compared with 
placebo in reducing all-cause hospitalization or all-cause death in COVID-19 outpatients 
receiving only supportive care. 
3.1.2. 
Secondary Objectives 
The following are secondary objectives: 
x To evaluate the efficacy of BEM compared with placebo on: 
o All-cause hospitalization, all-cause death, or COVID-19 related medically 
attended visits through Day 29 and Day 60 
o COVID-19 related hospitalization or all-cause death through Day 29 and Day 60 
o All-cause death through Day 29 and Day 60 
o COVID-19 related complications (eg, death, hospitalization, radiologically 
confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, 
pericarditis/myocarditis, cardiac failure) through Day 29 and Day 60 
o COVID-19-related medically attended visits (hospitalization, emergency room 
(ER) visit, urgent care visit, physician’s office visit, or telemedicine visit) or all-
cause death through Day 29 and Day 60 
o COVID-19 related medically attended visits through Day 29 and Day 60  
o COVID-19 symptom relapse 
x To evaluate the antiviral activity of BEM compared with placebo on viral load rebound 
x To evaluate the safety of BEM compared with placebo. 
3.1.3. 
Exploratory Objectives 
The exploratory objectives are  
x To evaluate the efficacy of BEM compared with placebo on: 
 Sustained alleviation or improvement of COVID-19 symptoms 
 Return to usual (pre-COVID-19) health 
 Requirement for post-randomization rescue therapy 
 The antiviral activity of BEM compared with placebo 
x To assess plasma concentrations of AT-511 (free base form of AT-527 [BEM]) and its 
metabolites from sparse PK sampling at steady-state. 
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3.2. 
Study Endpoints 
Estimands corresponding to primary and secondary endpoints are defined in Table 2 .  
3.2.1. 
Primary Endpoints 
The primary efficacy endpoint is the proportion of subjects in the supportive-care-only 
population who are hospitalized for any cause or died due to any cause through Day 29.  
3.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
Efficacy: 
x Proportion of subjects with all-cause hospitalization or all-cause death through Day 60 
x Proportion of subjects with all-cause hospitalization, all-cause death, or COVID-19 
related medically attended visits through Day 29 and Day 60 
x Proportion of subjects with COVID-19-related hospitalization or who died due to any 
cause death through Day 29 and Day 60 
x Proportion of subjects who died due to any cause through Day 29 and Day 60 
x Proportion of subjects with COVID-19-related complications (eg., death, hospitalization, 
radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, 
pericarditis/myocarditis, cardiac failure) through Day 29 and Day 60 
x Proportion of subjects with COVID-19-related medically attended visits (hospitalization, 
emergency room (ER) visit, urgent care or physician’s office visit or telemedicine visit) 
or who died due to any cause through Day 29 and Day 60 
x Proportion of subjects with COVID-19 symptom relapse through Day 29  
x Proportion of subjects with viral load rebound through Day 29.  
Safety: 
x The incidence and severity of adverse events (AEs) and serious adverse events (SAEs). 
The primary endpoint will also be assessed in the combination antiviral population as a 
secondary endpoint. All secondary endpoints will be assessed in both the supportive-care-only 
population and the combination antiviral population.  
3.2.3. 
Exploratory Endpoints 
Efficacy: 
x Time to sustained alleviation or improvement of COVID-19 symptoms  
x Time to self-reported return to usual (pre-COVID-19) health  
x Proportion of subjects requiring post randomization rescue therapy  
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 Note:  For subjects randomized into the combination antiviral population, antiviral medications 
administered post-baseline within 24 hours of first study drug, as part of the combination regimen, are 
not considered rescue medication. 
Note:  Rescue therapy for the purpose of the endpoint includes only treatments with direct activity against 
SARS-CoV-2; and that is administered for COVID-19-related clinical decline.  
x Duration and severity of COVID-19 symptom relapse 
x Proportion of subjects with both COVID-19 symptom relapse and viral rebound  
x Change from baseline in amount of SARS-CoV-2 viral RNA as measured by RT-qPCR 
overtime 
x Time to cessation of SARS-CoV-2 viral shedding by RT-qPCR 
x Proportion of subjects negative for SARS-CoV-2 viral RNA by RT-qPCR over time   
x Area under the curve (AUC) in the amount of SARS-CoV-2 viral RNA as measured by 
RT-qPCR   
x Potential future biomarker analyses 
 
 
x Pharmacokinetics: Plasma concentration of AT-511 (free base form of AT-527 [BEM]) 
and its metabolites 
 
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Table 2: 
Estimand Definitions for Primary and Key Secondary Endpoints 
Estimand 
Endpoint 
Intercurrent 
event handling 
Population-
Level Summary 
for the Variable 
Handling of 
Missing Data 
Study 
Withdrawal/ 
Lost to Follow-
Up 
Primary: difference in 
the proportion of 
subjects in the 
supportive-care 
population with all-cause 
hospitalization or death 
by Day 29 and Day 60, 
regardless of intercurrent 
events 
 
The proportion of subjects in 
the supportive-care-only 
population who are 
hospitalized for any cause or 
died due to any cause 
through Day 29 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care 
population with all-cause 
hospitalization, all-cause 
death, or COVID-19 
related medically 
attended visits through 
Day 29 and Day 60, 
regardless of intercurrent 
events 
The proportion of subjects in 
the supportive-care 
population who are 
hospitalized for any cause or 
died due to any cause, or had 
COVID-10 related medically 
attended visits through Day 
29 and Day 60 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
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Estimand 
Endpoint 
Intercurrent 
event handling 
Population-
Level Summary 
for the Variable 
Handling of 
Missing Data 
Study 
Withdrawal/ 
Lost to Follow-
Up 
Secondary: difference in 
the proportion of 
subjects in the 
combination antiviral 
population with all-cause 
hospitalization or death 
by Day 29 and Day 60, 
regardless of intercurrent 
events 
The proportion of subjects in 
the combination antiviral 
population who are 
hospitalized for any cause or 
died due to any cause 
through Day 29 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care-only 
population with COVID-
19 related hospitalization 
or any cause death by 
Day 29 and Day 60, 
regardless of intercurrent 
events 
 
The proportion of subjects in 
the supportive-care-only 
population with COVID-19-
related hospitalization or 
who died due to any cause 
death through Day 29 and 
Day 60 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
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Estimand 
Endpoint 
Intercurrent 
event handling 
Population-
Level Summary 
for the Variable 
Handling of 
Missing Data 
Study 
Withdrawal/ 
Lost to Follow-
Up 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care-only 
population with COVID-
19-related complications 
by Day 29 and Day 60, 
regardless of intercurrent 
events 
 
The proportion of subjects in 
the supportive-care-only 
population with COVID-19-
related complications 
through Day 29 and Day 60 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care-only 
population with COVID-
19-related medically 
attended visits or any 
cause death by Day 29 
and Day 60, regardless 
of intercurrent events 
 
The proportion of subjects in 
the supportive-care-only 
population with COVID-19-
medically attended visits or 
who died due to any cause 
through Day 29 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
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Estimand 
Endpoint 
Intercurrent 
event handling 
Population-
Level Summary 
for the Variable 
Handling of 
Missing Data 
Study 
Withdrawal/ 
Lost to Follow-
Up 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care-only 
population who died, 
regardless of intercurrent 
events through Day 29 
and Day 60 
 
The proportion of subjects in 
the supportive-care-only 
population who died due to 
any cause through Day 29 
and Day 60 
 
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy. 
Death: composite 
strategy, 
considered as event 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
Secondary: difference in 
the proportion of 
subjects in the 
supportive-care-only 
population with COVID-
19 symptom relapse by 
Day 29, regardless of 
intercurrent events 
 
Proportion of subjects with 
COVID-19 symptom relapse 
in the supportive-care-only 
population through Day 29 
 
Treatment 
discontinuation or 
rescue treatment 
prior to event: 
treatment-policy 
strategy approach 
will be taken.  
 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
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Estimand 
Endpoint 
Intercurrent 
event handling 
Population-
Level Summary 
for the Variable 
Handling of 
Missing Data 
Study 
Withdrawal/ 
Lost to Follow-
Up 
Secondary: difference in 
the proportion of 
subjects  in the 
supportive-care-only 
population with viral 
load rebound by Day 29, 
regardless of rescue 
medication 
 
The proportion of subjects in 
the supportive-care-only 
population with viral load 
rebound through Day 29 
 
Treatment 
discontinuation or 
rescue treatment 
prior to event: 
treatment-policy 
strategy approach 
will be taken.  
 
