Clinical trial NCT04396106
Conditions: COVID-19
Sponsor: Atea Pharmaceuticals, Inc.
Start date: 2020-05-26; Completion date: 2022-02-28
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the safety, tolerability, antiviral activity and efficacy of AT-527 in adult subjects ≥18 years of age with moderate COVID-19 and risk factors for poor outcomes (such as obesity (BMI\>30), hypertension, diabetes or asthma). Eligible subjects will be randomized to blinded AT-527 (nucleotide analog) tablets or matching placebo tablets to be administered orally for 5 days. Part A will evaluate an AT-527 dose of 550 mg BID and Part B will evaluate a second dose of AT-527 (1100 mg BID). Local supportive standard of care (SOC) will be allowed for all subjects. Efficacy, antiviral activity and safety observations will be compared for treatment with active AT-527 tablets vs. placebo tablets.

Detailed description:

Arms: arm 1: Part A arm 2: Part A arm 3: Part B arm 4: Part B
Interventions: intervention 1: AT-527 intervention 2: Placebo intervention 3: AT-527 intervention 4: Placebo
Intervention descriptions: intervention 1: One 550 mg tablet of AT-527 administered every \~12 hours (twice a day) for a total of 5 days intervention 2: One placebo tablet administered every \~12 hours (twice a day) for a total of 5 days intervention 3: Two 550 mg tablets of AT-527 administered every \~12 hours (twice a day) for a total of 5 days intervention 4: Two placebo tablets administered every \~12 hours (twice a day) for a total of 5 days

Protocol documents:
Prot_000.pdf: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of AT-527 in Subjects with Moderate COVID-19
Sponsor Protocol Number:
AT-03A-001
Investigational Product(s):
AT-527
Sponsor:
Atea Pharmaceuticals, Inc.
125 Summer Street
Boston, MA 02110 USA
+1 (857) 284-8891
COMPLIANCE
The study will be conducted in accordance with standards of Good Clinical Practice, as defined 
by the International Conference on Harmonisation and all applicable federal and local 
regulations.
Protocol Version
Date
9.0
Amendment 8
26-Aug-2021
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
1.
INTRODUCTION..............................................................................................................................................17
1.1.
Background ...................................................................................................................................................17
1.2.
Rationale for the Dose Selection...................................................................................................................23
1.2.1. Rationale for AT-527 550 mg BID Dose Regimen in Part A.................................................................23
1.2.2. Rationale for AT-527 1100 mg BID Dose Regimen in Part B...............................................................23
1.3.
Study Rationale .............................................................................................................................................25
1.4.
Risk/Benefit Assessment...............................................................................................................................26
2.
STUDY OBJECTIVES ......................................................................................................................................28
3.
STUDY DESIGN ................................................................................................................................................28
3.1.
General Study Design....................................................................................................................................28
3.2.
Number of Subjects.......................................................................................................................................30
4.
SUBJECT SELECTION....................................................................................................................................30
4.1.
Study Population ...........................................................................................................................................30
4.2.
Inclusion Criteria...........................................................................................................................................30
4.3.
Exclusion Criteria..........................................................................................................................................31
5.
STUDY TREATMENTS....................................................................................................................................32
5.1.
Description and Handling of Study Treatments ............................................................................................32
5.1.1. Test Product ...........................................................................................................................................32
5.1.2. Control Product(s)..................................................................................................................................32
5.1.3. Packaging and Labeling .........................................................................................................................33
5.1.4. Storage and Handling.............................................................................................................................33
5.2.
Method of Assigning Subjects to Treatment Groups ....................................................................................33
5.3.
Blinding.........................................................................................................................................................33
5.4.
Dosing and Administration ...........................................................................................................................33
5.4.1. Dispensing..............................................................................................................................................33
5.4.2. Administration Instructions....................................................................................................................34
5.4.3. Treatment Compliance...........................................................................................................................34
5.5.
Study Drug Accountability............................................................................................................................34
5.6.
Stopping Rules ..............................................................................................................................................34
5.6.1. Safety Stopping Rules for Individual Subjects.......................................................................................34
5.6.2. Study Stopping Rules.............................................................................................................................35
5.7.
Premature Treatment or Study Discontinuation ............................................................................................37
5.8.
Prior and Concomitant Medication ...............................................................................................................37
5.8.1. Permitted Therapy..................................................................................................................................37
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5.8.2. Cautionary Therapy................................................................................................................................38
5.8.3. Prohibited Therapy.................................................................................................................................39
5.9.
Other Study-Specific Restrictions and Requirements ...................................................................................39
6.
STUDY PROCEDURES AND GUIDELINES.................................................................................................40
6.1.
Medical History.............................................................................................................................................43
6.2.
Physical Examination....................................................................................................................................43
6.3.
Vital Signs.....................................................................................................................................................43
6.4.
Electrocardiogram Monitoring......................................................................................................................43
6.5.
Laboratory Evaluations .................................................................................................................................43
6.6.
COVID-Specific Tests ..................................................................................................................................44
6.7.
Pulse Oximetry..............................................................................................................................................45
6.8.
Chest Imaging ...............................................................................................................................................45
6.9.
Assessment of Study Subject Clinical Course...............................................................................................45
6.10. Sparse PK Sampling......................................................................................................................................46
6.10.1. Sample Processing, Storage and Shipping .............................................................................................47
6.10.2. Bioanalytical Methods for PK samples..................................................................................................47
7.
ADVERSE EVENTS..........................................................................................................................................48
7.1.
Definitions.....................................................................................................................................................48
7.1.1. Intensity Assessment..............................................................................................................................49
7.1.2. Causality Assessment.............................................................................................................................49
7.2.
Routine Reporting .........................................................................................................................................49
7.3.
Serious Adverse Event Reporting .................................................................................................................50
7.4.
Pregnancy Reporting.....................................................................................................................................51
8.
STATISTICAL ANALYSES.............................................................................................................................51
8.1.
Analysis Populations.....................................................................................................................................52
8.1.1. Safety Population ...................................................................................................................................52
8.1.2. Intention To Treat Population ................................................................................................................52
8.1.3. Modified Intent-to-Treat Population ......................................................................................................52
8.1.4. Per Protocol Population..........................................................................................................................52
8.1.5. PK Populations.......................................................................................................................................52
8.2.
Endpoints.......................................................................................................................................................53
8.2.1. Primary Efficacy Endpoint and Sample Size Calculations.....................................................................53
8.2.2. Key Secondary Efficacy Endpoints........................................................................................................54
8.2.3. A key secondary efficacy endpoint of the study is the proportion of subjects with Respiratory Failure 
or Death (RFD), for which the featured assessment will be at Day 28, with additional analyses at Days 10, 14, 
and 63. Other Secondary Efficacy Endpoints ....................................................................................................54
8.2.4. Exploratory Endpoints ...........................................................................................................................54
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8.2.5. Safety Endpoints ....................................................................................................................................55
8.3.
Efficacy Analysis Methods ...........................................................................................................................55
8.3.1. Primary Efficacy Analysis .....................................................................................................................55
8.3.2. Key Secondary Analyses........................................................................................................................55
8.3.3. Other Secondary Analyses .....................................................................................................................56
8.3.4. Handling of Missing Data ......................................................................................................................56
8.4.
Safety and PK Analyses ................................................................................................................................56
9.
ETHICS...............................................................................................................................................................57
9.1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .....................................................57
9.2.
Ethical Conduct of the Study.........................................................................................................................57
9.3.
Participant Information and Consent.............................................................................................................57
9.4.
Subject Confidentiality and Personal Data Protection...................................................................................58
10. DATA COLLECTION, RETENTION, AND MONITORING......................................................................58
10.1. Data Safety Monitoring Board (DSMB) .......................................................................................................58
10.2. Case Report Forms........................................................................................................................................59
10.3. Data Management and Processing.................................................................................................................59
10.4. Quality Assurance .........................................................................................................................................60
10.5. Record Retention...........................................................................................................................................60
10.6. Monitoring of the Study ................................................................................................................................60
11. ADMINISTRATIVE PROCEDURES..............................................................................................................61
11.1. Adherence to Protocol...................................................................................................................................61
11.2. Investigator Responsibilities and Delegation of Investigator Duties.............................................................61
11.3. Premature Termination or Suspension of a Study.........................................................................................61
11.4. Publication Policy .........................................................................................................................................61
12. REFERENCES ...................................................................................................................................................62
13. APPENDIX .........................................................................................................................................................64
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LIST OF IN-TEXT TABLES
Table 1-1
Exposure Multiples................................................................................................... 24
Table 3-1
Study Design............................................................................................................. 29
Table 6-1
Schedule of Assessments......................................................................................... 42
Table 6-2
Adverse Event Relationship to Study Drug............................................................. 49
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SYNOPSIS
Protocol Title:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety and Efficacy of AT-527 in Subjects with Moderate COVID-19
Protocol Number:
AT-03A-001
Clinical Phase:
2
Objectives:
x
Evaluate safety and efficacy of AT-527 in subjects with moderate COVID-19 
disease and risk factors for poor outcomes.
x
Primary objective for Part A:  reduce progressive respiratory insufficiency 
(PRI) by at least 50% in a population that is at high risk for PRI.
x
Primary objective for Part B:  evaluate the antiviral activity of AT-527 
compared with placebo
Safety
Assessment:
Assessing safety and tolerability of AT-527 at the selected doses will be an 
important objective of the study. 
x
Adverse events (AEs), blood oxygen saturation (SpO2), vital signs, physical 
examination, electrocardiogram (ECG) monitoring, standard safety laboratory 
tests, respiratory deterioration to requirement for mechanical ventilation
Efficacy 
Assessments:
Primary efficacy endpoint:
x
Part A (secondary for Part B):  The primary efficacy endpoint is PRI, defined 
as a ≥ 2-tier increase in respiratory support methods required to maintain 
satisfactory oxygenation (SpO2 ≥ 93%), using a 6-tier hierarchical scale of 
respiratory support methods, within the 14-day study period.  The primary 
efficacy goal is a 50% reduction in the incidence of PRI in active treatment
recipients compared to placebo recipients.
x
Part B (secondary for Part A):  Change from baseline in amount of SARS-
CoV-2 virus RNA as measured by RT-PCR over time.
Secondary efficacy endpoints (Parts A and B):
x
Median time (days) to Clinical Recovery, using an adapted National Institute 
of Allergy and Infectious Diseases (NIAID) ordinal scale of Clinical Status.  
The goal for active treatment is to reduce the median time to Clinical 
Recovery (status 6,7, or 8 in the NIAID Clinical Status scale) by at least 4 
days.
x
Proportion of subjects experiencing respiratory failure or death
x
Change (improvement vs. worsening) in the NIAID ordinal scale of overall 
Clinical Status
x
All-cause mortality
x
Duration of hospitalization/confinement for COVID-19
x
Time to sustained non-detectable SARS-CoV-2 virus in nose/throat
x
Proportion of subjects who are still SARS-CoV-2 positive over time
PK Assessment:
x
Plasma concentrations of AT-527 and its metabolites evaluated by sparse PK 
sampling
Study Design:
x
Adult subjects, ≥18 years of age, who are hospitalized/confined with
moderate COVID-19 and not on a ventilator.
x
Subjects must be diagnosed with COVID-19 (SARS-CoV-2 positive) by a 
standard assay or equivalent testing.  
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x
Note:  SARS-CoV-2 infection will be confirmed at Screening and 
assessed during the study with an FDA Emergency Use Authorization 
(EUA)-approved assay.  
x
Moderate disease defined by the following:
x
Symptoms of COVID-19, with initial symptom onset within 5 days 
prior to Screening:
x
At least 1 of the following: fever (> 38.3 °C), cough, sore throat, 
fatigue/malaise, headache, muscle pain, or more significant lower 
respiratory symptoms including dyspnea (at rest or with exertion)
x
Clinical signs indicative of COVID-19 (as above), with:
x
SpO2 ≥93% on room air or requires ≤2L/min oxygen by nasal 
cannula or mask to maintain SpO2 ≥93%
x
Subjects must also have at least one of the following known risk factors for 
poor outcomes:  obesity (BMI>30), hypertension, diabetes, asthma
x
Randomized, double-blind, placebo-controlled study 
x
Blinded study treatment:  AT-527 or matching placebo for 5 days in 
combination with supportive standard of care (SOC) treatments per local
SOC policies
The study will be conducted in 2 Parts. Part A will evaluate an AT-527 dose of 
550 mg BID for 5 days and Part B will evaluate a dose of 1100 mg BID for 5 
days.  Based on the interim analysis conducted after Part A (which demonstrated 
a positive antiviral signal but low disease progression rates in the population), 
Part B was added via an amendment with a virologic primary endpoint.   
x
Part A subjects will be randomized (1:1) to one of the two following arms:
Disease 
Severity
Treatment 
Duration
Dosing Arms
Moderate
5 days
active
550 mg AT-527 administered every ~12 hours
(10 doses) + SOC
placebo
AT-527 placebo administered every ~12 hours 
(10 doses) + SOC
*Randomized 1:1 (active:placebo)
x
A cohort of 20 subjects will initially be enrolled to preliminarily assess the 
safety of the 550 mg twice daily (BID) dosing regimen. Enrollment will be 
paused after the first 20 subjects, until the data safety monitoring board 
(DSMB) conducts a safety review.  If study stopping criteria are not met, a
second cohort of 20 subjects will be enrolled.  Again, enrollment will be 
paused until the DSMB conducts a safety review of these data.
x
Part A enrollment was paused after 81 subjects were randomized.  No 
additional subjects will be randomized in Part A.
x
Part B subjects will be randomized (1:1) to one of the two following arms:
Disease 
Severity
Treatment 
Duration
Dosing Arms
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Moderate
5 days
active
1100 mg AT-527 administered every ~12 hours
(10 doses) + SOC
placebo
AT-527 placebo administered every ~12 hours 
(10 doses) + SOC
*Randomized 1:1 (active:placebo)
x
Up to an additional 110 subjects will be enrolled in Part B.
x
An additional DSMB safety review will occur when 50% of the Part B 
subjects have been enrolled.
Key Study Design Features
x
An independent DSMB will be established for safety monitoring.
x
Sponsor, CRO, and site personnel will remain treatment-blinded to all DSMB 
analyses unless the DSMB alerts the Sponsor to significant 
recommendations regarding study discontinuation for efficacy, safety, or 
futility reasons.
Duration of 
Study:
x
The primary study period is 14 days from randomization.  
x
Additional follow-up data will be obtained at 7 days, 14 days and 49 days 
after primary study completion at Day 14.
Number of 
Subjects:
x
Targeted study enrollment is up to 190 eligible COVID-19 subjects.
o
Part A:  81 subjects were randomized at the time of the Part A 
interim analysis.
o
Part B:  Up to an additional 110 subjects will be enrolled in Part 
B.
Inclusion Criteria:
1. Willing and able to provide informed consent. 
2. Male or female subjects ≥18 years of age.
3. Subject is hospitalized or in a hospital-affiliated confinement facility for which 
the principal investigator is credentialed and study staff have access to study 
participants and their data.
4. Subject must be diagnosed with COVID-19 (SARS-CoV-2 positive) by a 
standard assay or equivalent testing. Note: SARS-CoV-2 infection will be 
confirmed with an FDA EUA-approved assay.
5. Moderate disease defined by the following:
x
Symptoms of COVID-19, with initial symptom onset within 5 days 
prior to Screening: 
x
At least 1 of the following: fever (> 38.3 °C), cough, sore throat, 
fatigue/malaise, headache, muscle pain, or more significant lower 
respiratory symptoms including dyspnea (at rest or with exertion)
x
Clinical signs indicative of COVID-19 (as above), with:
x
SpO2 ≥93% on room air or requires ≤ 2L/min oxygen by nasal 
cannula or mask to maintain SpO2 ≥ 93%
6. Subjects must also have at least one of the following known risk factors for 
poor outcomes:  obesity (BMI>30), hypertension, diabetes or asthma. 
7. QTcF interval ≤ 450 ms for males and ≤ 460 ms for females at Screening.  
8. Females of childbearing potential must agree to use protocol specified 
methods of contraception as described in Section 5.9.
9. Females of childbearing potential must have a negative pregnancy test at 
Screening.
10. Subject must be able to take oral tablet medications.
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11. Subject is, in the opinion of the investigator, willing and able to comply with 
the study drug regimen and all other study requirements.
Exclusion
Criteria:
1.
Female subject is pregnant or breastfeeding.  
2.
Clinical signs indicative of severe or critical COVID-19 illness, defined as any 
of the following:  RR ≥30, HR ≥125, SpO2 <93% on room air or requires 
>2L/min oxygen by nasal cannula or mask to maintain SpO2 ≥93%, systolic 
blood pressure < 90 mm Hg, diastolic blood pressure < 60 mm Hg or
PaO2/FiO2 <300
3.
Any subject with a concomitant life-threatening condition, including but not 
limited to the following: requiring mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO), acute respiratory distress syndrome 
(ARDS), shock, cardiac failure or suspected bacterial sepsis.
4.
Evidence of lobar or segmental consolidation on chest imaging.
5.
Congestive heart failure or myocardial infarction within the previous 6 
months.
6.
Recurrent nausea, vomiting or known malabsorption syndrome, that would 
interfere with oral medication treatment.
7.
Creatinine clearance < 60 mL/min (Cockcroft-Gault formula)
8.
Abuse of drugs or alcohol that could interfere with adherence to study 
requirements as judged by the investigator. 
9.
Treatment with other drugs thought to possibly have activity against SARS-
CoV-2.  Note:  If the subject was previously treated with such an agent, 
treatment must have been discontinued at least 7 days prior to planned 
dosing on the current trial. The use of hydroxychloroquine is not allowed in 
this trial. Convalescent plasma is permitted as part of local SOC.
10. Use of other investigational drugs within 30 days of dosing, or plans to enroll 
in another clinical trial of an investigational agent while participating in the 
present study.
11. S-T segment elevation or other clinically significant abnormal ECG at 
Screening, as determined by the investigator.
12. Subject has a history of active hepatitis B infection or uncured hepatitis C 
infection.  Subjects with human immunodeficiency virus (HIV) infection are 
allowed, as long as they are virologically suppressed with CD4 count at least 
500 cells/mm3.
13. Active clinically significant diseases including:  

