Clinical trial NCT04889040
Conditions: COVID-19
Keywords: Coronavirus Disease 2019; COVID-19; antiviral drug; SARS-CoV-2; Mild to Moderate COVID-19; antiviral efficacy
Sponsor: Hoffmann-La Roche
Start date: 2021-04-28; Completion date: 2021-12-02
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, antiviral activity, and pharmacokinetics of study drug RO7496998 (AT-527) compared to placebo in non-hospitalized adult and adolescent participants with mild to moderate coronavirus disease 2019 (COVID-19) in the outpatient setting.

Detailed description:

Arms: arm 1: The dose and regimen of the placebo will match that of AT-527. arm 2: Orally administered, 550 mg twice daily (BID) for 5 days
Interventions: intervention 1: RO7496998 intervention 2: Placebo
Intervention descriptions: intervention 1: 275 mg tablets intervention 2: Matching tablets

Protocol documents:
Prot_000.pdf: 
 
Official Title:  A Multicenter, Phase III Randomized, Double-Blind, Placebo-
Controlled, Outpatient Study to Evaluate the Efficacy, Safety, Antiviral 
Activity of RO7496998 (AT-527) in Patients With Mild or Moderate 
COVID-19 
NCT Number: 
NCT04889040 
Document Date: 
Protocol Version 3: 02-June-2021  
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland (as 
sponsor in countries outside the United States) and Atea Pharmaceuticals, Inc. (as sponsor in the 
United States).  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc. (or 
under their control) and therefore is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or 
Institutional Review Board.  It is understood that this information will not be disclosed to others without 
written authorization from Roche or Atea except to the extent necessary to obtain informed consent 
from persons to whom the drug may be administered. 
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc. 
Protocol CV43043, Version 3 
PROTOCOL 
TITLE: 
A MULTICENTER, PHASE III RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
OUTPATIENT STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND ANTIVIRAL ACTIVITY 
OF RO7496998 (AT-527) IN PATIENTS WITH MILD 
OR MODERATE COVID-19 
PROTOCOL NUMBER: CV43043 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-005759-18 
IND NUMBER: 
149508 
NCT NUMBER: 
To be determined  
TEST PRODUCT: 
RO7496998 (AT-527) 
MEDICAL MONITOR: 
 M.D., Ph.D. 
SPONSORS: 
F. Hoffmann-La Roche Ltd (Ex-United States)
Atea Pharmaceuticals, Inc. (United States)
DATE FINAL: 
See electronic date stamp below. 
PROTOCOL AMENDMENT APPROVAL 
Date 
Title 
Approver’s Name 
Signature 
 
Atea Pharmaceuticals, Inc. 
 M.D. 
June 1st 2021
02-Jun-2021 07:54:32
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
2/Protocol CV43043, Version 3
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
3
See electronic date 
stamp on title page



2
8 April 2021



1
12 February 2021
Japan
2
1 April 2021


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
3/Protocol CV43043, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol CV43043 has been amended to address the feedback and questions received 
as part of a multinational clinical trial authorization application process. Changes to the 
protocol, along with a rationale for each change, are summarized below:

Updates have been made to the Study Rationale and Benefit-Risk Assessment 
section to reflect recent developments in coronavirus diseases 2019 (COVID-19) 
treatment (Section 1.3).

Two new secondary efficacy endpoints have been added to evaluate maintenance 
of symptom alleviation or improvement out to 43 hours (48 hours 10% to allow for 
variability in the timing of completion of patient reported outcomes by patients) 
(Sections 2 and 6.4.2).

New exploratory endpoint has been added to include optional exit interviews in 
order to establish supportive evidence for the COVID-19 Symptom Diary (Sections
2, 3.3.5 and 6.4.5; Appendix 1).

The number of sites where the study will be conducted has been updated 
(Sections 3.1 and 9.5).

Adolescent enrollment numbers were clarified as approximately 100 adolescent 
patients to match text in Sections 3.1 and 4.2 (Section 3.3.2). 

Web links to CDC adolescent growth charts were added. These were previously 
erroneously omitted (Section 3.3.2).

The exclusion criterion and prohibited therapy related to prior use of amiodarone 
and hydroxychloroquine has been modified to exclude use within 3 months prior to
screening due to the long and variable half-life of both drugs, to further mitigate any
potential for drug-drug interaction with RO7496998 (AT-527) (Sections 4.1.2 and 
4.4.3).