The common 
risk difference 
The outcome 
measure up to 
point of study 
withdrawal will 
be used 
 
 
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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
AT-03A-017 is a Phase 3 randomized, double-blind, placebo-controlled study, conducted in 
non-hospitalized adult subjects (≥18 years of age) with mild or moderate COVID-19.  
Age and comorbidities will determine a patient’s risk and eligibility. Onset of COVID-19 
symptoms will have occurred ≤5 days before randomization. 
BEM 550 mg or matching placebo will be administered BID for 5 days (10 doses, with each dose 
including 2 tablets).  
Locally available standard of care (SOC) treatment is to be initiated in parallel with study drug 
(add-on). SOC treatments with direct antiviral activity against SARS-CoV-2 are allowed, but are 
to be initiated during screening and/or within 24 hours prior to or after randomization.  
Subjects will be randomized 1:1 (active:placebo) to one of the following arms: 
x 550 mg BEM (2 x 275 mg tablets) BID for 5 days 
x Placebo (2 tablets) BID for 5 days 
Randomization will be stratified by geographic region (North America, Europe, Asia, and rest of 
world [ROW]), age (< 65 years old vs ≥ 65 years old) and by the type of SOC which the 
investigator plans to administer in parallel at time of study drug initiation. The type of SOC 
received will be used to classify subjects into two categories: 
x Combination antiviral stratum (subsequently referred to as the combination antiviral 
population): In addition to study drug, the subject will be initiated on a local SOC 
regimen which includes a treatment with direct SARS-CoV-2 antiviral activity. Examples  
include nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs 
x Supportive-care-only stratum (subsequently referred to as the supportive-care-only 
population): the SOC regimen the subject will receive does not include any treatment 
with direct SARS-CoV-2 antiviral activity 
Although randomization is stratified by whether COVID-19 drugs with antiviral effects are 
administered, both strata allow local SOC therapies without direct antiviral effects (i.e., 
corticosteroids).  
Patients who require SOC treatment with a non-compatible antiviral treatment, defined as those 
with a potential drug-drug interaction (DDI) with BEM (e.g., remdesivir), are excluded. 
For subjects who deteriorate on study, any rescue therapy which is SOC for progression to severe 
COVID-19 is permitted. If rescue therapy will be remdesivir, study drug will be discontinued 
before initiation of remdesivir. 
Overall, up to 2510 eligible subjects with COVID-19 will be enrolled, with a target of 
2210 subjects in the supportive-care-only population and 300 subjects in the combination 
antiviral population. The primary study endpoint (hospitalization/death) will be evaluated in the 
supportive-care-only population. 
The primary study period is up to 30 days, including up to 1 day for screening and 29 days 
following randomization. Extended follow-up data will be collected through Day 60 for 
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mortality and medically attended visit (MAV) assessment. The Day 60 follow-up contact marks 
the end of study participation for each subject and the study ends when the last subject completes 
the Day 60 follow-up contact.
A schematic of the study design is presented in Figure 1.
Figure 1:
Study Design
4.2.
Definition of Study Drugs
Study drug (550 mg BEM or matching placebo) is to be administered twice daily for 5 days, i.e.,
a total of 10 doses (20 tablets total). Each dose will be taken as 2 tablets (2x 275 mg BEM tablets 
or 2 matching placebo tablets). 
4.3.
Sample Size Considerations
The primary endpoint of proportion of subjects with all-cause hospitalization and all-cause 
mortality through Day 29 will be compared between treatments using a Cochran-Mantel-
Haenszel (CMH) test adjusted for the stratification factors of age and region. The overall type I 
error will be controlled at a one-sided 0.025 level. Total beta spending was specified at a 0.10 
level.
The study was planned to have interim analyses at 30% (futility only) and 65% (futility, safety
and efficacy) of the originally planned number of subjects. The interim analyses were removed
due to fast enrollment such that the final sample size was reached prior to the first planned 
interim analysis.
4.3.1.
Sample Size Justifications
Assuming the combined all-cause hospitalization and all-cause mortality rate will be 4% in the 
placebo arm, the sample size needed to detect a true 60% reduction (corresponding to an absolute 
difference in rates of 2.4%) in the BEM treatment arm with 90% power at a 1-sided significance 
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level of 2.5% was determined to be 1982 randomized participants in the supportive-care-only 
population. Sample size was calculated using SAS (version 9.4) for a 2-sample proportion Chi-
square test. Considering the planned interim analyses with both alpha and beta spending 
according to Lan-Demets approximation of O’Brien Fleming method the sample size should be 
inflated by a multiplier of 1.055 to a target sample size of 2100 participants (see Section 11.1 ). 
Assuming 95% of randomized subjects who receive only supportive care as SOC will meet the 
mITT-S population criteria (see Section 6.5.4 ), the study targets total enrollment of 2210 
subjects in the supportive-care-only population.  If the true rate in the placebo arm is 3%, and 
assuming a reduction of 60% with BEM, the planned study has at least 80% power to detect a 
treatment effect. Planned enrollment in the combination arm is up to 300 subjects.  
4.4. 
Randomization 
Subjects will be randomized 1:1 (active:placebo) to one of the following arms: 
x 550 mg BEM (2 x 275 mg tablets) BID for 5 days 
x Placebo (2 tablets) BID for 5 days 
Randomization will be stratified by geographic region (North America, Europe, Asia, and 
ROW), age (< 65 years old, ≥ 65 years old) and by the type of SOC which the investigator plans 
to administer in parallel at time of study drug initiation. The primary stratification factor is the 
type of background SOC that the investigator plans to administer as this determines whether the 
subject is in the supportive-care only group (i.e. may be included in the primary analysis 
population) or the combination antiviral group. Within each of the primary strata, randomization 
is further stratified by geographic region (North America, Europe, Asia, and ROW) and age (<65 
and ≥65). 
The type of SOC received will be used to classify subjects into two categories: 
x Combination antiviral stratum (subsequently referred to as the combination antiviral 
population):In addition to study drug, the subject will be initiated on a local SOC regimen 
which includes a treatment with direct SARS-CoV-2 antiviral activity. Examples include 
nirmatrelvir/ritonavir, molnupiravir, favipiravir, mAbs 
x Supportive-care-only stratum (subsequently referred to as the supportive-care-only 
population): the SOC regimen the subject will receive does not include any treatment 
with direct SARS-CoV-2 antiviral activity 
4.5. 
Clinical Assessments 
The following assessments will be performed at Screening, defined as within 24 hours of first 
dose of study drug, only: 
x Demographics 
x Medical history and baseline characteristics 
x Pre-existing symptoms 
x Height and weight 
x Complete physical examination 
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x Pregnancy test (females of childbearing potential) 
x Rapid test for influenza. 
Information on study drug dosing will be collected on Days 1-6 and a plasma sample for 
evaluation of sparse pharmacokinetics will be collected on Day 5. 
The following assessments will be performed at visits corresponding to Days 1, 5, 14 and Early 
Termination (ET): 
x Central safety laboratory values 
x Potential blood biomarkers 
) 
The following assessments will be collected at each study visit from Day 1 onward (during the 
29-day follow-up period i.e., Days 1, 3, 5, 7, 14, 29, and ET if applicable) with exceptions noted: 
x Vital signs, to Day 14 
x Symptom-targeted physical examination, as clinically indicated 
x Nasopharyngeal (NP) swab for central assessment of SARS-CoV-2 virus (quantitative 
RT-PCR and potential viral titer) 
x Adverse events (SAEs out to Day 60) 