Active urinary tract infection

History of severe renal impairment or receiving renal replacement 
therapy (hemodialysis, peritoneal dialysis)
14. Subjects with malignant disease can continue antineoplastic therapy during 
the study period unless the antineoplastic therapy includes an 
immunomodulator or is expected to result in severe bone marrow 
suppression during the study (e.g., risk for grade 3 or higher anemia, 
leukopenia, or thrombocytopenia). 
15. Requires use of immunosuppressive doses of systemic corticosteroids,
defined as the equivalent of 20 mg prednisone daily during any two week 
time period (280 mg prednisone equivalent total dose) in the three months 
prior to study entry. Standard of care dexamethasone indication and dosing 
are permitted if needed for treatment of COVID-19 Syndrome.
16. Requires use of immunosuppressive drugs (e.g., for organ transplantation or 
autoimmune conditions) during the primary 14-day study period.  
17. Requirement of any prohibited medications (Section 5.8).
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18. Abnormal values at Screening:

ALT or AST > 5 x upper limit of normal (ULN)

Total bilirubin > 1.5 x ULN, unless the subject has known Gilbert’s 
syndrome

Hemoglobin < 10 g/dL for females or < 12 g/dL for males

Total white blood cell (WBC) count < 2,500/mm3 or absolute neutrophil 
count < 800/mm3

Platelet count < 80 x 109/L
19. Any clinically significant medical condition or 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.
20. Has received or is expected to receive any dose of a SARS-CoV-2 vaccine 
before the Day 14 visit.
Test Product:
x
AT-527 will be provided as 550 mg tablets  
x
Matching placebo tablets will also be provided.
Dose and Mode of 
Administration:
x
Study drugs (AT-527 or placebo) to be administered orally
x
Doses and frequency as described in the protocol
Statistical 
Methods:
Sample size calculations and power statements were performed using 
SAS/STAT v9.4 (SAS Institute Inc., Cary, NC, USA).  All analyses will be 
performed in this version of SAS/STAT or higher unless otherwise noted in the 
Statistical Analysis Plan (SAP). Efficacy analyses will be performed on the intent-
to-treat (ITT) population, which is defined as all randomized patients. Unless 
otherwise indicated, efficacy analyses will be carried out separately for Part A 
and Part B.
An interim analysis was carried out on the first 70 subjects randomized in Part A. 
Prior to conducting the interim analysis, a low overall PRI event rate was 
observed in the blinded aggregate dataset, indicating that it was likely that the 
initial powering assumptions for the primary endpoint were no longer reasonable 
and the study, as originally planned, would be unlikely to provide a sensitive 
assessment of the PRI endpoint. Consequently, it was decided to continue the 
study (i.e Part B), exploring a higher dose with a change in the primary endpoint 
to be based on SARS-CoV-2 virus RNA as measured by RT-PCR on 
nasopharyngeal swab samples.
Primary efficacy endpoint:
Part A
The primary endpoint of the study is the proportion of subjects with PRI.  
Proportions of subjects (active or placebo-treated) with PRI until Day 14 will be 
compared by study arm.  The Cochran Mantel Haenszel (CMH) test, adjusting for 
randomization strata, will be performed to compare the proportion of PRI rate 
(PRIR) in study arms. Assuming PRIR rates of 0.4 and 0.2 in the placebo and 
experimental arms, respectively, and testing at alpha one-sided of 0.025 with
power of 0.8, a total of 182 subjects are required at a 1:1 allocation, i.e. 91 per 
study arm.  Per Amendment 8, Part A will conclude and enrollment will continue 
in Part B.
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Part B
The primary endpoint of Part B is the change from baseline in amount of SARS-
CoV-2 virus RNA (viral load) as measured by RT-PCR. Viral load will be assessed 
quantitatively using a validated assay. Analyses will be carried out at each 
scheduled time point. Part B of the study is signal seeking. The primary analysis 
aims to identify and characterize any potential effect of AT-527 on viral load over 
time. Analyses and p-values are descriptive and no adjustment for multiple 
comparisons will be made.
Change from baseline viral load at each timepoint will be compared between the 
AT-527 group and the placebo group ANCOVA with treatment as a factor and 
log10 baseline viral load as a covariate. In the interim analysis of the first 70 
subjects from part A, the observed AT-527 effect at Day 2 was a reduction of 0.7 
log10 copies/mL relative to placebo. Assuming a standard deviation for change 
from baseline of 1.8 log10 copies/mL and 90% of Part B planned randomized 
patients eligible for analysis (i.e. 100 patients), there is at least 90% power to 
detect a true treatment effect of 0.7 using a one-sided test at 0.1 level of 
significance.
Only patients with a positive qualitative SARS-CoV-2 RT-PCR test result at 
baseline will be included in this analysis. The least squares mean (LSM) change 
and its standard error of means (SE) in each group, the differences between two 
groups in LSM change with corresponding 95% confidence intervals (CIs), and p-
values will be presented.
Key secondary endpoints:
The efficacy endpoint assessments are hierarchical in Part A.  The key 
secondary endpoints will be tested, in order, only if the primary efficacy endpoint 
meets its success criteria and each higher endpoint meets its success criteria.  
This hierarchical testing strategy will preserve study alpha.
The key secondary endpoints for Part A are indicated below with the hierarchical 
ordering. The hierarchical ordering pertains to Part A only. Following the change 
in protocol following the interim analysis, there will be no formal procedure to 
preserve study-wise type I error in Part B. All analyses are descriptive, and any 
findings would need to be confirmed in another study with prospective alpha 
control. With the change in primary endpoint in Part B, the primary endpoint and 
non-virological key secondary endpoints from Part A will be considered as key 
secondary endpoints in Part B.
x
First key secondary endpoint (Part A only): change from baseline in amount of 
SARS-CoV-2 virus RNA (viral load) as measured by RT-PCR. 
Viral load will be assessed quantitatively using a validated assay. Change 
from baseline viral load will be compared between the AT-527 group and the 
placebo group at scheduled time points using ANCOVA with treatment as a 
factor and log10 baseline viral load as a covariate.  The least squares mean 
(LSM) change and its standard error of means (SE) in each group, the 
differences between two groups in LSM change with corresponding 95% 
confidence intervals (CIs), and p-values will be presented. Statistical 
significance at Day 5 will be assessed using a one-sided 0.025 level test. If 
the Day 5 comparison is significant, then the Day 2 treatment effect would be 
tested.
x
Second key secondary endpoint: median time (days) to Clinical Recovery 
from randomization, based on achieving disease resolution (status 6,7, or 8) 
in the NIAID Clinical Status scale
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The planned statistical comparison will use the Wilcoxon Mann-Whitney test
with one-sided alpha=0.025. Patients without observed clinical recovery will 
have clinical recovery time assigned as 15 days to preserve the ranks for the 
comparison. 
x
Third key secondary endpoint: respiratory failure or death
A key secondary endpoint is the proportion of subjects with respiratory failure 
or death (RFD) in the first 28 study days. Treatments will be compared using 
the same methodology as that for the primary efficacy endpoint. 
To allow for a modest number of dropouts and subjects not testing positive for 
SARS-CoV-2 at baseline, the study enrollment goal will be 190 subjects.
Additional efficacy assessments include:
x
Change (improvement vs worsening) in the NIAID ordinal scale of overall 
Clinical Status
x
All-cause mortality 
x
Duration of hospitalization/confinement for COVID-19
x
Time to sustained non-detectable SARS-CoV-2 RNA from randomization
x
Proportion of subjects who are still SARS-CoV-2 positive at Days 5 and 14
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LIST OF ABBREVIATIONS
Term
Definition
AE
Adverse event
ALT
Alanine aminotransferase
ARDS
Acute respiratory distress syndrome
AUC
Area under the curve
AST
Aspartate aminotransferase
BID
Bis in die; twice daily
BiPAP
Bi-level positive airway pressure
BMI
Body mass index
BNP
B-type natriuretic peptide
BUN
Blood urea nitrogen
CBC
Complete blood counts
CK
Creatine kinase
Cmax
Maximum observed plasma concentration
CMH
Cochran Mantel Haenszel
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CPAP
Continuous positive airway pressure
CRO
Contract research organization
DAIDS
Division of AIDS
dNHBE
Differentiated normal human bronchial epithelial
DSMB
Data safety monitoring board
EC90
90% effective concentration
eCRF
Electronic case report form
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation
EDC
Electronic Data Capture
ET
Early termination
EU
European Union
EUA
Emergency use authorization
FDA
Food and Drug Administration
FiO2
Fraction of inspired oxygen
GCP
Good Clinical Practices
GLP
Good Laboratory Practice
HAE
Human airway epithelial
HbA1c
Hemoglobin A1c
HBV
Hepatitis B virus
HCO3-
Bicarbonate
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate or Hazard ratio
Huh-7
Human hepatoma cell line
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intention to treat
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IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
MCV
Mean corpuscular volume
MDCR
Median days to clinical recovery
MedDRA
Medical dictionary for regulatory activities
MERS
Middle East Respiratory Syndrome
NHP
Nonhuman primate
NIAID
National Institute of Allergy and Infectious Diseases
NOAEL
No observed adverse effect level(s)
NT-proBNP
N-terminal pro b-type natriuretic peptide 
P-gp
P-glycoprotein
PaO2
Partial pressure of oxygen
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PK
Pharmacokinetics
POLRMT
Mitochondrial RNA polymerase
PP
Per protocol
PRI
Progressive respiratory insufficiency
PRIR 
Progressive respiratory insufficiency rate
PT
Prothrombin time
QTcF
QT interval with Fridericia’s correction
RFD
Respiratory failure or death
RFDR
Respiratory failure or death rate
RR
Respiratory rate
RT-PCR
Reverse transcription polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS
Severe acute respiratory syndrome
SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
SOC
Standard of care; System organ class
SOP
Standard Operating Procedure
SpO2
Blood oxygen saturation
TC
Telephone contact
TP
Triphosphate
ULN
Upper limit normal
WBC
White blood cell
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SPONSOR PROTOCOL APPROVAL
Protocol Number: AT-03A-001
TITLE: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of AT-527 in Subjects with Moderate COVID-19
On behalf of the Sponsor, we have read this study protocol and agree with its contents:
_____________________________
____________________
Date (dd-mmm-yyyy)
_____________________________
____________________
Date (dd-mmm-yyyy)
___________________
____________________
Date (dd-mmm-yyyy)

_______________________
___
__
__
__
__
__
__
__
__
_ _________


___
_ _____________________
448
(
DocuSigned by: 
I 
l(J 
Signer Name:
 
L
Signing Reason: I approve this document 
Signing Time: 8/27/2021 112:53:02 PM EDT 
6A77546D48B9728C389BBF8DF 
(
DocuSigned by: 
I 
 
l(J 
Signer Name:
 
L
Signing Reason : I approve this document 
Signing Time: 8/27/2021 110:04:23 AM PDT 
D4B04AB435948FED9F4B6 
(
DocuSigned by: 
I 
 