x Concomitant medications 
x Assessment of COVID-19 related medically attended visit(s) (out to Day 60). 
Patient reported COVID-19 symptoms will be collected daily on Days 1-29. Symptoms are 
captured via the COVID-19 symptom diary (see Section 11.1 ). 
At the extended follow-up visit on Day 60, planned collection includes assessment of medically 
attended visit(s) and serious adverse events. 
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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
A Data and Safety Monitoring Board (DSMB) will be responsible for ongoing monitoring of 
safety for the study. The DSMB members are independent of the study team and are external to 
the Sponsor. Unblinded analyses will be prepared and provided to the DSMB by an independent 
statistical group at the contract research organization (CRO). A DSMB charter describes the role 
of the DSMB in more detail. 
Efficacy and futility interim analyses were planned at the beginning of this study but were 
removed due to fast enrollment such that the final sample size was reached prior to the first 
planned interim analysis. 
5.2. 
Final Analyses 
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6. 
FINAL ANALYSES WILL BE PERFORMED AFTER DATABASE 
LOCK WHEN ALL SUBJECTS HAVE COMPLETED OR 
DISCONTINUED FROM THE STUDY AND DATA CLEANING 
HAS BEEN COMPLETED. GENERAL CONSIDERATIONS FOR 
DATA ANALYSES AND HANDLING 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Unless otherwise specified, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation (SD), minimum, first quartile, 
median, third quartile and maximum values as summary statistics; categorical variables will be 
summarized by using the frequency count and the percentage of subjects in each category as 
summary statistics.  Descriptive summaries will be tabulated by treatment group.  
When a summary tabulates the number of subjects, subjects will only be counted once for a 
category (e.g., a particular adverse event type, a particular adverse event term, a particular 
concomitant medication) unless otherwise specified.  
All statistical tests will be performed at a 0.025 significance level using one-sided tests, unless 
otherwise noted. Statistical tests will use stratification factors (age and region) according to 
randomization.  Stratification factors may need to be removed or have their levels combined so 
that low or zero counts in one stratum do not invalidate relevant statistical tests. 
Unless otherwise specified, all efficacy and virology analyses will be performed on the modified 
intent-to-treat (mITT) analysis populations for each stratum. All safety analyses, demographics, 
and baseline characteristics will be performed on the safety population. Refer to Section 6.5 for 
details on analysis population definitions. 
All Safety, Efficacy, and Tolerability data will be listed. In cases where additional information 
may be helpful, considerations for listings will be noted in this document. 
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
By-subject listings will be sorted by population stratum (i.e. supportive-care only, combination 
antiviral), antivirals used (for combination antiviral only), treatment, subject ID number, 
assessment/start date, and assessment/start time (where applicable). Subject identification will 
include age, sex, country (as 3-digit code) and race. 
6.3. 
Data Management 
Data management and cleaning will be conducted in accordance with the standard operating 
procedures (SOP) of the CRO for the study with oversight in accordance with the Sponsor’s 
corresponding SOP. Derived datasets, data analyses and summary tables will be created using 
SAS® software, version 9.4 or above.   
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6.4. 
Data Presentation Conventions 
Unless otherwise indicated, data summaries and individual listings will be presented by 
population stratum and treatment. Treatment will be considered as BEM and placebo within each 
population stratum.  For presentations of efficacy analysis, subjects will be grouped according to 
the treatment to which they were randomized. For presentations on the safety analysis, subjects 
will be grouped according to the treatment that was received. 
6.5. 
Analysis Populations 
6.5.1. 
Screen Failures 
Screen failures will include subjects who fail to meet inclusion/exclusion (I/E) criteria. Subjects 
who are enrolled and do not fail any I/E criteria but decide not to participate in the study prior to 
randomization will also be included here. 
6.5.2. 
Safety Population 
The safety population will include all subjects who received at least one dose of the study drug 
(BEM or placebo). The study population will be analyzed as treated. Any subjects who were 
randomized more than once will be excluded from the summary tables, but the data will be 
included in listings and indicated appropriately. 
6.5.3. 
ITT Population 
The intent-to-treat (ITT) population will include all randomized subjects and will be analyzed as 
randomized. 
6.5.4. 
mITT Population 
The modified intent-to-treat (mITT) population includes all randomized subjects who received ≥ 
1 dose of study drug and have ≥ 1 positive SARS-CoV-2 result (from NP swab samples via 
central testing) through Day 5. The majority of subjects are expected to have the positive SARS-
CoV-2 qualifying sample at baseline, but the window is extended to allow the inclusion of 
subjects who may have a baseline false negative (via central testing) or missing sample at 
baseline. Any subjects who were randomized more than once will be excluded from the 
summary tables, but the data will be included in listings and indicated appropriately. 
The modified intent-to-treat-S (mITT-S) population includes all randomized subjects who 
received ≥ 1 dose of study drug, have ≥ 1 positive SARS-CoV-2 result (from NP swab samples 
via central testing) through Day 5, and who are stratified into the supportive-care-only 
population according to the standard of care received (i.e., per EDC).   
The modified intent-to-treat-C (mITT-C) population includes all randomized subjects who 
received ≥ 1 dose of study drug, have ≥ 1 positive SARS-CoV-2 result (from NP swab samples 
via central testing) through Day 5, and who are stratified into the combination antiviral 
population according to the standard of care received (i.e., per EDC).  
The mITT populations are further restricted from the ITT population, but the intent-to-treat 
principle has been maintained as the requirements only define the target population while not 
introducing bias between the two treatment arms. The mITT-S and mITT-C populations are 
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displayed separately to present the treatment comparisons in two different standard of care 
scenarios. If a subject is mis-stratified in randomization, actual stratification will be used in the 
analysis performed by strata. 
6.5.5. 
Per Protocol Population  
The per-protocol population for the supportive care population is a subset of the mITT-S 
population that: 
x Received all 10 doses of study drug as per protocol (with the exception of those subjects 
who discontinued study drug to initiate remdesivir rescue therapy, or discontinued study 
due to hospitalization or death) 
x Did not have any inclusion/exclusion criteria protocol violations. 
Subjects are excluded from the mITT-S per-protocol population if they received non-study drugs 
with SARS-CoV-2 antiviral activity (e.g. nirmatrelvir/ritonavir, molnupiravir, favipiravir, 
monoclonal antibodies (mAbs)) for the current SARS-CoV-2 infection from screening (or 24 
hours prior to randomization) through Day 29 (with the exception of non-study drugs 
administered as rescue antiviral therapy). 
6.5.6. 
Completers 
Subjects considered as having completed the primary study follow-up are those in the mITT 
population who were followed through to at least Day 29 or had a hospitalization or death event 
prior to Day 29. Any subject who has a Day 29 (or subsequent scheduled) visit or an assessment 
on a date corresponding to study day 29 or later (see Section 6.7.2 ) will be considered as having 
been followed through to at least Day 29. 
6.5.7. 
PK population 
The PK population will include all subjects who receive at least 1 dose of AT-527 and have at 
least 1 pharmacokinetic measurement. 
 
6.6. 
Baseline Definition 
Baseline is defined as the last available assessment prior to first dose of study treatment (BEM or 
placebo).  For analyses of virology data, if there is no pre-study drug assessment available then 
baseline can be up to 4 hours post first dose, with the earliest assessment within this time 
window used as baseline in the case of multiple qualifying assessments. For analysis of 
symptoms, Day 1 assessment will be used as the baseline. 
 
6.7. 
Derived and Transformed Data 
6.7.1. 
Baseline Age  
Baseline age is the age at the time of randomization. 
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6.7.2. 
Study Day 
Study day will be calculated from the first dosing date of study drug (FDD) and derived as 
follows: 
x Assessment date ≥ date of first study drug: Assessment Date – FDD + 1 
x Assessment date < date of first study drug: Assessment Date – FDD. 
If a subject is randomized but does not receive any study drug, the randomization date will be 
used for reference, in place of FDD. 
Relative symptom start day will be calculated from the symptom start date and derived as 
follows: 
x FDD – symptom start date +1 
 
6.7.3. 
Change from Baseline 
Where applicable, change from baseline will be computed simply as the difference between the 
post-baseline value and the baseline value. 
6.7.4. 
Visit Windows 
For the purposes of by-visit analyses for scheduled clinical assessments (i.e., excluding patient-
reported assessments), visit windows for inclusion in the analysis are defined in Table 3 .  Note 
that the definition of baseline is provided in Section 6.6.  
Table 3: 
Visit Windows (Days)  
Visit 
Target Study Day 
Visit Window, Study Day(s) 
Baseline/Day 1a 
1 
1 
Day 3 
3 
2 – 4 
Day 5 
5 
4 – 6 
Day 7 
7 
7 – 10  
Day 14 
14 
11 – 21 
Day 29 
29 
22 - 36  
Day 60 
60 
>36 
a. If a Day 1 assessment is not available, a qualifying baseline assessment can be utilized. 
Patient reported outcomes are to be reported daily on Days 1 – 29 and data will be based on the 
corresponding day. If there is more than one assessment on a day, then the least favorable 
assessment will be utilized for analysis. 
There is overlap at study day 4 for the Day 3 and Day 5 windows to increase the chance to have 
qualifying observations at both of these timepoints. In the case where a measurement is captured 
on Day 4, the assignment for the observation will be according to the following: 
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x If there is another measurement on study day 5 and: 
o Another qualifying measurement for Day 3: day 4 measurement not assigned to 
Day 3 or Day 5 
o Otherwise, day 4 measurement assigned to day 3 and day 5 measurement assigned 
to Day 5. 
x Else if there is another measurement on study day 6 and: 
o Another qualifying measurement for Day 3: day 4 measurement not assigned to 
Day 3 or Day 5 
o Otherwise, day 4 measurement assigned to Day 3 and day 6 measurement 
assigned to Day 5. 
x Else day 4 measurement is assigned to Day 5. 
6.7.5. 
Multiple Assessments 
If multiple measurements are obtained within a visit window for a subject, the value obtained 
closest to the target timepoint will be used. For any visit, no more than one value per subject will 
be included in an analysis. In the event of multiple observations that are equidistant from, but not 
on, the target day (i.e., observations made in a similar time frame before and after target), the 
later value, based on date and time, will be selected.  
6.8. 
Handling of Missing Data 
6.8.1. 
Missing Efficacy Endpoints 
Missing efficacy data will not be imputed unless otherwise specified in the specific section 
describing an endpoint. Sensitivity analyses will be carried out to evaluate the impact of missing 
efficacy data. 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Where the start date for a concomitant medication is missing, the medication will be assumed to 
have started prior to enrolment in the study. Where the stop date for a concomitant medication is 
missing, the medication will be assumed to be ongoing to the date of the subject’s last 
assessment. 
6.8.3. 
Missing Start and Stop Dates for Adverse Events 
Where the entire start date for an adverse event is missing, the adverse event will be assumed to 
be treatment-emergent. In this case, if the duration of an adverse event is computed, the start date 
will be considered as the date associated with Day 1. If the month and year of an adverse event is 
provided, then the start date will be considered as the later date between the first day of the 
month/year and the treatment start date. 
Where the stop date for an adverse event is missing, the adverse event will be assumed to be 
ongoing to the date of the subject’s last assessment. If the month and year of the stop date is 
provided, then the stop date will be considered as the earlier date between the last day of the 
month/year and the last assessment date. 
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6.8.4. 
Missing Numeric Viral Load Assessment 
Where SARS-CoV-2 RNA is detected but the numeric value is “<500”, it will be assigned as 
LLoQ-1 (i.e., 499). If SARS-CoV-2 RNA is not detected, it will be imputed as LOD – 1 (i.e., 
249). If SARS-CoV-2 RNA is “>500000000”, it will be assigned as 500000001 for the purpose 
of quantitative summaries. For samples reported outside the limits of quantification (e.g.., 
‘<500’, or ‘>500000000’), listings will display “<500” or “>500000000”, as appropriate. 
6.8.5. 
Missing COVID-19 symptom diary assessment 
If a subject was missing all symptom diary assessments, this subject will be excluded from 
analysis. For the time-to-event analyses, missing individual symptom assessments at times will 
be imputed prior to statistical analysis. If there is missing data between two assessments, the 
missing data will be imputed as the worst outcome of the two. Missing data after the last 
recorded assessment will not be imputed; instead censoring may be utilized for the time to event 
endpoint in cases where the endpoint was not achieved. For time to sustained 
alleviation/improvement of symptoms, censoring will be applied thus:  
x 
if the last observed time point does not meet alleviation/improvement criteria, the 
result is censored at the time of the last recorded result  
x 
if the last observed time point meets alleviation/improvement criteria but the 
requirement for sustainment (i.e. criteria not maintained over 4 day period) has not 
yet been met, the result is censored using the approach described in Section 8.8.   
Missing baseline assessments will be imputed according to the following rules: 1) missing 
individual symptoms and worst severity of COVID-19 symptoms will be imputed as ‘mild’. 2) 
Missing assessments for “loss of taste” and “loss of smell” will be imputed as ‘no’. 3) Missing 
general physical health will be imputed as “fair”. 4) Missing returned to usual health will be 
imputed as “no”. 5) Missing symptom relapse will be imputed as “not applicable”.  
 