 
l(J 
Signer Name
 
ing Reason: I approve this document 
ing Time: 8/27/2021 11 :54:48 PM EDT 
FF1498EA550A47887014AB1 
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PRINCIPAL INVESTIGATOR PROTOCOL APPROVAL
Protocol Number: AT-03A-001
TITLE:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of AT-527 in Subjects with Moderate 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
In December 2019, a cluster of patients in Wuhan, China were diagnosed with pneumonia with 
symptoms similar to the severe acute respiratory syndrome (SARS) outbreak in 2002-2003. 
Early in January 2020, the causative agent, a novel coronavirus now named severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified.  This virus has close RNA 
sequence homology to SARS-CoV, the name for the virus associated with the 2002-2003 SARS 
outbreak. The new life-threatening coronavirus, SARS-CoV-2, causes a potentially severe 
disease now called coronavirus disease 2019 (COVID-19), which has rapidly spread across the 
world. The COVID-19 outbreak was categorized as a pandemic by the World Health 
Organization (WHO) on 11 March 2020.
COVID-19 is an acute febrile respiratory disease that is usually mild-moderate in clinical 
severity but can be severe or fatal. Aside from fever and dry cough, many patients find the other 
common acute symptoms (fatigue/malaise, dyspnea/chest tightness, headache, myalgias, and 
gastrointestinal disturbance) to be very uncomfortable for 5-10 days or more, and some require 
hospitalization for close observation and supportive care. The acute COVID-19 clinical 
syndrome spontaneously resolves in most affected individuals (≥80%), but COVID-19 can be 
clinically severe, leading to a need for respiratory support (supplemental oxygen or even 
mechanical ventilation) in about 15-20% of patients, more in some series. Aside from 
respiratory insufficiency, accumulating COVID-19 clinical reports indicate an accompanying 
hyper-coagulopathy in many patients, resulting in thromboembolic processes that can damage 
any body organ, with reports of severe cardiac events, renal failure, liver damage, central 
nervous system events, and other disease manifestations.  Reports of clinical features of COVID-
19 patient populations have indicated common risk factors for poor outcomes, i.e.: older age 
(e.g., > 45 years), obesity, hypertension, diabetes, and chronic lung conditions (asthma, chronic 
obstructive pulmonary disease (COPD)) (Goyal P, et al. 2020).  Progression to respiratory 
failure, with a need for mechanical ventilation, is common in the more severely ill COVID-19 
patients, especially patients with the aforementioned risk factors, and is associated with a high 
risk of death. In two reports involving non-U.S. patients, 81-97% of patients who progressed to 
needing mechanical ventilation died, while a report on 24 early U.S. patients in Seattle ICU care 
indicated ≥ 50% mortality for ventilated patients (Weiss P and Murdoch DR 2020; Bhatraju PK, 
et al. 2020). 
As of 28 June 2021, almost 180.5 million cases of COVID-19 and approximately 3.9 million 
COVID-19-related deaths were reported in over 200 countries and territories worldwide (World 
Health Organization 2021). The ~2% mortality rates for COVID-19 are lower than the 9.6% 
fatality rate observed during the 2003-2003 SARS outbreak, but fatality rates for both “SARS-1” 
and the current “SARS-2” (COVID-19) are well above the average 0.1% mortality rate observed 
year-on-year with globally recurring Influenza A pandemics. 
Prevention and control of SARS-CoV-2 infection have focused on public health measures to 
slow transmission, such as social distancing, the use of face masks, and national or regional 
lockdowns.  A number of vaccines have recently been approved for the prevention of SARS-
CoV-2 infection, but these vaccines remain in the distribution phase and there are logistical 
challenges in vaccinating large populations globally.  Additionally, the duration of protection 
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afforded by these vaccines as well as coverage of emerging variants is currently unknown.  
Intravenous remdesivir, an inhibitor of RNA-dependent RNA polymerase, and dexamethasone 
have shown benefit in hospitalized patients with severe COVID-19.  However, in patients with 
moderate COVID-19, dexamethasone is not efficacious (and may be harmful) and the use of 
remdesivir is not approved for non-hospitalized patients (Gandhi et al. 2020).  Since the initiation 
of the AT-03A-001 study, virus-neutralizing monoclonal antibody therapies [including 
sotrovimab, bamlanivimab plus etesevimab (with subsequent pause in distribution in the US), 
and casirivimab plus imdevimab] have been authorized for use in various regions (through
emergency use authorization (EUA) in the US or conditional approvals in the EU).  These 
monoclonal antibody therapies are not generally authorized for use in patients who are 
hospitalized due to COVID-19; they are administered intravenously (IV) in a hospital setting and 
are indicated for the treatment of mild to moderate COVID-19 in adults and pediatric patients 
(12 years and older weighing at least 40 kilograms) with positive results of direct SARS-CoV-2 
viral testing and who are at high risk for progressing to severe COVID-19 and/or hospitalization.  
Thus, there may be some overlap in the AT-03A-001 population for those high-risk patients with 
moderate disease who are confined (instead of hospitalized for COVID-19).  Access to treatment 
(remdesivir and monoclonal antibody therapies) and standard of care will be variable in each 
participating country.
Atea Pharmaceuticals is developing AT-527, a unique 6-modified purine nucleotide prodrug 
that, in laboratory studies, potently inhibits the RNA-dependent RNA polymerases of several
single-stranded RNA viruses (e.g. flaviviruses [HCV, dengue] and coronaviruses).  AT-527 
demonstrated sub-micromolar potency against a range of coronaviruses, including SARS-CoV-1
(90% inhibitory concentration (EC90)=0.34 μM) and SARS-CoV-2 (mean EC90=0.5 μM), as 
described in Section 4 of the AT-527 Investigator’s Brochure.  AT-527 can be administered
orally once- or twice-daily, as tablets, and was previously in Phase 1-2a clinical testing for the
treatment of chronic hepatitis C virus (HCV) patients.  For that clinical testing program, 
comprehensive non-clinical studies were completed, which included 13-week repeat-dose animal 
toxicology studies conducted to Good Laboratory Practice (GLP) standards in two animal 
species (rat and monkey), to support long-term (up to 12 week) dosing in clinical studies.  
Supported by these and other non-clinical data, AT-527 has already been evaluated in two 
completed clinical studies involving healthy human volunteers and HCV patients.  In a recently 
completed Phase 2 study, AT-527 was well-tolerated for durations up to 12 weeks in HCV-
infected subjects and achieved a high rate of antiviral efficacy, with no safety/tolerance issues. In 
healthy and HCV-infected subjects, AT-527 exhibited a predictable and predictive 
pharmacokinetic (PK)/pharmacodynamic (PD) profile associated with the observed antiviral 
efficacy in HCV patients. This supportive human PK profile is likely to be observed with dosing 
of COVID-19 patients and is expected to be sufficient for achieving antiviral efficacy with AT-
527 dosing of COVID-19 patients, based on the sub-micromolar EC90 for the active triphosphate 
of AT-527 against SARS-CoV-2 virus replication in laboratory studies. 
The demonstrated clinical safety/tolerability of AT-527 in HCV patients, with an established 
supportive human PK profile, coupled with the potent in vitro activity of AT-527 against SARS-
CoV-2, provide a strong scientific rationale to rigorously evaluate AT-527 in COVID-19 
patients.
In the current phase 2 study, the safety, antiviral activity and efficacy of AT-527 will be 
evaluated in adult subjects (≥18 years of age) with risk factors for poor outcomes. Preventing 
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disease progression to successive stages of respiratory insufficiency is potentially lifesaving, as 
ultimate progression to dependence on intubated respiratory support is associated with a high 
rate of fatal outcomes (over 50% in U.S. patients, and over 80% in ex-U.S. patients, as noted 
above). 
Additional information for AT-527 can be found in the AT-527 Investigator’s Brochure.
Rationale/Background for Amendment 8
The clinical development program has been designed on the basis of the emergency nature of the 
ongoing pandemic.  Although the initial primary efficacy goal of the originally designed study 
was to significantly reduce progressive respiratory insufficiency (PRI), it has become apparent, 
from blinded analysis, that the background rates of disease progression in this targeted study 
population are too low to demonstrate clinical efficacy differences between the treatment arms.  
With a better understanding of the disease resulting in improvements in patient management over 
time, the disease progression rates observed in this study are much less than the initial 
assumptions made at the beginning of the study/pandemic, which postulated that 40% of placebo 
recipients would progress and experience PRI.   Due to the low progression rates and in order to 
support interactions with regulatory agencies, the Sponsor decided to pause enrolment and 
conduct an interim analysis during the course of the study.  
Enrollment in the study was paused after the 81st patient was randomized and the interim 
analysis (in which the study team remained blinded to individual treatment assignment) was 
performed on the first 70 patients who completed through Day 14 of the study.  Of 62 patients
evaluable for the virology analysis, 58 had baseline quantitative viral load data. This interim 
analysis indicated that AT-527 rapidly reduced viral load levels.  At Day 2, patients receiving 
AT-527 experienced a 0.7 log10 greater mean reduction from baseline viral load as compared to 
placebo.  A sustained difference in viral load reduction was maintained through Day 8 (see figure 
below).  After Day 8, the curves in the groups converge, however, this is expected considering 
the natural history of the disease in which viral load generally peaks at the time of symptom 
onset and decreases spontaneously with time.
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Quantitative SARS-CoV-2 RNA, mITT (all evaluable patients)
This antiviral signal was further interrogated in the subset of patients with higher baseline viral 
loads (VL) above the median of 5.26 log10 as compared to placebo (see figure below).  Similarly, 
antiviral activity of AT-527 was also observed in this subset of patients, further suggesting a 
signal that warrants additional study. As the AT-527 group had lower viral loads at baseline 
in this sub-set of patients, an exploratory analysis with the baseline viral load threshold lowered 
to 5.0 log10 was conducted in which both treatment groups had similar mean viral loads at 
baseline. Results were consistent and showed a similar trend toward earlier viral clearance in the 
AT-527 group.
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Quantitative SARS-CoV-2 RNA, mITT with Baseline VL ≥ median (5.26 log10 copies/mL) 
Patients in the AT-527 arm achieved SARS-CoV-2 clearance (no detectable RNA or target not 
detected (TND)) as early as Day 2 (6%), Day 8 (7%) and Day 10 (33%), Day 12 (31%) 
compared to 0% in the placebo arm at the same timepoints. By Day 14 (last viral sampling study 
day) approximately 47% of patients in the AT-527 arm and 22% in the placebo arm had no 
detectable RNA virus (TND) (see figure below).
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Qualitative SARS-CoV-2 RNA, mITT Patients with Baseline VL ≥ median (5.26 log10 
copies/mL)
AT-527 dosed as 550 mg BID for 5 days was generally well-tolerated in this population.  There 
were no drug-related SAEs.  Non-serious AEs were equally distributed across treatment arms.  
Most were mild-to-moderate in severity and assessed as not related to the study drug.  No 
clinically significant abnormal ECGs were reported.  No safety concerns or newly determined 
risks were identified.
Although the Sponsor acknowledges the futility of demonstrating a treatment effect on PRI in 
this study, as the small number of disease progression events will not be sufficient to provide a 
meaningful measure of clinical effect, the Sponsor believes that the rapid and sustained antiviral 
activity described above warrant further evaluation in this high-risk patient population.  As such, 
the Sponsor has decided to continue the study with a second cohort of patients receiving a higher 
AT-527 dosing regimen of 1100 mg BID for 5 days.  The original design utilizing the 550 mg 
BID dose, which enrolled 81 patientswill be referred to as Part A; the second half of the study 
which will dose patients at 1100 mg BID will be considered Part B of the study.  Part B will have 
a virologic primary endpoint and will explore whether higher doses result in a more pronounced
antiviral effect in this population.  If so, these data would further support dose selection for the 
program and this patient population.  The 1100 mg BID dose is also being evaluated in an 
ongoing Phase 2 outpatient study (NCT04709835) and ongoing Phase 1 study in health 
volunteers (AT-03A-002).
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1.2.
Rationale for the Dose Selection
1.2.1. Rationale for AT-527 550 mg BID Dose Regimen in Part A 
The starting dose regimen in Part A of this study was 550 mg AT-527 BID for 5 days. This 
regimen was supported by the following data:
x
Tissue distribution data for the active triphosphate metabolite AT-9010 in non-human 
primate and production rates of AT-9010 in human and cynomolgus monkey hepatocytes 
incubated with 10 PM AT-511 (see details in the AT-527 Investigator's Brochure, Section 
4.2.2.2 and Table 6-1)
x
Predicted PK profiles for AT-9010 in the lung at the studied 550 mg BID regimen (see 
details in the AT-527 Investigator's Brochure, in Figure 6-1)
At steady state, the 550 mg BID regimen was predicted to deliver the following values:
x
Mean trough AT-9010 (the active triphosphate metabolite) concentrations at 12 hours 
(C12 hr) in the lung at about 0.9 PM, 1.8-fold higher than the mean EC90 of 0.5 PM 
determined for the free base AT-511 in an in vitro antiviral activity assay in SARS-CoV-
2-infected human airway epithelial cells (AT-527 Investigator's Brochure)
x
Mean maximum lung AT-9010 concentrations at about 1.5 PM (time to maximum 
concentration at about 4 hours postdose), 3-fold higher than the mean EC90 of 0.5 PM.
The 550 mg BID regimen has been evaluated in the ongoing Phase I Study AT-03A-002; 20 
healthy subjects (blinded, 1:1 randomization active vs. placebo) were enrolled and have 
completed dosing and follow-up through Day 10; no safety concerns have been identified.  
Data for AT-527 550 mg once a day (QD) combined with daclatasvir 60 mg QD in HCV 
infected patients was also available from a completed 12-week study (AT-01B-002).  In that 
study, most patients received a cumulative total dose of AT 527 30,800 mg (over 8 weeks).  
Safety and tolerability data from the study provide a safety margin of 5.6-fold for a 5-day (5500 
mg cumulative dose) treatment regimen for COVID-19 patients.  
The animal and human systemic exposure parameters summarized in Table 6-2 of the AT-527 
Investigator's Brochure indicate that the steady-state exposures of AT-511 and its metabolites 
achieved at the NOAEL doses in the 13-week toxicology studies exceed or approximate unity for 
the AT-527 550 mg BID dose in the target population of this study.
These considerations supported an expected favorable safety profile for the evaluation of the 550 
mg BID dose regimen in the target population in Part A of the study. 
Based on the emerging data described in the interim analysis above as well as the favorable
safety profile observed at 550 mg BID, the Sponsor is proposing a subsequent cohort (Part B) to
evaluate a higher dose of 1100 mg BID for 5 days.
1.2.2.
Rationale for AT-527 1100 mg BID Dose Regimen in Part B 
The available nonclinical and clinical evidence supported the starting regimen of 550 mg BID.  
However, a higher dose regimen (1100 mg BID for 5 days) has been selected to further explore 
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the dose-exposure-response profile for AT-527 and delineate the relationship between plasma 
concentration of AT-273, a surrogate for the intracellular concentration of the active triphosphate 
metabolite AT-9010, and antiviral activity.  
At steady state, this regimen is predicted to achieve the following values:
x
Mean trough AT-9010 concentrations at 12 hours (C12 hr) in the lung at about 1.8 PM, 3.6-
fold higher than the mean EC90 of 0.5 PM determined for AT-511 in the in vitro antiviral 
activity assay in SARS-CoV-2 infected human airway epithelial cells
x
Mean maximum AT-9010 concentrations in the lung at about 3.0 PM, 6-fold higher than 
the mean EC90 of 0.5 PM
Exposure multiples for the maximum concentration (Cmax) and the area under the concentration-
time curve over the dosing interval at steady state (AUCW,ss) of AT-511, AT-551, AT-229, and AT-
273 in plasma at the highest planned AT 527 dose in this study (1100 mg BID) are presented in 
Table 1-1.
Plasma exposures achieved in the repeat-dose toxicity studies in the rat and the non-human primate 
either exceed or approximate the anticipated clinical exposures for the different metabolites in one 
or both species, depending on the metabolite, and are consistent with the International Council for 
Harmonisation (ICH) document on metabolite coverage including prodrug approaches (ICH 
2008).
  