 
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7. 
STUDY POPULATION 
7.1. 
Subjects Disposition 
The following will be tabulated (number and percentage) by treatment group for the ITT 
population: 
x Received study drug as randomized 
x Did not receive study drug as randomized, overall and by reason (e.g., not treated, 
incorrect treatment received) 
x Completed treatment 
x Discontinued treatment, overall and by reason 
x Completed assessment through Day 29 
x Did not complete assessment through Day 29, overall and by reason 
x Completed extended follow-up (i.e., to Day 60). 
x Did not complete extended follow-up, overall and by reason.  
The following will also be tabulated (number and percentage) by treatment for the ITT 
population: 
x Subjects randomized and treated in each country and investigator site 
x Subjects randomized and treated by each randomization stratum 
x Subjects included and excluded (with reason) for each analysis population. 
7.2. 
Screen Failures 
The numbers and proportions of subjects who enrolled but were not randomized will be 
presented as: 
x Screen failures who were not randomized 
x Subjects who do not have indication of failing to meet I/E criteria but were not 
randomized.  
Screen failure reasons will also be tabulated.  A subject may have more than one reason for 
screen failure and all reasons for a subject will be counted, i.e., the sum of subjects across screen 
failure reasons may exceed the total number of screen failures. 
7.3. 
Protocol Deviations 
A final identification and classification of important protocol deviations will be made prior to the 
final unblinding of the database and will be documented, in accordance with the study’s Protocol 
Deviations Management Plan. The number and percentage of subjects with important protocol 
deviations and the total number of important protocol deviations by deviation reason (e.g., 
nonadherence to study drug, violation of select inclusion/exclusion criteria, lab assessment, 
randomization, or study procedures, etc.) will be summarized by treatment for the ITT 
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population. A by-subject listing will be provided for those participants with important protocol 
deviations.  
7.4. 
Demographic and Baseline Characteristics 
To review treatment group comparability within the study, a number of variables collected at 
baseline will be presented by treatment groups on the mITT-S, mITT-C and safety analysis 
populations. No statistical comparisons will be made on these characteristics. 
Demographic variables to be summarized include: 
x Age  
x Age group (18-49, 50-64, 65 - 79 , ≥ 80) 
x Sex 
x Race 
x Ethnicity 
x Country 
x Region 
x Weight 
x Body mass index (BMI). 
Baseline Disease Characteristics to be summarized include: 
x SARS-CoV-2 RT-PCR viral load at baseline 
x SARS-CoV-2 IgG seropositive status at baseline 
x Presence of individual high-risk factors (age groups, obesity by age groups, diabetes by 
age groups, cardiovascular disease by age groups, chronic lung disease by age groups, 
immunocompromised or immunosuppressed by age groups, other high-risk conditions by 
age groups) 
x Time from symptom onset to study treatment in days 
x COVID-19 vaccination status 
x Baseline lineage 
 
7.5. 
Medical History and Medical Conditions Present at Entry 
Complete medical history will be obtained at screening. Medical history records will be coded, 
using the current version of Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized descriptively using the safety population. 
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7.6. 
Prior Medication History and Medications Present at Entry 
Medications will be coded using the most recent version of the World Health Organization Drug 
Dictionary (WHODRUG). Prior medications will be summarized descriptively by treatment 
group for the safety population.  Previous treatments that have been stopped prior to date of first 
study drug dose will be summarized separately from medications that were started and continued 
into the study drug treatment period.   
A summary of prior medications with indication of COVID-19 will also be provided. 
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8. 
EFFICACY 
8.1. 
General Considerations 
Where adjustment for stratification factors (age and region) is specified, the group will be based 
on the randomization assignment. All efficacy endpoints will be evaluated post treatment. 
8.2. 
Testing Statistical Assumptions Including Comparability at Baseline 
No testing will be carried out on baseline characteristics.  
The primary analysis method for comparison of treatment groups is the Cochran-Mantel-
Haenszel (CMH) test.  For CMH, small cell counts could be problematic. The Mantel-Fleiss 
criterion will be used to assess the validity of the chi-square approximation for the distribution of 
the Mantel-Haenszel statistic in the analyses. In the event there is indication that the test statistic 
may not be valid, strata will be removed from the analysis until the criterion for validity is met. 
Any removal of strata will be carried out in the following order: age first, then region. If all strata 
are indicated to be removed, then an unstratified comparison will be carried out. 
8.3. 
Statement of the Null and Alternate Hypotheses 
The null hypothesis is that the likelihood of all-cause hospitalization or death to Day 29 is the 
same between treatment groups in the supportive care population. The likelihood of the event is 
estimated by the proportion of subjects with the event, i.e., the primary endpoint.  
The alternative hypothesis is that the treatment groups differ in the likelihood of all-cause 
hospitalization or death to Day 29, with the rate being lower in the BEM arm as the one-sided 
(0.025 level) alternative of interest. 
8.4. 
Subgroup Analyses 
To examine the robustness of the treatment effect, estimates of the difference between treatments 
in the proportions of subjects in the supportive-care-only population who are hospitalized for any 
cause or who died due to any cause through Day 29 (i.e., the primary endpoint) will be computed 
with corresponding 95% confidence intervals, per Wilson (Score) method without continuity 
correction, for the subgroups listed below. Estimates with confidence intervals will be presented 
in forest plots. 
x Geographic region (North America, Europe, Asia, ROW) 
x Age (<65, ≥ 65 years) 
x Sex (female, male) 
x Race  
x Time from onset of symptoms (≤3 days, >3 days) 
x Baseline serology status (positive, negative) 
x Baseline viral lineage (as applicable) 
x COVID-19 vaccination status 
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x Age (<80, ≥80) 
x BMI (<30, ≥ 30) 
x Diabetes mellitus (yes, no) 
x Cardiovascular disease or hypertension (yes, no) 
x Chronic lung disease (yes, no) 
x Immunocompromised/immunosuppressed (yes, no) 
x Baseline viral load (<median, >=median). 
8.5. 
Multiple Comparisons and Multiplicity 
If a statistically significant result is found on the test of the primary endpoint, sequential testing 
will be performed for the secondary endpoints in the following order. When endpoint is tested 
for both Day 29 and Day 60, the order will be Day 29 first, followed by D60. 
1. Proportion of subjects in the supportive-care-only population with all-cause 
hospitalization or all-cause death through Day 60  
2. Proportion of subjects in the supportive-care-only population with all-cause 
hospitalization, all-cause death, or COVID-19 related medically attended visits through 
Day 29 and Day 60.  
3. Proportion of subjects in the supportive-care-only population with COVID-19-related 
hospitalization or who died due to any cause death through Day 29 and Day 60 
4. Proportion of subjects in the supportive-care-only population who died due to any cause 
through Day 29 and Day 60 
5. Proportion of subjects in the supportive-care-only population with COVID-19-related 
complications (e.g., death, hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, cardiac failure) through 
Day 29 and Day 60 
6. Proportion of subjects in the supportive-care-only population with COVID-19-related 
medically attended visits (hospitalization, ER visit, urgent care or physician’s office visit 
or telemedicine visit) or who died due to any cause through Day 29 and Day 60.  
7. Proportion of subjects in the supportive-care-only population with COVID-19-related 
medically attended visits through Day 29 and Day 60  
8. Proportion of subjects in the supportive-care-only population with COVID-19 symptom 
relapse through Day 29 
9. Proportion of subjects in the supportive-care-only population with viral load rebound 
through Day 29 
10. Proportion of subjects in the combination-antiviral population with COVID-19 symptom 
relapse through Day 29 
11. Proportion of subjects in the combination-antiviral population with viral load rebound 
through Day 29 
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8.6. 
Analysis of the Primary Efficacy Endpoint 
 
Table 4: 
Summary of Analyses Related to the Primary Efficacy Endpoint 
Analysis  
Population 
Handling of 
Intercurrent Events 
Analysis Approach 
Primary Analysis: All-
cause hospitalizations and 
deaths (through Day 29) 
mITT-S 
Treatment policy 
Cochran-Mantel-Haenszel 
Supplemental Analysis: 
All-cause hospitalizations 
and deaths (through Day 
29) 
mITT-S Completers 
Treatment policy 
Cochran-Mantel-Haenszel 
Supplemental Analysis: 
All-cause hospitalizations 
and deaths (through Day 
29) 
mITT-S Per-protocol 
Treatment policy 
Cochran-Mantel-Haenszel 
Supplemental Analysis: 
All cause hospitalizations 
and deaths (through Day 
29) 
mITT-S 
Intervention with 
COVID-19 rescue as 
event (composite 
handling); Treatment 
policy otherwise 
Cochran-Mantel-Haenszel 
Supplemental Analysis: 
Time to all cause 
hospitalization and death 
(through Day 29) 
mITT-S 
Intervention with 
COVID-19 rescue as 
event (composite 
handling); Treatment 
policy with censoring for 
early study 
discontinuation (prior to 
Day 29) without event 
Kaplan-Meier plot, 
stratified logrank test 
 
8.6.1. 
Primary Efficacy Analysis 
The primary efficacy objective of this study is to evaluate the efficacy of BEM based on the 
proportion of subjects who are hospitalized for any cause or who died due to any cause through 
Day 29 in the supportive-care-only population. Hospitalization is defined as >24 hours of acute 
care, in a hospital or similar acute care facility, including Emergency Rooms or temporary 
facilities instituted to address medical needs of those with severe COVID-19 during the COVID-
19 pandemic. This includes specialized acute medical care unit within an assisted living facility 
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or nursing home. This does not include hospitalization for the purposes of public health and/or 
clinical trial execution.  Furthermore, scheduled hospitalization for a pre-planned procedure 
(including chemotherapy) to treat a pre-existing condition that has not worsened is not an SAE, 
and would not be considered a hospitalization for the purposes of the efficacy analyses. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of study drug and is 
documented in the subject’s medical history. 
The primary estimand is the difference in the proportions of subjects who are hospitalized for 
any cause or who died due to any cause through Day 29 in the supportive-care-only population, 
and the primary treatment effect comparison will be between the BEM arm and the placebo arm. 
This proportion will be compared between the BEM and placebo arms using a CMH test 
adjusted for the stratification factors of age and region. The CMH p-value and estimated 
common risk difference, odds ratio and relative risk, along with the corresponding 95% 
confidence intervals (CIs) for these estimates, will be presented. The confidence interval for the 
common risk difference will be computed using the Klingenberg method5. Summary tables will 
include tabulation of the number of events, by type of event (hospitalization, death). 
The analysis will be carried out using the following sample SAS code: 
proc freq data=response_tabulated_by_stratum_and_trt; 
   tables strata*trt01a*resp / 
          relrisk cmh(mantelfleiss) oddsratio(cl=score(correct=no)) 
relrisk(cl=score(correct=no)) 
               alpha=0.05 commonriskdiff(cl=klingenberg test correct=no 
column=1); 
   weight Count; 
run; 
Each region-age combined strata has a 2×2 table with counts for BEM hospitalized, BEM not 
hospitalized, Placebo hospitalized, and Placebo not hospitalized. In total there will be 8 strata. 
When low number of events happens and the model can’t be carried out, removal of strata will 
be carried out in the following order: age first, then region. If all strata are indicated to be 
removed, then an unstratified comparison will be carried out. 
Intercurrent events are those that occur after treatment initiation and either preclude observation 
of the variable or affect its interpretation. For the intercurrent events of rescue (e.g., intervention 
with remdesivir; these will be identified by blinded medical review prior to analysis), a treatment 
policy approach will be taken, whereby use of rescue and concomitant medications will be 
ignored, and observations collected after they are administered to the subject will be used. In 
addition, subjects will be followed, assessed, and analyzed irrespective of their completion of the 
course of the study treatment. The analysis will be performed based on observed data, and the 
following measures will be used to reduce missing hospitalization/death data:  
x eCRFs capturing clinical information that may be indicative of hospitalization will be 
reviewed to mitigate the risk of unreported hospitalizations 
x study staff may use a public information source to obtain information about survival 
status if a patient withdraws from the study. 
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8.6.2. 
Sensitivity Analyses of the Primary Efficacy Results 
Planned supplemental analyses to support the primary endpoint result are identified in Table 4 .  
The supplemental analyses investigate the impact of significant COVID-19 rescue therapy and 
data handling for early study discontinuations. For the CMH and stratified log-rank analyses, 
incorporation of strata will be the same as that used for the primary analysis. The Kaplan-Meier 
and log-rank analyses will include all data to Day 29.  
The primary endpoint may also be analyzed for each of the subgroups defined in Section 8.4 . 
8.7. 
Analysis of the Secondary Efficacy Endpoints 
The following secondary endpoints will be analyzed using the same approach as that for the 
primary endpoint: 
x Proportion of subjects in the supportive-care-only population with all-cause 
hospitalization or all-cause death through Day 60  
x Proportion of subjects in the supportive-care-only population with all-cause 
hospitalization, all-cause death, or COVID-19 related medically attended visits through 
Day 29 and Day 60.  
x Proportion of subjects in the supportive-care-only population with COVID-19-related 
hospitalization or who died due to any cause death through Day 29 and Day 60 
x Proportion of subjects in the supportive-care-only population who died due to any cause 
through Day 29 and Day 60 
x Proportion of subjects in the supportive-care-only population with COVID-19-related 
complications (e.g., death, hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, cardiac failure) through 
Day 29 and Day 60 
x Proportion of subjects in the supportive-care-only population with COVID-19-related 
medically attended visits (hospitalization, ER visit, urgent care or physician’s office visit 
or telemedicine visit) or who died due to any cause through Day 29 and Day 60.  
x Proportion of subjects in the supportive-care-only population with COVID-19-related 
medically attended visits through Day 29 and Day 60  
x Proportion of subjects in the supportive-care-only population with COVID-19 symptom 
relapse through Day 29 
x Proportion of subjects in the supportive-care-only population with viral load rebound 
through Day 29 
x Proportion of subjects in the combination-antiviral population with COVID-19 symptom 
relapse through Day 29 
x Proportion of subjects in the combination-antiviral population with viral load rebound 
through Day 29 
COVID-19 related complications will be adjudicated by blinded medical review prior to 
analysis. 
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The proportion of subjects with COVID-19 symptom relapse in each population through Day 29 
will be tabulated. This summary will be based on the response to “Have your COVID-19 
symptoms returned after previously improving?” (i.e., question 4 in the Symptom Diary, see 
Section 11.1).  
The proportion of subjects with viral load rebound through Day 29 will be tabulated. Viral load 
rebound is defined as a ≥1 log10 increase in viral load (measured by RT-qPCR) at any non-
missing time point (including unscheduled assessments) after EOT. Subjects must have at least 
one post-EOT measurement result to be evaluated for viral load rebound.  
8.8. 
Analysis of Exploratory Efficacy Endpoints 
 
. The following exploratory endpoints will be examined in both supportive 
care only and combination antiviral arms. 
Time to sustained alleviation or improvement of COVID-19 symptoms  
Sustained alleviation/improvement of COVID-19 signs/symptoms is defined as the first 
occurrence of 4 consecutive days when all symptoms recorded as moderate or severe at study 
entry are recorded as mild or absent and all symptoms scored mild or absent at study entry are 
scored as absent. The first day of the 4 consecutive-day period corresponds to the day that the 
event is achieved. The endpoint will be based on targeted symptoms, which are the 13 symptoms 
with severities ranging from none to severe in Item 3 of the COVID-19 symptom diary. Subjects 
who do not achieve the endpoint will be censored according to the following rules: 
Case 
LOD-3 
LOD-2 
LOD-1 
Last 
Observed 
Day (LOD) 
Censoring 
time 
1 
Not Met 
Not Met 
Not Met 
Not Met 
LOD+1 
2 
Not Met 
Not Met 
Not Met 
Met 
LOD 
3 
Not Met 
Not Met 
Met 
Met 
LOD-1 
4 
Not Met 
Met 
Met 
Met 
LOD-2 
  