Table 1-1
Predicted Rat and Non-Human Primate Exposure Multiples for AT-511 (Free 
Base Form of AT-527) and Its Major Metabolites AT-551, AT-229 and AT-273 
at a Human Dose of AT-527 1100 mg BID
Monkey: Day 5
1000 mg/kg
Monkey: 13-wk
650 mg/kg
Rat: 13-wk
1000 mg/kg
Males
Females
Males
Females
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Cmax
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1.6
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AT-229
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AT-273
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1.1
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AUCW,ss area under the concentration–time curve during the dosing interval at steady state; 
Cmax  maximum concentration.
The 1100 mg BID dose is also being evaluated in an ongoing Phase 2 outpatient study 
(WV43042) and ongoing Phase 1 study in health volunteers (AT-03A-002).
1.3.
Study Rationale
As there are currently very limited treatment options for COVID-19, there is an unprecedented 
urgent need to develop new therapies.  These should be agents that are proven safe and effective 
in controlled clinical trials.  Rigorously studied agents could prove to be lifesaving for COVID-
19 patients if they substantially reduce disease progression to respiratory failure.  Progression of 
respiratory insufficiency to respiratory failure (requiring mechanical ventilation or ECMO) is 
often fatal for severely ill COVID-19 patients and is more common in older patients with 
associated risk factors.  As noted above, fatality rates for COVID-19 patients who have 
progressed to intubated mechanical ventilation have been reported to be about 50% or higher in 
U.S. patients and over 80% in ex-U.S. patients.
Participants in this clinical trial represent a high-risk population with significant comorbidities 
associated with poor outcomes such as obesity, diabetes, asthma and hypertension. Although the 
risk for severe COVID-19 increases with age, recent data indicate that younger adults are also at 
significant risk. In the US, the median age of COVID-19 cases continues to decline from the 
earlier times of the epidemic, most recently from 46 years old in May 2020, to 37 years old in 
July 2020, and 38 years old in August 2020. Similar trends were reflected in the increased 
frequency of emergency room visits in younger adults. The highest incidence of COVID-19 
during June through August 2020 was in 20–29 year old adults, accounting for >20% of all 
confirmed cases (Boehmer TK, DeVies J, Caruso E, et al. 2020).  As a consequence of the 
declining average age of infection, there is now a significant overlap of moderate and severe 
COVID-19 in younger adults with risk factors. In a recent database analysis, adults age 18 to 34 
years old hospitalized with COVID-19 experienced frequent adverse outcomes: 21% required 
intensive care, 10% required mechanical ventilation, with a 2.7% of overall mortality rate
(Cunningham JW, Vaduganathan M, Claggett BL, et al. 2020). In this series, obesity, 
hypertension, and diabetes were associated with the worst outcomes, with younger patients with 
more than 1 factor having a comparable risk to older adults without them. In the US population, 
these risk factors are a common finding in young adults: the prevalence of obesity in the US in 
2017-2018 was 40.0% among adults aged 20–39, hypertension now affects 1 in 8 adults aged 
between 20 and 40 years old, and approximately 13% of those > 18 years old in the US have 
diabetes, with 4% being between the age of 18-44 years (Hales CM, et al. 2020; Centers for 
Disease Control and Prevention - National Diabetes Statistics Report 2020; Hinton TC, et al. 
2020). These trends have also been growing internationally with a surge in new COVID 19 cases 
linked to young people in multiple countries in Europe. Obesity and its associated comorbidities 
are also on the rise in young people in many areas of the world (World Health Organization
2017).  Based on these considerations, derived from our evolving understanding of the disease, 
an expansion of the age criteria was warranted in order to address the emerging unmet need and 
to allow participation in the trial of a younger, more representative population at risk.
Urgent clinical evaluation of AT-527 in COVID-19 patients is supported by extensive non-
clinical safety data, Phase 1-2 clinical safety data in healthy volunteers and HCV-infected 
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patients, the supportive human PK data, and the potent activity of AT-527 against SARS-CoV-2 
replication.  The in vitro virology data for AT-527 show potent inhibition of SARS-CoV-2 
replication, with a mean EC90 concentration (0.5 μM).  This is a level that can be easily achieved 
and continuously maintained systemically with the AT-527 dosing regimens stipulated for this 
study.  As noted above in Section 1.1, a promising antiviral activity and safety profile at 550 mg 
BID in Part A was described with the interim analysis, although clinical efficacy could not be 
demonstrated due to the low disease progression rates.  Nevertheless, with the positive antiviral 
signal, the Sponsor is proposing to explore a higher AT-527 dose of 1100 mg BID for 5 days to 
potentially optimize the antiviral activity.  
In summary, AT-527 is an orally administered, well-tolerated, potent anti-RNA virus candidate 
recently progressing in Phase 2 studies with hepatitis C patients, which has been repurposed for 
evaluation in COVID-19 patients.  Initial efficacy goals in Part A were to substantially reduce 
progression to higher levels of respiratory insufficiency and to shorten patients’ acute illness, 
however, clinical efficacy could not be demonstrated due to the small number of patients 
achieving the PRI endpoint.  The current trial is a randomized, double-blind, placebo-controlled
clinical study to rigorously evaluate the safety and efficacy of AT-527 in hospitalized/confined 
adult (≥18 years of age) COVID-19 patients with moderate disease and risk factors for poor 
outcomes. The primary efficacy goal in Part A was to significantly reduce progressive 
respiratory insufficiency in this high risk population, assessed by comparing the proportions of 
subjects (active vs. placebo recipients), who experience a 2-tier or greater increase in required 
respiratory support methods, using a 6-tier scale described in Section 6.9.  As the futility of 
demonstrating a treatment effect on PRI in this study has become apparent based on the low 
event rates, the primary endpoint for Part B will be changed to a virologic endpoint.  
AT-527 (or placebo) will be administered along with supportive local standard of care (SOC) 
therapy per local/institutional practices or guidelines, with the exception of antiviral drugs with
activity against SARS-CoV-2.  Supportive SOC will not be dictated by the protocol.  Placebo 
plus SOC control groups will be utilized to assess whether AT-527 can demonstrate 
clinical/antiviral benefit over currently available SOC.  Treatment-assignments (active vs. 
placebo) will be randomized and double-blind. Positive data from this study could potentially 
support subsequent outpatient studies in patients with milder disease as well as controlled studies 
of early-treatment of asymptomatic or minimally symptomatic SARS-CoV-2 positive persons,
and controlled prophylaxis studies in important risk populations (e.g. close contacts of COVID-
19 patients, healthcare workers and first responders).  An orally administered SARS-CoV-2 
direct-acting antiviral which demonstrates safety and clinical benefit in COVID-19 patients 
would have important impact on ameliorating illnesses in the current crisis, and could be life-
saving if treatment is found to reduce patients’ disease progression.
1.4.
Risk/Benefit Assessment      
The extensive non-clinical data and clinical data from HCV patients summarized above and in 
the AT-527 Investigator’s Brochure indicate an encouraging risk-benefit expectation for AT-527 
treatment of COVID-19 patents, supporting program advancement to the present Phase 2 clinical 
trial with an expectation of satisfactory clinical safety and appreciable antiviral activity.  Non-
clinical and clinical safety studies have not revealed any pattern of drug-attributable clinical 
adverse effects or any consistent clinically significant laboratory abnormalities related to any 
body system.  Total daily doses in this COVID-19 study are higher than evaluated in the HCV 
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program; however, the 5-day cumulative AT-527 dosing exposure for COVID-19 subjects is
much less than the cumulative AT-527 exposures in the HCV program (8-12 weeks).  Based on 
cumulative total dose received in the HCV program (30,800 mg for most subjects), there is a
safety margin of 5.6-fold for the 5-day 550 mg BID COVID-19 treatment regimen (5,500 mg 
cumulative dose) and a 2.8-fold margin for the 1100 mg BID (11,000 mg cumulative dose)
treatment regimen.  
While in vitro data are consistent with AT-527 having a low potential for mitochondrial toxicity, 
some nucleoside analogues have been associated with this toxicity, resulting in damage to liver, 
muscles, heart, nerve, pancreas and other organs.  Nephrotoxicity has also been associated with 
the use of some nucleoside analogs (e.g. tenofovir), but is not a class effect.  The completed non-
clinical assessments of AT-527 suggested negligible potential for mitochondrial toxicity. The 
active triphosphate of AT-527 did not inhibit the in vitro enzyme activities of human cellular 
DNA-dependent DNA polymerases (D, E or J) and was poorly incorporated by human 
mitochondrial RNA polymerase (POLRMT), with a low efficiency that was similar to that of the 
triphosphate of sofosbuvir, a nucleoside analog that has been quite safe in broad use in HCV 
patients.  Additionally, neither AT-527 nor sofosbuvir had any effect on mitochondrial integrity 
using cell-based assays.  To date, there have been no clinical signs of adverse events (AEs) 
suggesting mitochondrial toxicity for AT-527 dosing, in animal toxicology studies or the clinical 
studies.
The present protocol mandates thorough clinical and laboratory safety monitoring, with routine 
frequent testing of the following parameters: liver function tests (including alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and alkaline 
phosphatase), creatine kinase (CK) and isoenzyme levels, electrocardiogram (ECG) monitoring 
and renal function parameters (including serum creatinine and blood urea nitrogen (BUN)).  
Standard serum chemistries, complete blood counts (CBC) with differentials, urinalyses and 
clinical AEs will also be monitored. Current medically used nucleoside analogs are primarily 
renally cleared, but dose adjustments are generally not needed for patients with creatinine 
clearance values ≥ 60 mL/min. With this perspective, the present protocol excludes patients with 
creatinine clearance < 60 mL/min
Although it is reasonable to expect that a SARS-CoV-2 direct-acting antiviral with potent (sub-
micromolar) in vitro antiviral activity will result in clinical benefit, AT-527 is still currently 
being tested in clinical trials in COVID-19 patients.  Thus, it is possible that subjects will not 
receive any benefit from participation in this study. As noted, an independent DSMB has been
established to periodically assess safety and potential risk/benefit, as described in Section 3.1 and
Section 10.1.
The likelihood of substantial antiviral efficacy in these subjects is supported by the favourable 
human PK profile observed in human volunteers and HCV patients, which is predicted to be 
sufficient for achieving and maintaining systemic AT-527 concentrations above the SARS-CoV-
2 EC90.  
The non-clinical and clinical data for AT-527 summarized in this protocol therefore support the 
probability of a favourable benefit-risk profile for AT-527 in the treatment of COVID-19 
patients.
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2.
STUDY OBJECTIVES
The objectives of this study are to evaluate the safety, antiviral activity, tolerability and efficacy 
of AT-527 in adult subjects (≥18 years of age) with moderate COVID-19 and risk factors for 
poor outcomes.  
The primary efficacy goal for Part A (secondary for Part B) is to significantly reduce PRI, 
assessed with the 6-tier scale of increasing levels of respiratory support described in Section 6.9.  
The most important potential treatment benefit is significantly reducing subjects’ PRI, which will 
be assessed as the proportions of subjects experiencing a 2-tier or greater need in respiratory 
methods, with a goal to reduce such progressions by 50% in active-treated subjects vs. placebo 
recipients.  
The primary efficacy goal for Part B (secondary for Part A) is to provide greater reduction in 
SARS-CoV-2 virus RNA as measured by RT-PCR at specified timepoints.
Secondary efficacy goals include: shortening in median time to clinical recovery by at least 4 
days (based on achieving disease resolution in the National Institute of Allergy and Infectious 
Diseases (NIAID) Clinical Status scale); reduction in progression to respiratory failure or death,
using the 6-point scale; improvement in overall Clinical Status using the NIAID ordinal scale, 
reduction in all-cause mortality, shortening of duration of hospitalization for COVID-19, 
shortening of time to sustained non-detectable SARS-CoV-2 and reduction in proportion of 
subjects SARS-CoV-2 positive at Days 5 and 14.
As an exploratory objective, plasma concentrations of AT-527 and metabolites will be monitored
in sparse samples collected from subjects with COVID-19.
3.
STUDY DESIGN
3.1.
General Study Design
This is a phase 2 double-blind, placebo-controlled, randomized treatment study evaluating AT-
527 (or placebo) for 5 days in combination with supportive SOC compared to SOC alone in 
hospitalized/confined subjects with moderate COVID-19 disease and risk factors for poor 
outcomes.  The study will enroll adults, ≥18 years of age, with moderate COVID-19, not on a 
ventilator.  Subjects must also have at least one of the known common risk factors for poor 
outcomes:  obesity (BMI>30), hypertension, diabetes or asthma.  Subjects will be documented as
SARS-CoV-2 positive in an assay granted EUA by the U.S. FDA. 
Moderate disease will be defined by the following:
x
Symptoms of COVID-19, with initial symptom onset within 5 days prior to Screening: 
o
At least 1 of the following: fever (> 38.3 °C), cough, sore throat, fatigue/malaise, 
headache, muscle pain, or more significant lower respiratory symptoms including 
dyspnea (at rest or with exertion)
x
Clinical signs indicative of COVID-19 (as above), with:
o
SpO2 ≥ 93% on room air or requires ≤ 2L/min oxygen by nasal cannula or mask 
to maintain SpO2 ≥ 93%
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The study will be conducted in 2 Parts. Part A will evaluate an AT-527 dose of 550 mg BID for 
5 days and Part B will evaluate a dose of 1100 mg BID for 5 days.  Based on the interim analysis 
conducted after Part A (which demonstrated a positive antiviral signal but low disease 
progression rates in the population), Part B was added via an amendment with a virologic 
primary endpoint.
Part A subjects will be randomized 1:1 (active:placebo).  Subjects will receive one (1) tablet of 
550 mg active drug (or matching placebo) every ~12 hours to complete 5 days of treatment.  
Table 3-1
Study Design
Disease 
Severity
Treatment 
Duration
Dosing Arms
Moderate
5 days
active
550 mg AT-527 administered every ~12 hours (10 doses) + 
SOC
placebo
AT-527 placebo administered every ~12 hours (10 doses) + 
SOC
*Randomized 1:1 (active:placebo)
x
In Part A, a cohort of 20 subjects was initially enrolled to preliminarily assess the safety 
of the 550 mg BID dosing regimen. Enrollment was paused after the first 20 subjects, 
until the DSMB conducted a safety review.  Upon DSMB review, a second cohort of 20 
subjects was enrolled in Part A and enrollment was paused until the DSMB conducted a 
safety review of these data. Again, the DSMB allowed the study to continue without 
modification.
x
In order to perform the interim analysis, Part A enrollment was paused by the Sponsor 
after 81 subjects were randomized.  As described in Section 1.1, no additional subjects 
will be randomized in Part A with implementation of Amendment 8.
x
Part B subjects will be randomized (1:1) to one of the two following arms:
Disease 
Severity
Treatment 
Duration
Dosing Arms
Moderate
5 days
active
1100 mg AT-527 administered every ~12 hours (10 doses) + 
SOC
placebo
AT-527 placebo administered every ~12 hours (10 doses) + 
SOC
*Randomized 1:1 (active:placebo)
x
Up to an additional 110 subjects will be enrolled in Part B.
x
An additional DSMB safety review will occur when 50% of the Part B subjects have 
been enrolled.
For each interim safety review, pooled safety data will be reviewed by the DSMB. The DSMB 
will alert the Sponsor if there are any safety concerns for active-treated subjects compared to
placebo recipients.
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3.2.
Number of Subjects
x
The study is planned to enroll 190 subjects with moderate COVID-19 and risk factors for 
poor outcomes; determination of the targeted sample size is described in Section 8.2. 
o
Part A:  81 subjects were randomized at the time of the Part A interim analysis.
o
Part B:  Up to an additional 110 subjects will be enrolled in Part B.
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. Male or female subjects ≥18 years of age.
3. Subject is hospitalized or in a hospital-affiliated confinement facility for which the 
principal investigator is credentialed and study staff have access to study participants and 
their data.
4. Subject must be diagnosed with COVID-19 (SARS-CoV-2 positive) by a standard assay 
or equivalent testing. Note: SARS-CoV-2 infection will be confirmed with an FDA EUA-
approved assay.
5. Moderate disease defined by the following:
x
Symptoms of COVID-19, with initial symptom onset within 5 days prior to 
Screening: 
o At least 1 of the following: fever (> 38.3 °C), cough, sore throat, 
fatigue/malaise, headache, muscle pain, or more significant lower 
respiratory symptoms including dyspnea (at rest or with exertion)
x
Clinical signs indicative of COVID-19 (as above), with:
o SpO2 ≥93% on room air or requires ≤ 2L/min oxygen by nasal cannula or 
mask to maintain SpO2 ≥ 93%
6. Subjects must also have at least one of the following known risk factors for poor 
outcomes:  obesity (BMI>30), hypertension, diabetes or asthma.  
7. QTcF interval ≤ 450 ms for males and ≤ 460 ms for females at Screening.  
8. Females of childbearing potential must agree to use protocol specified methods of 
contraception as described in Section 5.9.
9. Females of childbearing potential must have a negative pregnancy test at Screening.
10. Subject must be able to take oral tablet medications.
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11. Subject is, in the opinion of the investigator, willing and able to comply with the study 
drug regimen and all other study requirements.
4.3.
Exclusion Criteria
1. Female subject is pregnant or breastfeeding.  
2. Clinical signs indicative of severe or critical COVID-19 illness, defined as any of the 
following:  RR ≥30, HR ≥125, SpO2 <93% on room air or requires >2L/min oxygen by 
nasal cannula or mask to maintain SpO2 ≥93%, systolic blood pressure < 90 mm Hg, 
diastolic blood pressure < 60 mm Hg or PaO2/FiO2 <300
3. Any subject with a concomitant life-threatening condition, including but not limited to 
the following: requiring mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO), acute respiratory distress syndrome (ARDS), shock, cardiac failure or 
suspected bacterial sepsis. 
4. Evidence of lobar or segmental consolidation on chest imaging.
5. Congestive heart failure or myocardial infarction within the previous 6 months.
6. Recurrent nausea, vomiting or known malabsorption syndrome, that would interfere with 
oral medication treatment.
7. Creatinine clearance < 60 mL/min (Cockcroft-Gault formula)
8. Abuse of drugs or alcohol that could interfere with adherence to study requirements as 
judged by the investigator. 
9. Treatment with other drugs thought to possibly have activity against SARS-CoV-2.  
Note:  If the subject was previously treated with such an agent, treatment must have been 
discontinued at least 7 days prior to planned dosing on the current trial. The use of 
hydroxychloroquine is not allowed in this trial. Convalescent plasma is permitted as part 
of local SOC.
10. Use of other investigational drugs within 30 days of dosing, or plans to enroll in another 
clinical trial of an investigational agent while participating in the present study.
11. S-T segment elevation or other clinically significant abnormal ECG at Screening, as 
determined by the investigator.
12. Subject has a history of active hepatitis B infection or uncured hepatitis C infection.  
Subjects with human immunodeficiency virus (HIV) infection are allowed, as long as 
they are virologically suppressed with CD4 count at least 500 cells/mm3.
13. Active clinically significant diseases including:  
x
Active urinary tract infection
x
History of severe renal impairment or receiving renal replacement therapy 
(hemodialysis, peritoneal dialysis)
14. Subjects with malignant disease can continue antineoplastic therapy during the study 
period unless the antineoplastic therapy includes an immunomodulator or is expected to 
result in severe bone marrow suppression during the study (e.g., risk for grade 3 or higher 
anemia, leukopenia, or thrombocytopenia). 
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15. Requires use of immunosuppressive doses of systemic corticosteroids, defined as the 
equivalent of 20 mg prednisone daily during any two week time period (280 mg 
prednisone equivalent total dose) in the three months prior to study entry.  Standard of 
care dexamethasone indication and dosing are permitted if needed for treatment of 
COVID-19 Syndrome.
16. Requires use of immunosuppressive drugs (e.g., for organ transplantation or autoimmune 
conditions) during the primary 14-day study period.  
17. Requirement of any prohibited medications (Section 5.8).
18. Abnormal values at Screening:
x
ALT or AST > 5 x upper limit of normal (ULN)
x
Total bilirubin > 1.5 x ULN, unless the subject has known Gilbert’s syndrome
x
Hemoglobin < 10 g/dL for females or < 12 g/dL for males
x
Total white blood cell (WBC) count < 2,500/mm3 or absolute neutrophil count < 
800/mm3
x
Platelet count < 80 x 109/L
19. Any clinically significant medical condition or 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.
20. Has received or is expected to receive any dose of a SARS-CoV-2 vaccine before the 
Day 14 visit.
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.
5.
STUDY TREATMENTS
5.1.
Description and Handling of Study Treatments
5.1.1. Test Product
AT-527 will be provided by the Sponsor as 550 mg tablets.  
5.1.2. Control Product(s)
Matching placebo tablets for AT-527 will also be provided by the Sponsor. 
AT-527 (or placebo) will be administered along with local supportive SOC therapy per 
local/institutional practices or guidelines.  Other than restrictions listed in Section 5.8, SOC will 
not be dictated by the protocol.
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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.
5.2.
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.  
5.3.
Blinding
Treatment assignments will be blinded to the investigator, research staff, subjects, CRO and 
Sponsor for the entire study, unless unblinding is mandated by a DSMB recommendation.  The 
study blind will be broken upon completion of the clinical study and after the study database has 
been locked.  The only exceptions will be those described with the DSMB analyses and 
procedures (Section 10.1).
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.
As noted in Section 10.1. the Sponsor, CRO, and clinical site personnel will remain treatment-
blinded to the data reviews by the DSMB, unless the DSMB promulgates a study guidance 
recommending study halt for efficacy, safety, or futility.
5.4.
Dosing and Administration
5.4.1. Dispensing
Based on their randomization assignment, blinded study drug (active or placebo) will be assigned 
depending on treatment arm.  Designated site staff will dispense the blinded study drugs (active 
or placebo) to each subject at each dispensing day/time.  The date and time of each dose must be 
recorded.  If subjects are discharged from the hospital prior to study drug completion, they will 
be provided with study drug to be taken at home to complete their assigned treatment course. 
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5.4.2. Administration Instructions
Part A
Subjects will take one (1) tablet (550 mg AT-527 or placebo x 1) administered approximately 
every 12 hours (i.e. BID) for the 5-day treatment period.  
Part B
Subjects will take two (2) tablets (550 mg AT-527 or placebo x 2) administered approximately 
every 12 hours (i.e. BID) for the 5-day treatment period.  
Study drugs will be taken orally and should be taken at approximately the same time each day, 
ideally within an approximate 2 hour window (as a guidance). The drugs may be given with 
water. Previous studies indicate no appreciable effect of food on AT-527 absorption, so study 
dosing can be done between or during mealtimes. Regular daily timing is preferred, to 
consistently achieve dose intervals of approximately 12 hours. Dosing on Day 1 can occur at any 
time of day (AM or PM).
If a dose is missed, subjects should be instructed to take the missed dose(s) of study drugs as 
soon as possible during the same day.  Subjects should never double the next dose with a missed 
dose.  
5.4.3. Treatment Compliance
Doses will be administered under the supervision of designated site staff to ensure treatment 
compliance.
If subjects are discharged from the hospital prior to study drug completion, they will be provided 
with study drug to be taken at home to complete their assigned treatment course, and compliance 
will be confirmed by follow-up telephone call or potentially an at-home visits by trained medical 
professional(s) (if feasible). 
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 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.
Stopping Rules
5.6.1. Safety Stopping Rules for Individual Subjects
Treatment will be discontinued in any subject who experiences any one of the following:
x
progression to requirement for mechanical ventilation or ECMO
o
Note:  For any subject who progresses to mechanical ventilation or ECMO, 
study treatment should be discontinued, as there is no IV form of the study 
drug.  The subject may then receive any other available treatments, with 
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continued study observation for post-treatment safety data to hospital 
discharge or death as locally feasible. Subjects who have completed or 
discontinued study drug may be treated with any other available therapeutic 
agent, as locally allowed. If the agent is investigational it should be an agent 
that has institutional Ethics Committee or Research Committee approval, or 
FDA EUA.
x
confirmed elevation of ALT or AST > 3 x baseline with direct bilirubin > 2 x ULN or 
INR increased from baseline and  > 1.5 x ULN, without evident alternative cause for 
these elevations 
x
confirmed new onset ≥ grade 3 serum creatinine (> 1.8 x ULN and > 2 x baseline), or 
decreased creatinine clearance to < 60 mL/min
x
any SAE, or a grade 4 AE or clinically significant confirmed grade 4 laboratory 
abnormality for an individual subject which is considered by the investigator to have a