The cumulative distribution function for time from Day 1  to sustained alleviation/improvement 
of symptoms will be estimated by Kaplan-Meier methodology and plotted by treatment group. 
The summary display will include the Kaplan-Meier estimates of proportion achieving the 
endpoint by day. The analysis will also be carried on subgroups of time from onset of symptoms 
(<=3 days, > 3days).  
Sensitivity analysis will be carried using the same methods for 2 selected subsets of symptoms: 
1) runny/stuffy nose, sore throat, cough, feeling hot or feverish, and fatigue; 2) runny/stuffy 
nose, sore throat, shortness of breath, feeling hot or feverish, headache, and chills; 3) all 
symptoms from Item 3 of the COVID-19 symptoms diary except fatigue. 
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Additional subgroup analyses on age group (<65 and >=65), and symptom onset days (<=3 days 
and >3 days) for time to sustained alleviation of all 13 symptoms will be performed. 
Time to self-reported return to usual (pre-COVID-19) health  
Self-reported return to usual health is defined as the occurrence of 4 consecutive days when the 
response to “Have you returned to your usual (pre-COVID) health?” in question 3 of the 
COVID-19 symptom diary indicates return to usual health. Analysis and data handling will be 
the same as that described for the endpoint of time to alleviation or improvement of COVID-19 
symptoms. The analysis will also be carried on subgroups of time from onset of symptoms (<=3 
days, > 3days). 
Proportion of subjects requiring post randomization rescue therapy 
Post randomization rescue therapies will be identified by blinded medical review. The number 
and proportion of subjects requiring post randomization rescue therapy will be tabulated.  
Duration and severity of COVID-19 symptom relapse 
For subjects who meet the criteria of COVID-19 symptom relapse, duration of relapse will be 
computed by counting the number of days that the relapse question (i.e., question 4 of the 
COVID-19 symptom diary) is answered “yes”. Severity will be based on the average response to 
question 1 of the COVID-19 symptom diary during the days where relapse is indicated. Subjects 
with the last record indicating relapse will have duration of relapse right censored. Kaplan-Meier 
analysis will be used to summarize symptom relapse duration by treatment group. Severity of 
symptom relapse will be summarized descriptively. The analysis will also be carried on 
subgroups of time from onset of symptoms (<=3 days, > 3days). 
Proportion of subjects with symptom relapse and viral rebound 
The proportion of subjects who meet both the symptom relapse and viral rebound criteria will be 
compared between the BEM and placebo arms using the same method as in the primary analysis. 
The analysis will also be carried on subgroups of time from onset of symptoms (<=3 days, > 3 
days) and baseline viral load groups (<median, >=median). 
Time to cessation of SARS-CoV-2 viral shedding by RT-qPCR Time to cessation of SARS-
CoV-2 viral shedding will be explored using Kaplan-Meier analysis in two ways: 1) time from 
first detectable observation of SARS-CoV-2  to the time of the first observation with non-
detectable SARS-CoV-2; 2) time from first detectable observation of SARS-CoV-2  to the time 
of first non-detectable observation of SARS-CoV-2 where the non-detectable status is sustained 
through Day 29. Where a subject does not meet the cessation endpoint, time to cessation will be 
censored at the time of the last viral RNA assessment. In cases where the result of SARS-CoV-2 
testing is reported as inconclusive, the following rules will be applied: 
x If inconclusive observation happens before the first non-detectable observation and all 
follow up observations are non-detectable, time to sustained cessation is time to the first 
non-detectable observation. 
x If inconclusive observation happens between two non-detectable observations, it is 
treated the same as non-detectable observation. 
x If inconclusive observations happen in the last assessments, time to cessation will be 
censored at the time of last non-inconclusive assessment. 
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Change from baseline in amount of severe acute respiratory syndrome coronavirus-2 (SARS-
CoV-2) viral RNA as measured by reverse transcription quantitative polymerase chain 
reaction (RTqPCR) over time and Proportion of subjects negative for SARS-CoV-2 viral RNA 
by RT-qPCR over time  
SARS-CoV-2 viral RNA (and change from baseline) will be summarized at each scheduled time 
point by descriptive statistics on log10 viral load and tabulation of the number and percentage of 
subjects with non-detectable virus. The analysis will also be carried on subgroups of baseline 
viral load (<median, >=median). 
Area under the curve (AUC) in the amount of SARS-CoV-2 viral RNA as measured by RT-
qPCR   
Area under the log10 viral load curve will be computed, out to each of Days 5, 7 and 14, and 
summarized using descriptive statistics. AUC will be derived using the trapezoidal rule and 
consider actual study day (per Section 6.7.2) as time. The analysis will also be carried on 
subgroups of baseline viral load (<median, >=median). 
 
 
  