reasonable possibility of relatedness to study drug
o
Note:  To warrant treatment discontinuation for a study subject, a confirmed 
grade 4 laboratory abnormality should have clinically significant findings
expected to be associated with the laboratory abnormality.  Subjects with 
isolated asymptomatic laboratory abnormalities, without any clinical 
correlations, are allowed to remain on treatment with continued monitoring 
according to the preference of the investigator. Also, subjective clinical 
symptoms not reflecting major organ dysfunction, such as severe headache, 
may or may not warrant treatment discontinuation in the judgement of the 
investigator.    
x
Pregnancy
A confirmed value is defined as one that is found to have a similar value at the next subsequent 
test.  Any of the above laboratory results and all ≥ grade 3 new onset laboratory abnormalities must 
be repeated as soon as possible, preferably within 24 hours upon reporting of the initial value.
If a grade 3/4 lab abnormality is determined to be clinically significant, it should be reported as an 
AE and should include an assessment of causality. Definitions of clinical significance of laboratory 
abnormalities are summarized in Section 7.1.1.  For any grade 3/4 AE or laboratory abnormalities, 
the site must enter the data into the Electronic Data Capture (EDC) system within 24 hours.  
Subjects who prematurely discontinue study treatment should complete early termination (ET) 
assessments at the time of treatment discontinuation, as described in Table 6-1.  However, these 
subjects should be encouraged to remain in the study and maintain the same protocol schedule and 
assessments as described in Table 6-1.  This will allow for continued follow-up for key study 
outcome data.   
5.6.2. Study Stopping Rules
COVID-19 is a protean, sometimes fatal, illness for which the spectrum of disease-related signs 
and symptoms is still being delineated. Aside from principal involvement of the respiratory tract, 
with potentially severe pneumonia, it is increasingly clear that clinical manifestations can also 
include multi-organ manifestations due to a hyper-coagulopathy with widespread 
thromboembolic processes in other body organs - liver, heart, brain, etc. With this perspective, a 
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multi-organ variety of clinical AEs and laboratory abnormalities can be expected from COVID-
19 study populations, regardless of treatment. Effective therapies may reduce COVID-19 disease 
manifestations over time, but the wide variety of COVID-19 related AEs and laboratory 
abnormalities will be seen in both active- and placebo-treated subjects until therapy mitigates the 
disease or the disease spontaneously resolves. 
This clinical trial will be paused for a DSMB review of safety data, for any of the following 
reasons:
x
Death in any subject in which the cause of death is judged to have a reasonable possibility 
of relatedness to the study drug by the investigator.
x
The occurrence in any subject of a life-threatening SAE whose causal relationship is 
judged to have a reasonable possibility of relatedness by the investigator.
x
>20% of the enrolled subjects experience clinically significant grade 3/4 AEs or clinically 
significant confirmed grade 3/4 laboratory abnormalities considered by the investigator to 
have a reasonable possibility of relatedness to the study drug.
Additional rules will be applied for the first two enrolling cohorts of 20 subjects each in Part A.  
For each 20-subject cohort, the study will also be paused for a DSMB safety review for any of the 
following reasons:  
x
Two (2) occurrences of grade 3 or higher clinical AEs that are assessed to have a
reasonable possibility of relatedness to the study drug by the investigator.
x
Two (2) occurrences of a clinically significant grade 3 or higher laboratory abnormality 
assessed to have a reasonable possibility of relatedness to the study drug by the 
investigator.
For any of the above circumstances, a pause in further study enrollment will be triggered.  The 
DSMB will then review unblinded safety data for the referenced events, to determine if active 
treatment poses an appreciably greater risk for these events or other concerning safety events 
compared to placebo treatment. If the latter appears to be the case, the Sponsor will collect and 
review all the available safety data with the DSMB, clinical investigators, and regulatory 
authorities (including US FDA), to obtain an overall risk assessment for active vs. placebo 
treatment, and agreement on a plan forward.
Collaborative decisions on study stoppage will include consideration of the relative occurrence of 
the given AE or lab abnormality in active- vs. placebo-treated subjects, and the clinical severity of 
the specific AE or lab abnormality. For example, in consideration of the severity gradations in the 
Division of AIDS (DAIDS) table, transient episodes of grade 3-4 headaches, anorexia, 
fatigue/malaise, myalgias/arthralgias, psychologic manifestations, and other AEs and lab 
abnormalities in the DAIDS table, are likely to be observed with placebo recipients and active-
treated subjects in this clinical trial; and early datasets could by chance show more events for 
active-dosed subjects vs. placebo recipients. In those circumstances an agreed plan for further 
study conduct will be achieved by a collaborative safety review involving the Sponsor, DSMB, 
clinical investigators, and regulatory authorities (including US FDA). 
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In addition, this study could be stopped by a DSMB recommendation for study stoppage due to 
efficacy, safety, or futility as described in Section 10.1.
5.7.
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 discontinuation may occur for any of the following reasons:
x
Persistent noncompliance with the protocol requirements
x
Pregnancy
x
Adverse event precluding further study participation due to safety concerns or 
compliance issues
x
Subject request
x
Investigator request
x
Sponsor request
Subjects who prematurely discontinue study treatment should complete Early Termination (ET)
assessments at the time of treatment discontinuation, as described in Table 6-1.  However, 
subjects who prematurely discontinue treatment should be encouraged to remain in the study and 
maintain the same protocol schedule and assessments as described in Table 6-1.  This will allow 
for continued follow-up for key outcomes.
The end of the study for any individual subject will be defined as the 49-day follow-up visit.
5.8.
Prior and Concomitant Medication
Continuation of subject’s maintenance medications is allowed -  e.g. medications for treatment of 
hypertension, high cholesterol, anti-coagulation prophylaxis, asthma, diabetes, HIV,  
musculoskeletal disorders, cardiac arrhythmias, anxiety disorders, medication-controlled 
psychosis, etc. Concomitant medications will be documented in the study case records.   If there 
are questions regarding concomitant medications for individual subjects, the Investigator or a site 
team member should contact their CRO site monitor.
As convalescent plasma may be considered standard of care in some regions, it’s concomitant 
use is allowed in this study.
5.8.1. Permitted Therapy
Patients are permitted to use the following therapies during the study:
x
Hormonal contraceptives 
x
Acetaminophen (paracetamol)
x
Hormone replacement therapy
x
Prescribed medications for concomitant conditions as per medical history
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x
Low dose aspirin
5.8.2. Cautionary Therapy
Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety 
profiles, and potential drugdrug interactions (DDI) are generally unknown.
In vitro experiments, AT--511 (the free base form of AT-527) demonstrated the potential for the 
following DDIs (see Appendix 2 for more details):
P-glycoprotein (P-gp)
AT-511 is a substrate and an inhibitor of P-gp.
x
P-gp inhibition:  staggered dosing can effectively mitigate potential for a clinical DDI at the 
level of the gastrointestinal tract.  In the event that sensitive substrates of P--gp with a NTI 
cannot be safely discontinued or substituted, they should be dosed 2 hours after study drug 
administration, by which time absorption of AT-511 is considered essentially complete.  
Common examples of P-gp sensitive substrates with NTI include digoxin and tamoxifen.
For a list of sensitive P-gp substrates with NTI refer to 
https://go.drugbank.com/categories/DBCAT004027.
x
Use of P-gp inhibitors (other than hydroxychloroquine or amiodarone; see Prohibited 
Therapy section below) may be permitted by staggering the dosing of study drug and the P-
gp inhibitor by 2 hours (with study drug dosed first).  
For a list of P-gp inhibitors, refer to 
https://go.drugbank.com/categories/DBCAT002667
Macrolides (including azithromycin) may be used if dosing is staggered as described above.
Breast Cancer Resistance Protein (BCRP) sensitive substrates
AT-511 is an inhibitor of BCRP.
x
BCRP inhibition: staggered dosing can effectively mitigate potential for a clinical 
DDI.  In the event that sensitive substrates of BCRP with NTI cannot be safely 
discontinued or substituted, they should be dosed 2 hours after study drug 
administration.  Common examples of BCRP sensitive substrates include 
ivermectin, pravastatin, rosuvastatin, apixaban and rivaroxaban.
For a list of sensitive BCRP substrates refer to 
https://go.drugbank.com/categories/DBCAT002663.
Organic Anion Transporter 1 and 3 (OAT1 and OAT3) inhibitors
The plasma circulating nucleoside metabolite AT-273 (inactive metabolite of AT-511) is a 
substrate of OAT1 and 3 (See Appendix 2 for more details).
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x
OAT1 and OAT3 inhibitors may affect plasma levels of AT-273.  However, AT-273 is 
considered an inactive metabolite, and changes in AT-273 PK are not expected to affect 
the antiviral activity of AT-527.  Consider stopping drugs that are major OAT1/3 
inhibitors during study treatment and resume 12 hours after the final dose of study drug.  
In the event that the OAT1/3 inhibitors cannot be safely discontinued or substituted, they 
should be used with caution.  Common examples of OAT1/3 inhibitors include 
furosemide, losartan and cimetidine.
For a list of OAT1 and OAT3 inhibitors, refer to 
https://go.drugbank.com/categories/DBCAT004041 and 
https://go.drugbank.com/categories/DBCAT003946, respectively.
5.8.3. Prohibited Therapy
Use of the following concomitant therapies is prohibited from Day 1 (unless otherwise specified 
below) until study completion or early termination, as described below:
x
Treatment with other drugs thought to possibly have activity against SARS-CoV-2
Note:  If the subject was previously treated with such an agent, treatment must have been 
discontinued at least 7 days prior to planned dosing on the current trial. The use of 
hydroxychloroquine is not allowed in this trial.
x
Other investigational drugs within 30 days of dosing.
x
Subjects with malignant disease can continue antineoplastic therapy during the study period 
unless the antineoplastic therapy includes an immunomodulator or is expected to result in 
severe bone marrow suppression during the study (e.g., risk for grade 3 or higher anemia, 
leukopenia, or thrombocytopenia). 
x
Use of immunosuppressive doses of systemic corticosteroids, defined for this study as the 
equivalent of 20 mg prednisone daily during any two week time period (280 mg prednisone 
equivalent total dose) in the three months prior to study entry.  Standard of care 
dexamethasone indication and dosing are permitted if needed for treatment of COVID-19 
Syndrome.
x
Use of immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions) 
during the primary 14-day study period.  
x
Sofosbuvir, for patients with active HCV
x
Abacavir for patients with HIV
x
P-gp inhibitors hydroxychloroquine or amiodarone within 3 months prior to screening and 
during the study
Use of other P-gp inhibitors may be permitted by staggering the dosing of study drug and 
the P-gp inhibitor (as described in the Cautionary Therapy Section above).  
5.9.
Other Study-Specific Restrictions and Requirements
x
Female subjects of childbearing potential must agree to use one of the following methods 
of birth control from Screening through 30 days after the last dose of the study drugs:
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o
intrauterine device (IUD)
o
bilateral tubal occlusion
o
vasectomized partner
o
sexual abstinence*
o
hormonal contraception (including combined, progesterone only or intrauterine 
hormone-releasing system (IUS)) together with a barrier method such as (i) male 
or female condom with or without spermicide or (ii) cap, diaphragm or sponge 
with spermicide
Note:  A female subject of non-childbearing potential is defined as a female ≥ 54 
years old with menses cessation for ≥ 12 months since previous menses, or a female 
of any age who had a hysterectomy, bilateral oophorectomy or bilateral tubal ligation.
* 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 (e.g., calendar, ovulation, symptothermal, or postovulation 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.
Should acceptable methods of birth control be more restrictive per local regulations, 
guidance or investigator practice than the methods listed above, a more restrictive list may be 
included within the site/country-specific Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved informed consent form (ICF).
6.
STUDY PROCEDURES AND GUIDELINES
Study-specific assessments and the study schedule are summarized in Table 6-1. An "X" 
indicates when the assessments are to be performed.
Due to COVID-19 restrictions/policies/quarantines and to maintain safety of staff at individual 
sites and for individual subjects, it is acknowledged that strict adherence to Table 6-1 for those 
procedures requiring direct contact with patients (such as laboratory sampling, physical 
examination, etc) may not be possible for every timepoint listed.  The sites should try to maintain 
the schedule as closely and as safely as feasible, but temporal divergence for these direct contact 
procedures will not be considered a protocol deviation.  
Hospital discharge may occur at any point.  The date and time for the hospital discharge decision
should be documented in the study records, as duration of hospitalization is a secondary study 
endpoint.
For subjects who are discharged before Day 14, assessments through Day 14 may be collected, 
either through at-home visits by trained medical professional(s), outpatient visits or by telephone 
follow-up, as feasible depending on the site and subject limitations.  
If a subject is discharged before dosing is complete, the discharge plan should include 
completion of study drug dosing.
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Follow-up evaluations will occur at 7 days, 14 days and 49 days after study completion at 
nominal Day 14, according to the table below.  
Additional logistical considerations and clarifications
x
It is logistically feasible and acceptable for Screening and Day 1 to occur on the same day, as 
long as eligibility is confirmed before dosing is initiated.  If the Screening and Day 1 visits 
are on the same day, duplicate assessments and laboratory samples do not need to be 
collected twice.  
x
Once subjects are confirmed eligible at Screening, randomization and dosing should be 
initiated within 24 hrs.
x
It is possible that historical laboratory results obtained as part of the subjects’ standard of 
care prior to consenting into the current study could be used to confirm eligibility. This is 
acceptable as long as the samples were collected per routine standard of care, and no study-
specific procedures were conducted prior to obtaining consent for the current study.  
However, qualifying historical laboratory results used for safety assessments must be 
available at Screening, and they must have been obtained within 48 hours prior to planned 
dosing from the same local laboratory to be used during the study.
x
Samples collected for D-dimer levels, stored serum/plasma and PK are for future exploratory
analyses only.  If collection or processing of these exploratory samples impact site logistics
(considering COVID-19 blood processing restrictions/limitations) or delay the ability to start 
study drug treatment as soon as possible for eligible subjects, collection of these exploratory 
samples can be skipped.  This will not be considered a protocol deviation.  If the site uses D-
dimer levels for patient management, separate D-dimer levels can be obtained locally as 
available, at investigator preference per their local standard of care.
x
It is recognized that some hospitalized subjects may have recovered sufficiently to not 
require further close medical care for their COVID-19 illness, but may be retained in the 
hospital/site for quarantining purposes or with consideration that the subject may be a 
medically or cognitively fragile individual without available family or caregiver support in 
their home residence, a situation which requires time for arrangement of outpatient social 
services support. These hospitalized subject circumstances correspond to category 6 on the 
NIAID ordinal scale of overall Clinical Status (“Hospitalized, not requiring supplemental 
oxygen – no longer requires ongoing medical care for COVID-19”, described in Section 
6.9.).
x
All subjects who prematurely discontinue study treatment should complete early termination 
(ET) assessments at the time of treatment discontinuation.  However, these subjects should 
be encouraged to remain in the study and maintain the same protocol schedule and 
assessments as described in Table 6-1.  This will allow for continued subject follow-up for 
key outcome data.   
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Table 6-1
Schedule of Assessments 
STUDY DAY(D)
EVENTS 
Screening 
1
2
3
4 
5
6
7
8
9
10
11
12
13
14 
ETe
7, 14 and 49-
day follow-up 
after Day 14f
Informed Consent
X
Randomization
Prior to dosing
Dosing
Xm
X
X
X
X
Determine Eligibility
X
Medical History
X
Demographics
X
Complete Physical Examination
X
X
Symptom-targeted Examination for AE 
evaluation, when needed
Xa
X
X
X
X
Xi
X
Xi
X
Xi
X
Xi
X
X
AEs + Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hemoglobin A1c
X
Vital signs
X
Xa
X
X
X
X
X
Xi
X
Xi
X
Xi
X
Xi
X
X
Height (screen only)b and Weight
X
X
ECG monitoringj
X
Xa
X
X
X
X
X
X
X
X
X
Safety Labs
X
Xa
X
X
X
X
X
X
Urinalysis
X
X 
D-Dimer, and stored samples for future
analyses
Xa
X
X
Xi
Xi
X
SARS-CoV-2 Test
X
Xa,g
Xn
Xo
X
X
X
X
X
Xg
Xg
Pregnancy Testc
X
Pulse Oximetryk
X
Xa
X
X
X
X
X
Xi
X
Xi
X
Xi
X
Xi
X
X
Chest Imagingl
X
Ordinal scales/Clinical course data 
collectionh
X
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma samples collected for sparse 
PKd
X
X
X
X
a) Prior to the first dose b) Height at Screening only.  c)  For females of childbearing potential: serum pregnancy test at Screening.  d) Collected at same time as safety lab draw. e)
ET=Early Termination f) As quarantine and other factors may limit the subject’s ability to return to the clinic, the follow-up assessments may be conducted by telephone, video platform or at-
home visits by trained medical professional(s) (with a ± 2 day window). If this follow-up is done by telemedicine, no SARS-CoV-2 samples will be collected. g) Optional  h) See Section 6.9
for details of assessments, including ordinal scales for overall Clinical Status and Respiratory Support. i) Not necessary if subject already discharged from hospital j) After discharge, cardiac
ECG parameters will be collected on outpatients. k) After discharge, pulse oximetry to be done on Days 2-6,8,10,12, and 14, or more frequently as needed if SpO2 < 93% l) Chest imaging
(chest x-ray, CT scan, etc.) will be obtained ideally at Screening but can occur within 48 hours before screening as long as the clinical status of the subject has not changed, in the opinion
of the investigator. m) Dosing on Day 1 can occur at any time of day (AM or PM). n) Collect prior to the 3rd dose (on Day 2). o) Collect prior to the 5th dose (on Day 3).
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6.1.
Medical History
Complete medical history will be obtained at Screening.  Information about COVID-19 disease 
history, 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.
6.2.
Physical Examination
A complete physical examination will be performed by a medically qualified individual as 
scheduled in Table 6-1. 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, body mass index (BMI)) 
will be recorded.  
On study days which may not require a complete physical examination, a symptom-targeted 
physical exam should be done when needed for AE evaluation, as medically indicated.
6.3.
Vital Signs
Vital sign measurements (body temperature, pulse rate, respiratory rate and blood pressure) 
should be captured as specified in Table 6-1. Vital signs should be assessed after subjects have 
had at least 3 minutes of rest and may be taken via digital vital sign monitoring.
6.4.
Electrocardiogram Monitoring
ECG monitoring will be performed per hospital or intensive care unit procedures, with at least 
one timepoint captured for the study analysis, as specified in Table 6-1.
If logistically feasible considering COVID-19 institutional restrictions and limitations, the 
Screening assessment should be done using a twelve-lead ECG.
6.5.
Laboratory Evaluations
Laboratory evaluations will be performed as scheduled in Table 6-1. The investigator or designee 
will assess each abnormal value to determine if it is clinically significant. 
x
Chemistry: Sodium, calcium (ionized or total calcium is acceptable per local standard of 
care), potassium, chloride, magnesium, bicarbonate, glucose, BUN, creatinine, creatinine 
clearance (Cockcroft-Gault formula), total bilirubin, indirect bilirubin, direct bilirubin, 
alkaline phosphatase, AST, ALT, albumin, CK (elevation may trigger CK isoenzyme 
analysis), triglycerides, cholesterol, amylase and lipase
x
Hematology: WBC count with differential, red blood cell count, hemoglobin, hematocrit, 
reticulocyte count, mean corpuscular volume (MCV) and platelet count
x
Hemoglobin A1c (glycated hemoglobin; at Screening only)
x
Coagulation: Prothrombin time (PT) and INR; Note: Depending on logistics, the laboratory 
may use the PT to calculate INR and only report the INR to the clinical sites.
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x
Troponin, N-terminal pro b-type natriuretic peptide (NT-proBNP) and B-type natriuretic 
peptide (BNP)
x
Urinalysis: Color, appearance, specific gravity, pH, leukocyte, protein, glucose, ketones, 
bilirubin, blood, nitrite, urobilinogen. Microscopic examination may be performed if the 
urinalysis is abnormal.
x
Pregnancy tests (serum or urine) will be performed on female subjects of childbearing 
potential as specified in Table 6-1.
The total volume of blood withdrawn during the course of 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 safety assessments.
6.6.
COVID-Specific Tests
Diagnostics and SOC treatment of COVID-19 are constantly evolving.  The current protocol 
targets capture of COVID-specific parameters known to be important or potentially important at 
this time:
x
SARS-CoV-2 qualitative testing. At Screen, subjects will typically have been identified 
as presumptively SARS-CoV-2 infected. The initial local SARS-CoV-2 test result will 
be confirmed at Screening by one of the FDA-EUA assays. The FDA-EUA assay will 
be used to assess SARS-CoV-2 viral presence in nasopharyngeal (preferentially) or 
throat swabs at periodic timepoints in this study, as indicated in Table 6-1.  As this may 
be a relatively uncomfortable procedure for some subjects, and such sampling is 
biohazardous for caregivers, it is acknowledged that some subjects may not be able to 
provide samples for all timepoints listed.  Although sampling should be encouraged at 
all timepoints listed through Day 14, key SARS-CoV-2 testing assessments are at 
Screening, Day 5 and Day 14.  Sampling during follow-up is supplemental, to be
collected as feasible, considering those visits are likely to be conducted via 
telemedicine.      
x
Residual eluates (in solution) from nasopharyngeal or throat swabs obtained for SARS-
CoV-2 may be stored frozen for eventual quantitative testing, possible resistance 
analyses, and viral infectivity assays if the additional handling and storage do not 
impose undue exposure biohazards for site staff and the central laboratory.  
x
Serologic D-dimer levels, a reflector of a potential hyper-coagulopathy that is common 
in COVID-19 patients, for future exploratory analyses.  Note:  If the site uses D-dimer 
levels for patient management, separate D-dimer levels can be obtained locally as 
available, at investigator preference per their local standard of care.
x
Stored serum or plasma samples will be collected for possible eventual analyses of 
various cytokines (including interleukin-6), antibody to SARS-CoV-2, other relevant 
COVID-specific tests (e.g. C-reactive protein) or SARS-CoV-2 tests (e.g. antibody 
tests), as reliable validated assays become available.
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Note:  In an effort to standardize the method for collection of nasopharyngeal samples during the 
study, the same nostril in an individual subject should be used (if possible) if only one nostril 
will be sampled.  
The sampling schedule for the above tests is specified in Table 6-1.  
6.7.
Pulse Oximetry
Blood oxygen saturation will be monitored by pulse oximetry, as specified in Table 6-1.  
6.8.
Chest Imaging
Chest imaging (chest x-ray, CT scan, etc.) will be obtained ideally at Screening but can occur 
within 48 hours before screening as long as the clinical status of the subject has not changed, in 
the opinion of the investigator. This is specified in Table 6-1.  For evaluations of respiratory 
worsening or other AEs, additional chest imaging may be required for affected subjects during 
the study.  Summaries of findings/radiology reports for study subjects will be captured/collected.
6.9.
Assessment of Study Subject Clinical Course
Assessment of study subject signs, symptoms and daily clinical course will be conducted
regularly, as specified in Table 6-1. These will include (and are not limited to):
x
Daily recording of subjects’ overall Clinical Status, from most severe to least severe, 
using a categorical scale similar to the ordinal scale of Clinical Status being used in the 
NIAID controlled trial design for comparatively assessing parallel study arms for treating 
COVID-19 patients (NCT04280705).  From most severe disease to progressively less 
severe disease, the stages of this adapted ordinal scale of overall Clinical Status are 
defined as follows:
1. Death
2. Hospitalized, on invasive mechanical ventilation or ECMO
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices
4. Hospitalized, requiring supplemental oxygen
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise)
6. Hospitalized, not requiring supplemental oxygen – no longer requires close 
medical care for COVID-19 
(Note:  Examples include recovered subjects needing inpatient 
quarantining/confinement or needing social services connections for outpatient 
living.)
7. Not hospitalized, but with limitation on activities and needing close outpatient 
care for COVID-19 manifestations
8. Not hospitalized, no limitations on activities, no need for continued close medical 
care
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Subjects with Status 2 or 3 disease at Screening would not be eligible for the study, 
but enrolled subjects who progress to respiratory failure/mechanical ventilation 
during the study will have deteriorated to Status 2 on this scale.  It is anticipated that 
most “moderate” COVID-19 patients eligible for this study will be enrolled with an 
overall Clinical Status of 4 or 5.  During the study, subjects’ overall Clinical Status
may worsen or improve.  Maximal deteriorations will be to Status 1 (death).  
Deterioration to Status 2, corresponding to respiratory failure/mechanical ventilation, 
would require the subject to be discontinued from study treatment, and the subject 
would thereby be eligible for treatment with any therapies appropriate for severe 
COVID-19.  Subjects will have achieved the secondary endpoint of “clinical 
recovery” with improvement to Status 6, 7 or 8. 
o
Timepoints (date and time) for physicians’ documented hospital discharge orders 
(in subjects’ hospital charts) should be recorded in study subjects’ electronic case 
record forms for this study.
x
Recording (date and time) of changes in respiratory support levels for subjects’ 
worsening or improving levels of respiratory insufficiency, according to the following 
ordinal scale of increasing Respiratory Support levels: 
o
LEVEL 1:  Normal oxygenation on room air (SpO2 ≥93), no need for 
supplemental O2
o
LEVEL 2:  Persistent hypoxemia on room air (SpO2 < 93) with requirement for 
low-level supplemental O2 by nasal cannula or mask (up to 2L/min) to maintain 
SpO2 ≥93
o
LEVEL 3:  Requirement for higher levels of passive supplemental O2 by nasal 
cannula or mask (≥2/L min) to maintain SpO2 ≥93
o
LEVEL 4:  Requirement for oxygenation by positive-pressure devices, e.g 
Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway 
Pressure (BiPAP) or other non-invasive positive-pressure respiratory support 
methods to maintain satisfactory oxygenation and/or ventilation
o
LEVEL 5:  Requires invasive respiratory support (intubated mechanical 
ventilation or ECMO)
o
LEVEL 6:  Death
x
Level of consciousness assessment (alert-responds to voice-responds to pain-
unresponsive)
x
Date and time of death
x
Eventual hospitalization summary details, including date of admission, reasons for 
hospitalization, discharge planning and date of discharge
x
An assessment of signs/symptoms may also be captured at each visit.
6.10.
Sparse PK Sampling 
PK samples will be collected, as specified in Table 6-1, 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 
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recorded as well as the date and time of study drug administration.  The sparse sampling 
schedule is to limit exposure of site staff to subjects with COVID-19 as well as to limit 
workload.
6.10.1. Sample Processing, Storage and Shipping
All PK samples will be processed, stored, and shipped according to the sample processing 
instructions supplied by the Sponsor or receiving laboratory.
6.10.2. Bioanalytical Methods for PK samples
Plasma concentrations of AT-527 and metabolites (as appropriate) will be measured according to 
validated bioanalytical methods. 
Samples from all subjects who received at least one dose of AT-527 will be analyzed.  Samples 
from subjects who received placebo will not be analyzed.
Bioanalytical laboratory personnel will have access to the randomization assignment. The 
bioanalytical facility will preserve the blind by reassigning alternative subject numbers for any
interim data reviews.
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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:
x
A new illness,
x
Worsening of a previous chronic illness or a concomitant illness,
x
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.
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose:
x
Results in death,
x
Is life-threatening,
x
Requires inpatient hospitalization or prolongation of existing hospitalization,
x
Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions),
x
Is a congenital anomaly or birth defect,
x
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 (eg, clinical chemistry, hematology, and urinalysis) 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 SAE, if they meet the definition above. 
In addition, laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) 
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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. 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 electronic 
case report form (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 
meets one or more of the SAE criteria described above.
The Division of AIDS (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 6-2.
Table 6-2
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 (e.g., 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 
drug(s) and the AE.
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 until the end of the study.
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.
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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 
but 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 (e.g., 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 (e.g., 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:  
An unlisted (unexpected) AE is one in which the nature or severity is not consistent with the 
applicable product reference safety information. For investigational product(s), the expectedness 
of an AE will be determined by whether or not it is listed in the Investigator’s Brochure(s).  At 
this time in the clinical development of AT-527, based on non-clinical data and limited clinical 
experience to date, there are no clinical AEs or clinically significant laboratory abnormalities that 
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are considered to be “expected” with AT-527, at any dose level. Investigators will be notified, 
and the Investigator Brochure will be updated, if any pattern of AEs or laboratory abnormalities 
is found to be related to AT-527 dosing during studies going forward.
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:
x
the event resolves;
x
the event stabilizes;
x
the event returns to baseline, if a baseline value is available;
x
the event can be attributed to agents other than the study drugs or to factors unrelated to 
study conduct;
x
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. 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 must be reported to 
(see Section 7.3 for contact 
information) by the investigational staff within 24 h of their knowledge of the event using the 
paper Pregnancy Reporting Form provided. After the expected delivery date and/or once an 
outcome is known, the site will provide 
with pregnancy outcome, delivery, and 
infant details for completion of reporting. 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 drugs.
In addition, pregnancies in partners of male subjects included in the study will be reported by the 
investigational staff within 24 h of their knowledge of the event using the paper Pregnancy 
Reporting Form.
8.
STATISTICAL ANALYSES
This section summarizes the statistical analyses pertinent to the efficacy and safety assessments 
in this study.  A statistical analysis plan (SAP) describing the detailed statistical methods for this 
study will be prepared and finalized before database lock.  Sample size calculations and power 
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statements, with the exception of those for time to Clinical Recovery, were performed using 
SAS/STAT v9.4 (SAS Institute Inc., Cary, NC, USA).  The power estimates for time to Clinical 
Recovery were computed by simulation. Corresponding code is provided in Section 13.
All analyses of trial data will be performed in this version of SAS/STAT or higher unless noted 
in the eventual SAP that other software will be utilized.
This is a double-blind randomized study, with variable size block randomization stratified by 
region.
In order to support interactions with regulatory agencies, the Sponsor may choose to conduct 
interim analyses during the course of the study.  The decision to conduct an interim analysis and 
the timing of the analysis will be documented in the Sponsor's trial master file prior to the 
conduct of the interim analysis.  The interim analysis will be performed and interpreted by 
members of the Sponsor study team and appropriate senior management personnel, who will be 
unblinded at the treatment group level.
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
(AT-527 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) analysis set will contain subjects in the ITT analysis set 
with positive qualitative SARS-CoV-2 RT-PCR test result at baseline from the central laboratory 
and who receive at least one dose of study drug (AT-527 or placebo).
For analyses and displays based on mITT analysis set, subjects will be classified according to 
randomized treatment.
8.1.4. Per Protocol Population
The per protocol (PP) population will include the subset of the ITT subjects who completed the 
study drug regimen without major protocol violations that would potentially affect the study’s 
primary endpoints.  
8.1.5. PK Populations
The PK population will include all subjects who received at least one dose of AT-527 and for 
whom evaluable plasma concentration data are available.  Subjects who received placebo will 
not be included in the PK population.
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8.2.
Endpoints
8.2.1. Primary Efficacy Endpoint and Sample Size Calculations
Part A
The primary endpoint for Part A of this study is the proportion of subjects with PRI, defined as a 
≥ 2-tier increase in respiratory support methods required to maintain satisfactory oxygenation 
(SpO2 ≥ 93%), using the 6-tier hierarchical scale of Respiratory Support methods described in 
Section 6.9.
The primary efficacy goal is to reduce the incidence of PRI by 50% for active-dosed subjects 
compared to placebo recipients. The featured timeframe for this primary endpoint analysis will 
be the 14-day primary study period, with secondary analyses at study Days 10, 21, and 28.
With this study’s relatively high-risk COVID-19 subject population (one or more known risk 
factors for poor outcomes), the study postulate is that 40% of placebo recipients will experience 
PRI during the 14-day study period, and the efficacy goal is therefore to reduce that incidence of 
PRI to 20% or less in active recipients. 
Assuming PRI rates (PRIR) of 0.4 and 0.2 in the control and experimental arms, respectively, at 
alpha one-sided of 0.025, and at a power of 0.8, a total of 182 subjects are required at a 1:1 
allocation, i.e. 91 per study arm.  The study statistical hypotheses are as follows:
H0: ExperimentalPRIR ≥ ControlPRIR
Ha: ExperimentalPRIR < ControlPRIR
Part B
The primary endpoint of Part B is the change from baseline in amount of SARS-CoV-2 virus 
RNA (viral load) as measured by RT-PCR. Viral load will be assessed quantitatively using a 
validated assay. Analyses will be carried out at each scheduled time point using the mITT 
population. Part B of the study is signal seeking. The primary analysis aims to identify and 
characterize any potential effect of AT-527 on viral load over time. Analyses and p-values are 
descriptive and no adjustment for multiple comparisons will be made. 
Change from baseline viral load at a timepoint will be compared between the AT-527 group and 
the placebo group ANCOVA with treatment as a factor and log10 baseline viral load as a 
covariate. In the interim analysis of the first 70 subjects from part A, the observed AT-527 effect 
at Day 2 was a reduction of 0.7 log10 copies/mL relative to placebo. Assuming a standard 
deviation for change from baseline of 1.8 log10 copies/mL and 90% of Part B randomized 
patients eligible for analysis (i.e. 100 patients), there is at least 90% power to detect a true 
treatment effect of 0.7 at a timepoint using a one-sided test at 0.1 level of significance, not 
adjusted for multiple comparisons. 
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8.2.2. Key Secondary Efficacy Endpoints
A hierarchical testing strategy to preserve study alpha when testing secondary endpoints was 
originally planned. The original hierarchical specifications for Part A are retained below for 
historical perspective. The primary endpoint for Part A is a key secondary endpoint for Part B.
Following the change in protocol following the interim analysis, there will be no formal 
procedure to preserve study-wise type I error. All analyses are descriptive and any findings 
would need to be confirmed in another study with prospective alpha control.
x
First Key Secondary Efficacy Endpoint:  Change from baseline (CFB) in log10 SARS-CoV-2 
virus RNA
x
Second Key Secondary Efficacy Endpoint:  Median days to Clinical Recovery (MDCR), 
from randomization to a disease resolution status in the NIAID Clinical Status scale
described in Section 6.9 -  i.e. achieving Clinical Status 6, 7, or 8 by Day 14, according to 
whether the subject is still hospitalized at Day 14 or is an outpatient. Patients without 
observed clinical recovery will have clinical recovery time assigned as 15 days to preserve 
the ranks for the comparison
x
Third Key Secondary Efficacy Endpoint: Respiratory failure or death
A key secondary efficacy endpoint of the study is the proportion of subjects with Respiratory 
Failure or Death (RFD), for which the featured assessment will be at Day 28, with additional 
analyses at Days 10, 14, and 63. 
8.2.3. Other Secondary Efficacy Endpoints Secondary endpoints include:
x
Change (improvement vs worsening) in the NIAID ordinal scale of overall Clinical Status
x
All-cause mortality, to be assessed at all study timepoints, including Days 10, 14, 28, and 
63
x
Duration of hospitalization/confinement for COVID-19, from start of treatment to 
achieving Status 6, 7, or 8 on the NIAID Clinical Status scale described in Section 6.9, 
assessed by time-to-event analyses and by descriptive statistics 
x
Duration of positive SARS-CoV-2 virus detection in nasopharyngeal/throat swabs, on the 
schedule indicated in Table 6-1, analysed as time-to-sustained nondetectable SARS-CoV-
2 RNA from randomization
x
Proportion of subjects who are still SARS-CoV-2 positive at Days 5 and 14 (and longer 
timepoints as available)
8.2.4. Exploratory Endpoints 
Exploratory endpoints include:
x
Sparse plasma PK analyses, to assess PK parameters of AT-527 in COVID-19 subjects
compared to PK data obtained in healthy human volunteers and HCV patients.
x
Time to a National Early Warning Score (NEWS) score ≤ 2, from Screening/Baseline, for 
subjects whose Screening NEWS score was >4 (the NEWS score is a patient triaging 
score developed in Europe)
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x
Serial assessment of the appearance of antibody to SARS-CoV-2 in study subjects’ serum 
samples, when validated antibody tests become more widely available
x
Other relevant COVID-specific tests or SARS-CoV-2 tests that may become available
8.2.5. Safety Endpoints
Safety-related comparisons for the two treatments in this trial will include:
x
Proportions of subjects experiencing SAEs
x
Proportions of subjects with fatal outcomes
x
Proportions of subjects experiencing AEs
o Overall, and by body system as coded by MedDRA
x
Proportions of subjects experiencing drug-attributed AEs
x
Proportions of subjects experiencing graded laboratory abnormalities
o With abnormality grades defined in the referenced DAIDS table
x
Proportions of subjects discontinuing study for AEs
x
Proportions of subjects discontinuing treatment for AEs
8.3.
Efficacy Analysis Methods
8.3.1. Primary Efficacy Analysis
Part A
The ITT population will be the primary efficacy analysis population for Part A.  Proportions of 
subjects (active or placebo-treated) with PRI until study completion (Day 14) will be compared 
by study arm.  The Cochran Mantel Haenszel (CMH) test will be performed to compare the 
proportion of PRI rate in study arms.  Stratification variables will include the randomization 
strata of geographic regions; additional stratification variables may be described in the eventual 
SAP, to be finalized prior to database lock.
Part B
Viral load will be assessed quantitatively using a validated assay. The analyses will compare 
change from baseline log10 viral load at each required scheduled timepoint. The analyses will be 
carried out on the mITT population. Change from baseline viral load will be compared between 
the AT-527 group and the placebo group at required post-baseline timepoint using ANCOVA 
with treatment as a factor and log10 baseline viral load as a covariate.  The least squares mean 
(LSM) change and its standard error of means (SE) in each group, the differences between two 
groups in LSM change with corresponding 95% confidence intervals (CIs), and p-values will be 
presented.
8.3.2. Key Secondary Analyses
Change from baseline in amount of quantitative viral load (Part A only)
Viral load will be assessed quantitatively using a validated assay. The analyses will compare 
change from baseline log10 viral load at each required scheduled timepoint. Only patients with 
measurable viral load at baseline will be included in the analyses. Change from baseline viral load 
will be compared between the AT-527 group and the placebo group at each of Days 2, 5, and 14 
using ANCOVA with treatment as a factor and log10 baseline viral load as a covariate.  The least 
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squares mean (LSM) change and its standard error of means (SE) in each group, the differences 
between two groups in LSM change with corresponding 95% confidence intervals (CIs), and p-
values will be presented. Statistical significance will be tested at Day 5, which is a time point with 
required sample collection in all versions of the protocol, using on one-sided 0.025 level test. If 
statistical significance is observed at Day 5, then Day 2 would also be tested. The Day 14 
comparison will be descriptive. Descriptive summaries and comparisons at non-required 
timepoints may also be presented.
Median Days to Clinical Recovery
The Wilcoxon Mann-Whitney test will be utilized for the first key secondary endpoint analysis 
because the distribution of days until clinical recovery is not anticipated to be normally distributed.  
Proportion of Subjects with Respiratory Failure or Death
This secondary endpoint will be analyzed in the same fashion as the primary endpoint, as it is 
similarly a proportion analysis.
8.3.3. Other Secondary Analyses 
The proportions of active-treated and placebo-treated subjects improving or worsening in their 
Clinical Status (NIAID scale) by at least one category will be indicated in tabular displays 
depicting end-of-treatment data (nominal Day 5) and primary study completion data (Day 14).  
Analyses (active vs. placebo) will compare the probabilities of ≥1-category improvement and 
≥1-category worsening  - for the treatment period (Days 1-5), and the primary study period 
(Days 1-14). 
Other secondary analyses will be delineated in the SAP and will include comparative analyses 
(active vs. placebo) of various efficacy and safety parameters by descriptive statistics, 
comparisons of proportions, and/or time-to-event analyses as appropriate.
x
Assessments of all-cause mortality will include sub-analyses of deaths primarily due to 
respiratory failure vs. deaths attributed primarily to other causes (e.g., co-morbidities, 
thrombo-embolic phenomena, etc). 
x
Longer-term outcome data (to Days 28 and 63) will be used to evaluate subjects’ longer-term 
COVID-19 Clinical Status, using the NIAID scale.
8.3.4. Handling of Missing Data 
Patients with missing data due to death will be assigned the worst possible outcome, where 
applicable. Patients who do not complete D14 assessment and have study discontinuation for 
lack of efficacy, non-compliance with study drug, progressive disease, lost to follow-up, or 
adverse event will have primary endpoint response imputed as PRI. If study discontinuation 
reason was recovery, the primary endpoint will be imputed as no PRI. Other strategies for 
handling missing data will be described in the SAP.
8.4.
Safety and PK Analyses
Safety Analyses
Assessing safety and tolerability of AT-527 at the selected dose will be an important objective of 
the study. 
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Proportions of subjects experiencing SAEs, AEs, AEs resulting in treatment discontinuation and 
graded laboratory abnormalities will be summarized. Treatment-emergent AEs and laboratory 
abnormalities, defined as post-Baseline new AEs or worsened AEs, or new or worsening 
laboratory parameters, beginning with or after the first dose of study drug, will be included in the 
safety analyses. These safety-related observations will be summarized by treatment group, 
primarily using descriptive statistics, with use of time-to-event sub-analyses when appropriate 
for comparative time-related analyses of any specific clinically severe findings (e.g. death, SAEs, 
grade 3-4 AEs, or clinically significant grade 3-4 laboratory abnormalities).
Laboratory, ECG and vital sign data will also be summarized with descriptive statistics.  
Descriptive statistics will also be used to summarize demographic variables.  Other data to be 
summarized will include medical history, physical examination findings and concomitant 
medications.
PK Analyses
Plasma concentrations of study drug and metabolites in sparse samples will be listed with time 
data and summarized using descriptive statistics, as applicable.
Additional details regarding safety and PK analyses will be provided in the SAP.
9.
ETHICS
9.1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
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 International Conference on Harmonisation 
(ICH) Guideline E6 for Good Clinical Practices (GCP) and local regulations.
9.3.
Participant Information and Consent
Despite the logistical challenges of obtaining written informed consent from quarantined subjects 
with COVID-19, the informed consent process still must occur such that each prospective subject 
must be given a full explanation of the purpose of the study, the procedures to be carried out and 
the potential hazards.  They will be given a copy of the ICF to review, with assistance from the 
study staff as needed to achieve subject understanding.  Because of SARS-CoV-2 contact risks, 
alternative procedures for obtaining written informed consent (including signature of the ICF) 
may be dictated by local site policy/infection control guidelines. It is likely that the hardcopy
consent form cannot leave an isolation room, and therefore may not be locally feasible as trial 
documentation of informed consent.  If written consent by the trial participant is not feasible
(because of physical isolation of the COVID-19 subject), consent can be given orally by the 
subject, with the consent process conducted by a study team member and confirmed by an
impartial witness. In such cases, the study team member and witness would be required to sign 
and date the informed consent document.  In addition, it could be considered that the trial 
participant and the persons obtaining and witnessing consent sign and date separate informed 
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consent forms. In either case, relevant subject consent records should be archived in the 
investigator site’s Trial Master File.
Subjects will be assured that they may withdraw from the study at any time without jeopardizing 
their medical care. 
If an amended or revised ICF is introduced during the study, each subject’s further consent must
be obtained according to the locally feasible process.
9.4.
Subject Confidentiality and Personal Data Protection
The investigators and the Sponsor (and contract research organization (CRO) partners) 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 CRO partners). 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
This clinical study is a process involving personal data from subjects and healthcare 
professionals, and as such is subject to EU general Data Protection regulation 2016/679 dated 26 
April 2016, and to local laws of participating EU countries regarding personal data protection.
The investigators, the Sponsor and its contractors and sub-contractors will comply with the EU 
general Data Protection regulation 2016/679 date 26 April 2016 and the local laws of its 
participating EU countries regarding personal data protection.
The legal basis of the clinical study are legitimate interests and scientific research; the data 
collection and processing will be also based on the express consent of the subject that they will 
give in the informed consent form.
Atea Pharmaceuticals Inc. is the data controller.  The clinical site(s) and other contractors and 
sub-contractors of Atea Pharmaceuticals Inc. are data processors.
The objective of the clinical study is research in connection with the development of therapeutics 
that will be commercially marketed and sold for the treatment of COVID-19. 
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.
10. DATA COLLECTION, RETENTION, AND MONITORING
10.1.
Data Safety Monitoring Board (DSMB)
A DSMB, comprising two independent clinical experts and an independent statistician, will be 
established to periodically assess safety and potential risk/benefit.
The DSMB will conduct planned serial safety reviews during the course of the study.  
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For interim safety reviews during Part A of the study, enrollment will be paused at the following 
timepoints:
x
After the first 20 subjects to assess safety of the 550 mg BID dosing regimen
x
After the second 20 subjects
For interim safety reviews during Part B of the study, enrollment will not be paused but a safety 
review will be conducted at the following timepoint:
x
After 50% of the Part B subjects have been enrolled.
In addition to these planned meeting, the DSMB may schedule ad hoc meetings during the 
course of the study.  
During their reviews of data, the DSMB will have the authority to unblind data to the DSMB 
members, if necessary for assessing safety for an individual subject or across treatment arms.  
Additional details will be described in the DSMB charter.  Regardless, the Sponsor, CRO, and 
clinical site personnel will remain treatment-blinded to all data reviewed by the DSMB, unless 
the DSMB promulgates a study guidance recommending study halt for efficacy, safety, or 
futility.
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 (e.g., 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.
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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 
clinical development of the investigational product. However, these documents should be 
retained for a longer period however 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 they 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)).
Once COVID-19 restrictions are lifted, 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.  Atea 
Pharmaceuticals will determine authorship of the principal study manuscript(s) in conjunction 
with the clinical investigator(s).  All clinical investigators contributing at least one evaluable 
subject to the study will be considered as co-authors for the principal study manuscript(s).  For 
such manuscript(s), masthead roles for individual clinical investigators will be determined based 
on subject enrollment and scientific contributions to the study.  
The publication or presentation of any study results shall comply with all applicable privacy 
laws.
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12. REFERENCES
1. [Bhatraju PK, et al. (2020)] Covid-19 in critically ill patients in the Seattle region — case 
series. NEJM. 2020 Mar 30. doi: 10.1056/NEJMoa2004500.
2. [Boehmer TK, DeVies J, Caruso E, et al. (2020)] Changing Age Distribution of the 
COVID-19 Pandemic — United States, May–August 2020. MMWR Morb Mortal Wkly 