8.9. 
Summary of Reasons for Efficacy Non-Evaluability/Exclusion from 
Efficacy Analyses 
Reasons for exclusion from mITT populations will be tabulated. Categories include did not 
receive study drug and did not have ≥ 1 positive SARS-CoV-2 result through Day 5 (from 
central testing on NP swab samples). 
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9. 
SAFETY AND TOLERABILITY 
9.1. 
Overall Summary of Tolerability 
All adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized by treatment group for the safety population. Only 
treatment-emergent adverse events (TEAEs) will be summarized. Treatment-emergent adverse 
events are those with start date/time within the treatment period, defined as the time from first 
study drug administration to Day 29. Events that occur after Day 29 with relationship to study 
drug recorded as ‘related’ will also be considered treatment-emergent. If the AE onset date is 
missing or partial, the conventions described in Section 6.8.3 will be used to determine if the 
event is treatment-emergent. 
Adverse event severity will be graded according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 20176. 
An overall summary of TEAEs will be presented and include tabulations (number and %, unless 
otherwise indicated) for the following: 
x Subjects with at least one TEAE, overall and by worst grade 
x Total number (number only) of TEAEs  
x Deaths 
x Subjects who discontinued study due to a TEAE 
x Subjects who discontinued treatment due to a TEAE 
x Subjects with a treatment-related TEAE resulting in treatment discontinuation 
x Subjects with a treatment-emergent serious adverse event (SAE) 
x Subjects with a treatment-related SAE 
x Subjects with a treatment-related TEAE, overall and by worst grade 
x Subjects with a COVID-19 related TEAE 
x Subjects with a non-COVID-19 related TEAE 
9.2. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
Adverse events will be coded by System Organ Class (SOC) and preferred term (PT) using the 
MedDRA. Summaries by SOC and PT will be provided for the following: 
x TEAEs 
x TEAEs by maximum severity 
x Related TEAEs 
x TEAEs leading to study discontinuation 
x TEAEs leading to treatment discontinuation 
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x SAEs 
x Deaths. 
A table of the most common TEAEs (≥ 5% in any treatment arm) will be presented by PT only 
with display from most common to least common. 
9.3. 
Exposure 
Study drug exposure will be characterized by the following: 
x Number of doses of study drug received will be tabulated and summarized using 
descriptive statistics 
x Total amount of study drug received will be summarized using descriptive statistics. 
9.4. 
Concomitant and Other Medications 
Concomitant medications (CM) are medications that are administered during the treatment-
emergent period. If the CM onset date and/or end date is missing or partial, the conventions 
described in Section 6.8.2  will be used to determine if the medication is concomitant. 
Medications will be presented based on WHODRUG coding, summarized using number and 
percentage of subjects, and listed by subject.  
9.5. 
Routine Laboratory Data 
Where applicable, the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Event, Version 2.1 dated July 20176 will be used for assigning toxicity grades (0 to 4) to 
laboratory results for analysis. Grade 0 will be used to designate a value that does not correspond 
to a grade. Lab parameters that require clinical input for grading will not be assigned grades; any 
events from these should be captured as adverse events. For laboratory tests with criteria for both 
increased and decreased levels, analyses for each direction (i.e., increased, decreased) will be 
presented separately. 
The following summaries will be provided by treatment group for each of the scheduled 
chemistry, hematology, and coagulation  laboratory parameters: 
x Shift from baseline to abnormal high and to worst overall 
x Shift from baseline to abnormal low and to worst overall 
x Listing of subjects with at least one post-baseline clinically significant abnormal 
laboratory observation 
x Shift from baseline at each visit and to worst overall toxicity grade (for quantitative 
parameters with available DAIDS toxicity grades) 
x Listing of subjects with at least one post-baseline laboratory observed value meeting a 
DAIDS toxicity grade ≥ 3 (for quantitative parameters with available DAIDS toxicity 
grades) 
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x Maximum post-baseline ALT/AST observed value categorized as < 3 x upper limit of 
normal (ULN), ≥ 3 to < 5 x ULN, ≥ 5 to < 10 x ULN or ≥ 10 ULN. Maximum post-
baseline total bilirubin (TBL) observed value categorized as < 2 x ULN or ≥ 2 x ULN 
x Listing of subjects with at least one post-baseline observed ALT value > 3 x ULN, AST 
value > 3 x ULN or TBL value ≥ 2 x ULN will be provided 
x Number and percentage of subjects in each laboratory parameter category by visit (for 
categorical measurements only). 
9.6. 
Vital Signs 
The following summaries will be provided for each scheduled vital sign parameter: 
x Observed and change from baseline by visit 
x Number and percentages of subjects with at least one markedly abnormal post-baseline 
observed value/change from baseline (refer to Table 5  ) 
x Listing of subjects with at least one markedly abnormal observed value/change from 
baseline. 
All vital sign data will be listed. 
Table 5: 
Criteria for Markedly Abnormal Changes in Vital Signs 
Parameter 
Low 
High 
SBP 
≤ 90 mmHg AND  
change from baseline ≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline ≥ 20 mmHg 
DBP 
≤ 50 mmHg AND 
change from ≤ -15 mmHg 
≥ 105 mmHg AND 
change from baseline ≥ 15 mmHg 
Pulse rate 
≤ 50 bpm AND 
change from baseline ≤ -15 bpm 
≥ 120 bpm AND 
change from baseline ≥ 15 bpm 
Oxygen saturation 
< 93 % 
Not applicable 
Body temperature 
Not applicable 
≥ 38.3 qC AND 
change from baseline ≥ 1.1 qC 
9.7. 
Physical Examination 
Physical examination data will be listed. 
9.8. 
Pharmacokinetics 
Descriptive summary statistics for concentration by time intervals from the most recent dose will 
be presented for: 
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x Plasma concentrations of AT-511 (free base form of AT-527 [BEM]) and its metabolites 
based on sparse pharmacokinetic (PK) sampling at steady-state. The time intervals to be 
summarized are: 0 – 0.5 hours, >0.5 – 1 hours, >1–2 hours, >2 – 4 hours, >4 – 8 hours, 
>8 – 12 hours, and >12 hours.  
Other analyses of PK data from this study (e.g., population PK analysis) will be described in 
a separate document, if applicable. 
 
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10. 
REFERENCES 
1. International Conference on Harmonization. Statistical Principles for Clinical Trials. Step 
5, dated September 2008. 
2. [Paxlovid. Prescribing Information] Pfizer; 2023.  Accessed June 1, 2023.  . 
https://labeling.pfizer.com/ShowLabeling.aspx?id=19599  
3. Lagevrio EUA 2022. US FDA Emergency Use Authorization for Lagevrio, Revised 
Authorization 23 Mar 2022. https://www.fda.gov/media/157300/download 
4. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe 
Covid-19 in outpatients. N Engl J Med 2022;386:305-15 
5. Klingenberg B. A new and improved confidence interval for the Mantel-Haenszel risk 
difference. Stat Med. 2014;33(17):2968-2983. doi:10.1002/sim.6122 
6. U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1. Available from:  
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
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11. 
APPENDICES 
11.1. 
COVID-19 Symptom Diary 
Date of completion:_____________   Time of completion:_______________ 
 
SYMPTOMS 
 
1. Please choose the response below that best describes the worst severity of your COVID-19   symptoms over the 
past 24 hours. 
 
 
No symptoms 
 
Mild 
 
Moderate 
 
Severe 
 
2. 
Please choose the response below that best describes your general physical health over the past 24 hours. 
 
 
Excellent 
 
Very good 
 
Good 
 
Fair 
 
Poor 
 
3. 
Have you returned to your usual (pre-COVID) health?  
 
     Yes 
 
No 
 
Indicate the worst severity of your symptoms DURING THE PAST 24 HOURS 
 
Symptoms 
Absent 
Mild 
Moderate 
Severe 
Cough 
 
 
 
 
Shortness of breath or difficulty breathing  
 
 
 
 
Feeling feverish 
 
 
 
 
Chills 
 
 
 
 
Fatigue (low energy) 
 
 
 
 
Body pain or muscle pain or aches 
 
 
 
 
Diarrhea (loose or watery or more frequent stools) 
 
 
 
 
Nausea (feeling like you want to throw up) 
 
 
 
 
Vomiting (throwing up) 
 
 
 
 
Headache 
 
 
 
 
Sore throat 
 
 
 
 
Nasal obstruction or congestion (stuffy nose) 
 
 
 
 
Nasal discharge (runny nose) 
 
 
 
 
 
 
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Indicate if you have had the following during the past 24 hours:
Yes
No
Loss of taste
Loss of smell
4.  Symptom Relapse: Have your COVID-19 symptoms returned after previously improving?
     Yes
No
Not applicable (symptoms have not yet improved)
11.2.
Sample Size Calculation Details
The base sample size to have 90% power to detect a statistically significant reduction in the rate 
of hospitalization/death, given the study assumed rates of hospitalization, based on a one-sided 
0.025 level test was computed using proc power is SAS (Version 9.4). This indicated that 991
subjects per arm (i.e. 1982 total subjects with 1:1 randomization). The corresponding code and 
output were:
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The gsDesign function in the “gsDesign” package in R (Version 4.0.3) was used to identify the 
sample size adjustment and testing criteria needed to implement the planned interim analyses at 
30% and 65% with O’Brien-Fleming spending for both alpha and beta (non-binding). The Lan-
Demets spending function is used to approximate the O’Brien-Fleming boundaries (specified as 
sfLDOF in the code below). This indicated that a sample size inflation of 1.055 (at final) is 
needed for 90% power with overall type 1 error at one-sided 0.025 level. Total beta spending 
was specified at a 0.10 level. The corresponding code and output were: 
 
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With a base sample size of 1982, inflation of 1.055 indicates a required sample size of 2100 
evaluable subjects for the primary analysis. 
 
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