Rep 2020;69:1404–1409. DOI: http://dx.doi.org/10.15585/mmwr.mm6939e1.
3. [Centers for Disease Control and Prevention (2020)]  Coronavirus (COVID-19).  
Available at:  https://www.cdc.gov/coronavirus/2019-nCoV/index.html.  Accessed 29
March 2020.
4. [Centers for Disease Control and Prevention (2020)] National Diabetes Statistics Report, 
2020. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and 
Human Services; 2020.
5. [Cunningham JW, Vaduganathan M, Claggett BL, et al. 2020] Clinical Outcomes in 
Young US Adults Hospitalized With COVID-19. JAMA Intern Med. Published online 
September 09, 2020. doi:10.1001/jamainternmed.2020.5313.
6. [Gordon CJ, et al. (2020)] The antiviral compound remdesivir potently inhibits RNA-
dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol 
Chem. 2020 Feb 24. doi: 10.1074/jbc.AC120.013056.
7. [Goyal P, et al. (2020)] Correspondence:  Clinical characteristics of Covid-19 in New 
York City. NEJM. 2020 Apr 17. doi:  10.1056/NEJMc2010419.
8. [Hales CM, Carroll MD, Fryar CD, Ogden CL (2020)] Prevalence of obesity and severe 
obesity among adults: United States, 2017–2018. NCHS Data Brief, no 360. Hyattsville, 
MD: National Center for Health Statistics. 2020.
9. [Hinton TC, et al (2020)] Investigation and Treatment of High Blood Pressure in Young 
People: Too Much Medicine or Appropriate Risk Reduction? Hypertension. 2020 
Jan;75(1):16-22. doi: 10.1161/HYPERTENSIONAHA.119.13820. Epub 2019 Nov 18. 
PMID: 31735086.
10. [Siegel D, Hui HC, Doerffler E, et al. (2017)] Discovery and synthesis of a 
phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-
5734) for the treatment of Ebola and emerging viruses. J. Medicinal Chemistry. 2017, 
60(5) 1648-1661.
11. 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. [July 2017]. Available from:  
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
12. [Weiss P and Murdoch DR (2020)] Clinical course and mortality risk of severe COVID-
19. Lancet. 2020 Mar 28;395 (10229): 1014-1015. doi.org/10.1016/S0140-
6736(20)30633-4.
13. [World Health Organization (2017)]  Adolescent obesity and related behaviours: trends 
and inequalities in the WHO European Region, 2002–2014.  ISBN 978 92 890 5240 5.  
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Available at:  https://www.euro.who.int/en/health-topics/disease-
prevention/nutrition/publications/2017/adolescent-obesity-and-related-behaviours-trends-
and-inequalities-in-the-who-european-region,-20022014.  Accessed 19 October 2020.
14. [World Health Organization (2020)]  Coronavirus disease (COVID-19) Pandemic.  
Available at:  https://www.who.int/emergencies/diseases/novel-coronavirus-2019.  
Accessed 29 March 2020.
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13. APPENDIX
Appendix 1 (Applicable to Part A only)
Sample Size Code:
Primary Endpoint (SAS):
proc power;   twosamplefreq test=fisher
      groupproportions = (.2 .4) ntotal = .  power = .8;  run;
First Key Secondary Endpoint (R):
p nsim <- 10000
pwil <- rep(NA,nsim)
set.seed(837820122)
for (i in 1:nsim) {
  y0 <- rexp(91,log(2)/7)
  y1 <- rexp(91,log(2)/12)
  ydf <- data.frame(yt=c(y0,y1),trt=rep(0:1,c(91,91)))
  ydf$yobs <- ifelse(ydf$yt>14,15,ceiling(ydf$yt))
  pwil[i] <- wilcox.test(ydf$yobs[ydf$trt==0],ydf$yobs[ydf$trt==1],alternative="less")$p.value
}
## power
mean(pwil<0.025)
Second Key Secondary Endpoint (SAS):
proc power; twosamplefreq test=fisher groupproportions =  (0.15 0.35)
ntotal = 182 power = .; run;
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Appendix 2
Update on AT-527 Reproductive Toxicity and Non-Clinical In 
Vitro Drug-Drug Interaction Data
New data from non-clinical in vitro drug-drug interaction and reproductive toxicity studies have 
become available since the release of the AT-527 Investigator’s Brochure Version 7.  The new data are 
summarized below.
Overall, these new data did not provide new safety concerns and support further development.  In vitro 
drug-drug interaction (DDI) flags of AT-527 with potential clinical relevance were taken into account in 
the concomitant therapy section.
REPRODUCTIVE TOXICITY
The potential for reproductive toxicity was assessed in dose range-finding and pivotal Good Laboratory 
Practice (GLP)-compliant embryofetal development studies in rats and rabbits and in a GLP-compliant 
fertility study in the rat.
EMBRYOFETAL DEVELOPMENT
Definitive GLP-compliant embryofetal development (EFD) studies did not reveal evidence of 
teratogenicity or embryofetal toxicity up to the highest maternal dose level tested of 1000 mg/kg/day in 
rats and 100 mg/kg/day in rabbits.
Administration of AT-527 by oral gavage to female rats at dose levels of 250, 500, and 1000 mg/kg/day 
once daily from gestation day (GD) 7 to GD17 in an initial dose range-finding study and in a subsequent 
definitive study induced no maternal or developmental toxicity at any dose level. 
In a dose range finding EFD study in pregnant rabbits, the two highest dose groups of 500 and 250 
mg/kg/day were terminated prematurely due to severe maternal toxicity.  The low dose level of 125 
mg/kg/day was tolerated, but induced maternal toxicity characterized by apparent reductions of food 
consumption, minimal body weight loss and slightly reduced gravid uterine weight.  There were no 
external fetal abnormalities at 125 mg/kg/day and resorption incidence was not noticeably increased, but 
fetal weight was reduced by 10%, which was secondary to maternal toxicity.
In a definitive GLP-compliant EFD study in pregnant rabbits, AT-527 was administered by once daily 
oral gavage to time-mated female New Zealand White rabbits at 25, 50, or 100 mg/kg/day from GD7 
through GD19.  The highest dose level of 100 mg/kg/day was above the maximum maternal tolerated 
dose, characterized by marked reductions in food consumption, body weight loss in the majority of 
rabbits and 3 associated abortions.  Reductions in maternal food consumption and body weight gain were 
also noted at both lower dose levels of 50 and 25 mg/kg/day.  Maternal administration of AT-527 did not 
affect embryofetal viability or fetal body weights at any dose level.  There were no AT-527-related fetal 
abnormalities at any dose level.  Therefore, the developmental no-adverse-effect level (NOAEL) for AT-
527 was 100 mg/kg/day. 
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FERTILITY AND EARLY EMBRYONIC DEVELOPMENT (FEED)
In a GLP-compliant FEED study, AT-527 was given to male and female rats by daily oral gavage at dose 
levels of 250, 500 and 1000 mg/kg/day.  Males were treated for 4 weeks and females for 2 weeks before 
pairing.  For females dosing stopped on GD6 and they were submitted to C-section on GD13.  Males 
were dosed for at least 7 weeks prior to necropsy. Administration of AT-527 reduced body weights and 
body weight gains in males at 1000 mg/kg/day and caused increased incidence of abnormal breathing 
sounds at 500 and 1000 mg/kg/day.  There were no AT-527-related effects on mating, fertility, or 
reproductive organ weights in males or females, estrous cycling and ovarian and uterine parameters in 
females, or male reproductive assessments (sperm motility or concentration) in males.  Therefore, the 
NOAEL for AT-527 for general toxicity, reproductive performance, and early embryonic development 
was 1000 mg/kg/day, the highest dose tested.
Table 1
Exposures for AT-511 (Free Base Form of AT-527) and Its Major Metabolites 
AT-551, AT-229 and AT-273 at No-Adverse Effect Level Doses from Pivotal 
Reproductive Toxicity Studies
Pivotal EFD rat 1000 mg/kg/day
Pivotal EFD rabbit 100 mg/kg/day
GD17 AUCtlast
(hr*ng/mL)
Multiple to human 
for 550 mg BID
GD19 AUCtlast
(hr*ng/mL)
Multiple to human for 
550 mg BID
AT-511
145
0.02
4080
0.5
AT-551
135000
26
33800
7
AT-229
160000
10
70100
4
AT-273
28600
5
14300
2
AUC˜ area under the concentration–time curve; BID˜ twice a day; EFD˜ embryofetal development; 
GD˜ gestation day.
Anticipated human exposures at 550 mg BID are an AUC of 7503 hr*ng/mL for AT-511, 5134 hr*ng/mL for 
AT-551, 16154 hr*ng/mL for AT-229 and 6136 hr*ng/mL for AT-273.
All studies were performed in the United States with bioanalysis and toxicokinetic evaluations performed 
in Canada, both countries members of the Organisation for Economic Co-operation and Development 
(OECD) Mutual Acceptance of Data (MAD) program.  All definitive reproductive toxicity studies were 
performed in compliance with OECD GLP Regulations.
IN VITRO AND CLINICAL DRUG-DRUG INTERACTION
The parent compound AT--511 and metabolites AT--551, AT--229 and AT--273 were characterized in 
vitro to determine the potential of CYP450, UGT1A1 and transporter-related victim and perpetrator DDI.  
In vitro DDI flags with potential clinical relevance were taken into account in the concomitant therapy 
section.
AT-511 as the parent drug is a substrate of P-glycoprotein (P-gp), and likely not a substrate of Breast 
Cancer Resistance protein (BCRP).  The breakdown of AT511 is not CYP450 dependent, and several 
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catabolism/metabolism processes have been postulated and are presented in the most recent version of the 
Investigator’s Brochure [v7].
The metabolites AT-551 and AT-273 are not substrates of P-gp or BCRP, metabolite AT-229 is a 
substrate of BCRP but not P-gp. AT-229 is not a substrate of a renal transporter (Organic Anion 
Transporter 1 [OAT1] and 3 [OAT3], Organic Cation Transporter 2 [OCT2], Multidrug and Toxin 
Extrusion protein 1 [MATE1] and 2-K [MATE2-K]) while AT-273 is a substrate of OAT1 and OAT3 but 
not OCT2, MATE1, MATE2-K.
The in vitro potential of the parent drug AT-511 and the metabolites (AT-551, AT-229 and AT-273) for 
perpetrator DDI against drug transporters (P-gp, BCRP, Organic Anion Transporting Polypeptide 1B1 
[OATP1B1] and 1B3 [OATP1B3], OAT1, OAT3, OCT2, MATE1 and MATE2-K) and CYP450’s (1A2, 
2B6, 2C8, 2C9, 2C19, 2D6 and 3A) has been characterized. 
AT-511 is an in vitro inhibitor of P-gp and BCRP with IC50 values below the estimated gut concentration 
(550 mg dose/intake water 250 mL) and for which a DDI risk may be anticipated.  The observed in vitro 
inhibition of OATP1B1 likely does not translate into a clinical relevant DDI.
The in vitro reversible/time-dependent inhibition and induction potential of the parent drug AT-511 on 
CYP3A4 is likely indicated, however, the impact of the perpetrator potential on net enzyme DDI effects 
in liver and intestine remains uncertain.  The direct inhibition IC50 values of AT-511 on CYP2C8, 
CYP2C19 and UGT1A1 in vitro are much higher than the unbound systemic exposure in the historical 
clinical studies, and no additional CYP related in DDI risks were identified. 
For metabolites AT-551, AT-229 and AT-273, no or weak perpetrator DDI risk for transporters and CYPs 
is anticipated based on in vitro data and the static perpetrator DDI risk assessment results.
A series of phase 1 clinical studies have been conducted/planned to assess the clinical implications of the 
in vitro DDI results.
Simultaneously administered CsA, a strong inhibitor of P-gp and BCRP, significantly increased plasma 
exposure of AT-511 but did not affect AT-229 in healthy subjects. Staggered dose of AT-527 2 hours 
ahead of CsA was effective in mitigating DDI risks of P-gp inhibitors.
Repeat dose of carbamazepine, a strong P-gp inducer, reduced plasma exposure of AT-511 but did not 
affect AT-273, plasma surrogate of the intracellular active triphosphate metabolite AT-9010. Doubling 
AT-527 dose to 1100 mg essentially eliminated the effect P-gp induction by carbamazepine. These results 
suggest that AT-527 1100 mg can be administered with strong P-gp inducers.
Repeat dose of AT-527 weakly inhibited (< 2-fold) the metabolism of midazolam, a probe substrate of 
CYP3A4, in healthy subjects, indicating that, among the possible effects including reversible/completive 
inhibition, induction and TDI, AT-511 acts overall as a weak inhibitor of CYP3A4. No dosage adjustment 
is therefore expected for co-medications that are CYP3A4 substrates including systemic contraceptives.
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION............................................................................................................. 10 
2. 
STUDY OBJECTIVES ..................................................................................................... 10 
2.1. 
Primary Objective ......................................................................................................................................... 10 
2.2. 
Secondary Objectives .................................................................................................................................... 10 
2.3. 
Exploratory Objectives ................................................................................................................................. 11 
3. 
STUDY DESIGN ............................................................................................................... 11 
3.1. 
General Description ....................................................................................................................................... 11 
3.2. 
Schedule of Events ......................................................................................................................................... 12 
3.3. 
Changes to Analyses from Protocol.............................................................................................................. 12 
4. 
PLANNED ANALYSES ................................................................................................... 14 
4.1. 
Data Safety Monitoring Board ..................................................................................................................... 14 
4.2. 
Interim Analysis ............................................................................................................................................. 14 
4.3. 
Final Analysis ................................................................................................................................................. 14 
5. 
ANALYSIS SETS.............................................................................................................. 14 
5.1. 
All Screened Subjects Analysis Set ............................................................................................................... 14 
5.2. 
Intent-to-Treat Analysis Set .......................................................................................................................... 15 
5.3. 
Modified Intent-to-Treat Analysis Set ......................................................................................................... 15 
5.4. 
Safety Analysis Set ......................................................................................................................................... 15 
5.5. 
Pharmacokinetic Analysis Set ....................................................................................................................... 15 
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17.4. 
Vital Signs ................................................................................................................................................... 52 
17.4.1. 
Vital Signs Markedly Abnormal Criteria ................................................................................................. 53 
17.5. 
ECG Evaluations ....................................................................................................................................... 54 
17.5.1. 
ECG Specific Derivations ........................................................................................................................ 55 
17.5.2. 
ECG Markedly Abnormal Criteria........................................................................................................... 55 
17.6. 
Physical Examination ................................................................................................................................ 56 
17.6.1. 
General Physical Examination ................................................................................................................. 56 
17.6.2. 
Chest Imaging .......................................................................................................................................... 56 
18. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 56 
19. 
REFERENCES .................................................................................................................. 57 
APPENDIX 1. PARTIAL DATE CONVENTIONS ............................................................. 58 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 58 
Algorithm for Prior / Concomitant Medications .................................................................................................... 59 
APPENDIX 2. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 62 
Dates & Times ............................................................................................................................................................ 62 
Spelling Format.......................................................................................................................................................... 62 
Paper Size, Orientation, and Margins ..................................................................................................................... 62 
Fonts ........................................................................................................................................................................... 62 
Presentation of Treatment Groups .......................................................................................................................... 62 
Presentation of Nominal Visits ................................................................................................................................. 63 
Descriptive Statistics .................................................................................................................................................. 63 
Percentages ................................................................................................................................................................. 64 
p-values ....................................................................................................................................................................... 64 
Listings ....................................................................................................................................................................... 64 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol AT-03A-001. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed.  
This SAP is based on protocol version 8.0 (amendment 7) dated 25Feb2021.  A separate SAP for the Virology Sub-
Study will be written by the 
 Pharmacokinetic (PK) group. 
2. STUDY OBJECTIVES  
2.1. PRIMARY OBJECTIVE 
The primary efficacy goal is to significantly reduce Progressive Respiratory Insufficiency (PRI), assessed with the 
6-tier scale of increasing levels of respiratory support and defined as a ≥ 2-tier increase in respiratory support 
methods required to maintain satisfactory oxygenation (SpO2 ≥ 93%), within the 14-day study period. The primary 
efficacy goal is a 50% reduction in the incidence of PRI in active treatment recipients compared to placebo 
recipients. 
2.2. SECONDARY OBJECTIVES 
The key secondary objectives are to evaluate the efficacy of AT-527 as compared to placebo in: 
x 
Providing greater reduction in SARS-CoV-2 virus RNA as measured by RT-PCR at specified timepoints. 
x 
Shortening the median time to clinical recovery by at least four days (based on achieving disease resolution in 
the National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status scale). 
x 
Reduction in progression to respiratory failure or death (RFD), using the 6-point scale. 
Other secondary objectives are to compare the active treatment vs. placebo in the following: 
x 
Improvement in overall Clinical Status using the NIAID ordinal scale. 
x 
Reduction in all-cause mortality. 
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efficacy endpoint, the primary analysis of the primary efficacy endpoint will be repeated: 
1. On mITT analysis set. 
2. Excluding the subjects with symptoms for more than 5 days prior to screening. 
As a third sensitivity analysis, subjects will get imputed as follows: 
1- If  ≥ 2 increase observed up to and including Day 14 then PRI 
2- Else, if there is an observed score at Day 14 without PRI then NO PRI 
3- Else, if a subject discontinues the study without having a PRI observed prior to Day 14, then PRI  
4- Else, if subject was discharged from hospital prior to Day 14, then NO PRI  
As a fourth sensitivity analysis, primary analysis of the primary efficacy endpoint will be repeated updating the 
imputation as follows:  
If a subject discontinues without having a PRI observed prior to Day 14, they will be considered as follows: 
Primary reason of early study discontinuation 
PRI? 
Adverse event, Death, Lack of efficacy, Lost to follow up, Non-compliance with 
study drug, Progressive disease, Met protocol lab criteria for 
Discontinuation, Protocol deviation, Physician decision, Sponsor Request, 
Withdrawal by subject, Study terminated by sponsor 
Yes 
Recovery, Pregnancy 
No 
The same CMH test will be performed as for the main analysis. 
16.1.5. 
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT 
The following supplementary analyses will be performed for the primary efficacy endpoint: 
x 
For each subgroup defined in Section 7.7, number and proportion of subjects with and without PRI during the 
study of 14 days will be provided by treatment group. 
x 
The primary analysis of the primary efficacy endpoint will be repeated to analyze the proportion of subjects 
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with PRI on or before Days 10, 21, 28 and 63, respectively, instead of the 14-day primary study period.  
16.2. SECONDARY EFFICACY 
16.2.1. 
KEY SECONDARY EFFICACY ENDPOINTS 
16.2.1.1. 
Change from Baseline in Quantitative SARS-CoV-2  
The first key secondary endpoint is the change from baseline in amount of quantitative SARS-CoV-2 as measured 
by RT-PCR at the time points required in the protocol schedule of assessments (Days 2, 5, and 14). Quantitative 
SARS-CoV-2 will be assessed quantitatively via the TaqPath assay, and qualitatively via a separate assay, COBAS.  
Analysis will be performed on the mITT analysis set only. 
16.2.1.2. 
Time to Clinical Recovery (days) by Day 14 
The second key secondary endpoint is time to clinical recovery in days on or before Day 14, defined as  
x 
Time to clinical recovery by Day 14 (days) = (Date of clinical recovery on or before Day 14 – Date of 
randomization) +1 
Clinical recovery is defined as achieving the NIAID clinical status of level 6 or above, which include subjects who 
are no longer hospitalized (level 7 or 8) or hospitalized but not requiring supplemental oxygen (level 6). The clinical 
status and assessment date/time will be reported on the Ordinal Scale for Clinical Severity page of the eCRF.   
The date of clinical recovery is based on the date the score is first ≥ 6.  Should there be no clinical recovery, then the 
time to clinical recovery is set to 15 days. 
The 8 levels of NIAID are the following: 
1. Death 
2. Hospitalized, on invasive mechanical ventilation or ECMO 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
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x 
If a subject is still on study and in the hospital at Day 28 but with no scale score at Day 28 they will be 
excluded from the denominator. 
16.2.3. 
OTHER SECONDARY EFFICACY ENDPOINTS 
16.2.3.1. 
Proportion of  Subjects Improving/Worsening from Baseline in Clinical Status 
Using the NIAID Ordinal Scale by Day 5 and 14 
The endpoint is based on the lowest observed value on the clinical status (NIAID) scale between D1 to D5 and D1 to 
D14.  Subjects will be classified as “improved”, “same” or “worsened compared to Baseline.  
16.2.3.2. 
All-cause Mortality 
A secondary endpoint is the all-cause mortality i.e., the proportion of subjects who died during the study including 
the follow-up visits regardless of the cause of death. Death may occur after the 14-day primary study period as some 
subjects might remain on prolonged ventilation before recovering or dying. Mortality will be assessed at Day 10, 14, 
28 and 63. Subjects who are discontinued from the study for a reason other than death, prior to each of Day 10, 14, 
28 and 63 will be excluded from the denominator. 
16.2.3.3. 
Duration of Hospitalization for COVID-19 (days) 
A secondary endpoint is the duration of hospitalization/confinement in days, defined as the time from start of 
treatment to either achieving Status 7 or 8 on the NIAID Clinical Status scale or hospital discharge (which ever 
happens first). Data from the follow-up period after Day 14 will be included. This endpoint will be calculated as 
follows: 
x 
Duration of Hospitalization for COVID-19 (days) = ((Date of achieving status 7 or 8 OR hospital discharge) – 
Study Day 1) +1  
Subjects who don’t achieve status 7 or 8 nor have hospital discharge will be censored at end of study (EOS).  
Subjects who die will be censored to the latest EOS date available. 
16.2.3.4. 
Time to Sustained Non-detectable SARS-CoV-2 (days) 
A secondary endpoint is the time to sustained nondetectable SARS-CoV-2 RNA from randomization in days, 
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calculated as follows: 
x 
Time to sustained nondetectable SARS-CoV-2 (days) = (Start date of sustained nondetectable SARS-CoV-2 – 
Date of randomization) +1 
The SARS-CoV-2 test results during the study will be captured by the Central Laboratory. The start date of 
sustained nondetectable SARS-CoV-2 is defined as the earliest date when the test result is negative and remains 
negative until end of the study or D14 as the test is not required after that day.  
Analysis of this endpoint will be performed on the mITT analysis set only. Both COBAS and TaqPath assays report 
results as detectable or non-detectable. Each method has its own limit of detection. The analyses will be performed 
separately on results from each assay.  
The following algorithm will be followed to determine how a subject which didn’t meet the event (i.e., Non-
detectable SARS-CoV-2) should be censored: 
1. If the subject has no post-baseline SARS-CoV-2 test results, the subject will be censored at the date of first 
dose of study drug; 
2. If the subject’s SARS-CoV-2 test remain positive during the study, the subject will be censored at the date 
of their latest of SARS-CoV-2 test with a non-missing result; 
3. If the subject has negative SARS-CoV-2 but not sustained, i.e. the negative result was not confirmed at a 
later scheduled visit (due to missing data, early discontinuation, study completion, etc.), the subject will be 
censored at the date of their latest SARS-CoV-2 test date with a non-missing result; 
4. If subject has missing baseline SARS-CoV-2 data, but has a post-baseline positive SAS-CoV-2 test result, 
the subject will be considered SARS-CoV-2 positive at baseline. Otherwise, a subject with missing baseline 
data will be censored at Day 1. 
5. If subject has negative SARS-CoV-2 at baseline, the subject will be censored at Day 1. 
16.2.3.5. 
Time to first SARS-CoV-2 Negative Test 
A secondary endpoint is the time to first SARS-CoV-2 negative test in days, calculated as follows: 
x 
Time to first SARS-CoV-2 negative test (days) = (First negative SARS-CoV-2 Date – Date of randomization) 
+1 
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DAIDS Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac Troponin I, 
High  
 
Troponin I (ng/L) 
Criteria for Grade 
4 not met 
NA  
NA  
NA  
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory * 
Glucose Fasting, High 
Glucose (mmol/L) 
< 6.11 
6.11 to < 6.95  
6.95 to < 13.89  
13.89 to < 27.75  
≥ 27.75  
Glucose, Low 
Glucose (mmol/L) 
≥ 3.55 
3.05 to <3.55  
2.22 to < 3.05  
1.67 to < 2.22  
< 1.67  
Cholesterol Fasting, 
High  
 
Total cholesterol 
(mmol/L) 
< 5.18 
5.18 to < 6.19  
6.19 to < 7.77  
≥ 7.77  
NA  
Triglycerides Fasting, 
High  
 
Triglycerides 
(mmol/L) 
< 1.71 
1.71 to 3.42  
>3.42 to 5.7  
>5.7 to 11.4  
> 11.4  
Creatine Kinase, High  
 
Creatine kinase 
(IU/L) 
< 3 x ULN 
3 to < 6 x ULN  
6 to < 10x ULN  
10 to < 20 x ULN  
≥ 20 x ULN  
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Changes to Planned Statistical Analyses Form 
Page 1 of 3 
 
Customer: 
ATEA Pharmaceuticals 
 
Protocol No.: 
AT-03A-001 
 
Project Code: 
SZA63631 
 
Date (DDMMMYYYY): 
16Mar2022 
 
 
Form No:  CS_FM_BS006 Revision 8 
Reference:  CS_WI_BS005, CS_WI_BS013 
Effective Date: 15Jan2020 
 
Copyright © 2003, 2006, 2008, 2010, 2012, 2016, 2017, 2020 
 All rights reserved. The contents of this document are 
confidential and proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
 
The timing of the change(s) was: 
  
 
 
After unblinding (or database lock for an open-label study) but before completion of the  
 
 
final Statistical Report/Clinical Study Report 
 
 
After completion of the final Statistical Report/Clinical Study Report 
 
Describe the change(s) required: 
- 
Precision on how to handle the subjects having a treatment start date the day after the date of 
randomization and who have a recovery ON Day 14. They will have time to recovery of 15 days and we 
will set those without recovery to 15.01 days. (Tables 14.2.3.X) 
- 
Using 65 for age group instead of 70. (Table 14.1.4.1, 14.2.1.3, 14.2.2.3, 14.2.3.3, 14.2.4.3) 
- 
Hypertension co morbidities will use MHTERM=Hypertension instead of baseline diastolic and systolic 
values. (Tables 14.1.4.1 and 14.1.4.2) 
- 
Updated derivation for symptom resolution: Time to symptom resolution (days) = (Latest post-baseline 
assessment symptom end date – Date of randomization) +1. (Tables 14.2.4.X) 
- 
We clarified in footnote that we are using both TaqPath and COBAS tests results for mITT population. 
(See footnotes in tables) 
- 
For titer data we updated AVAL to 1.2 and 0.45 respectively for results <1.5 and <0.75 in summaries: 
o 
It is as per Atea’s virologist request and the logic is (Tables 14.2.5.5 and 14.2.4.6): 
 
For “<1.5”, we should use 15.8, i.e. [10^1.5]/2, as the untransformed value which is 
1.2 on log10 scale. 
 
For “<0.75”, we’ll use 2.8, i.e [10^0.75]/2, as the untransformed value which is 0.45 
on the log10 scale. 
- 
Time to Sustained Non-detectable SARS-CoV-2 will be displayed by method (COBAS/ TaqPath). 
(Table 14.2.5.4) 
- 
Level of SARS-CoV-2 Infectious Titer analysis will use the same approach as for the “Time to 
sustained non-detectable SARS-CoV-2 (mITT)” output, we will be providing estimates of proportion of 
subjects with undetectable/negative results, using K-M estimates. (Table 14.2.5.6) 
- 
For all tests except ANCOVA, the 2-sided pvalue will be displayed. 
- 
Childbearing potential and HgbA1c are not included in Demographics and baseline characterics table. 
(Tables 14.1.4.1 and 14.1.4.2) 
- 
ANCOVA analysis: Present the Change-from-Baseline LSM (SE) for each treatment group. (Table 
14.2.5.1) 
- 
Subject level deviations and site level deviations are listed separately. 
- 
Information present in the SAP which are not presented: 
o 
Subjects with screen failure. 
o 
Inclusion and exclusion summary. 
o 
Deviation summary. 
o 
Medical History summary. 
o 
Disease history summary. 
o 
Medication summary. 
o 
Exposure summary. 
 
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