The exclusion criterion related to prior treatment with an investigational drug has 
been modified to exclude use within 3 months prior to screening (Section 4.1.2).

The exclusion criteria related to prior treatment with a COVID-19 therapeutic has 
been expanded and clarified to provide more examples and in response to a 
changing therapeutic landscape and questions from participating sites (Section 
4.1.2).

The units were standardized for the WBC, ANC, and platelet counts in the exclusion 
criteria (Section 4.1.2).

It has been clarified that patients with stable chronic viral infections are eligible to 
participate in the study, providing other eligibility criteria are met (Section 4.1.2).

COVID-19 vaccination within 40 days of enrollment has been added as an exclusion 
criteria and aligns with the information provided in the permitted therapy section. 
This was previously erroneously omitted from this section (Section 4.1.2). 

The permitted therapy section has been expanded and clarified in response to 
questions from participating sites (Section 4.4.1).


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
4/Protocol CV43043, Version 3

The cautionary therapy section has been updated with additional guidance related 
to potential drug-drug interaction involving P-gp, BCRP and OAT1/3 drug 
transporters (Section 4.4.2 and Appendix 7).

The prohibited therapy section related to treatment with a COVID-19 therapeutic has 
been expanded and clarified in response to a changing therapeutic landscape and 
questions from participating sites (Section 4.4.3).

Footnote reference has been updated to clarify that safety samples at all visits will 
be analyzed locally (Appendix 1). 

The timeframe for conducting Day 33 telephone call (TC) has been modified to only 
allow for the TC to occur on Day 33 or the following 3 days.  This will ensure 
adequate collection of safety data prior to study completion (Section 3.1, 
Appendix 1).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
5/Protocol CV43043, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 23
1.1
Background on COVID-19..................................................... 23
1.2
Background on RO7496998 (AT-527)................................... 24
1.3
Study Rationale and Benefit-Risk Assessment...................... 25
2.
OBJECTIVES AND ENDPOINTS ............................................................... 28
3.
STUDY DESIGN......................................................................................... 32
3.1
Description of the Study......................................................... 32
3.2
End of Study and Length of Study......................................... 34
3.3
Rationale for Study Design.................................................... 35
3.3.1
Rationale for RO7496998 (AT-527) Dose and 
Schedule................................................................................ 35
3.3.2
Rationale for Patient Population ............................................ 36
3.3.3
Rationale for Control Group................................................... 38
3.3.4
Rationale for Biomarker Assessments................................... 38
3.3.5
Rationale for Non-Standard Clinical Outcome 
Assessments ......................................................................... 38
4.
MATERIALS AND METHODS .................................................................... 39
4.1
Patients.................................................................................. 39
4.1.1
Inclusion Criteria.................................................................... 39
4.1.2
Exclusion Criteria................................................................... 40
4.2
Method of Treatment Assignment and Blinding..................... 42
4.2.1
Treatment Assignment........................................................... 42
4.2.2
Blinding.................................................................................. 42
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 43
4.3.1
Study Treatment Formulation and Packaging........................ 43
4.3.1.1
RO7496998 (AT-527) and Placebo ....................................... 43
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 43


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4.3.2.1
RO7496998 (AT-527) and Placebo ....................................... 43
4.3.3
Rescue Medication................................................................ 44
4.3.4
Investigational Medicinal Product Handling and 
Accountability ........................................................................ 44
4.3.5
Continued Access to RO7496998 (AT-527) .......................... 45
4.4
Concomitant Therapy, Prohibited Therapy, and 
Additional Restrictions ........................................................... 45
4.4.1
Permitted Therapy................................................................. 45
4.4.2
Cautionary Therapy ............................................................... 45
4.4.3
Prohibited Therapy ................................................................ 47
4.5
Study Assessments ............................................................... 48
4.5.1
Informed Consent Forms and Screening Log........................ 49
4.5.2
Medical History, Baseline Conditions, 
Concomitant Medication, and Demographic Data ................. 49
4.5.3
Physical Examinations........................................................... 49
4.5.4
Vital Signs.............................................................................. 50
4.5.5
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 50
4.5.5.1
Priority Order for Blood Samples for Adolescents ................. 52
4.5.6
Clinical Outcome Assessments ............................................. 52
4.5.6.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 53
4.5.6.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 54
4.5.6.3
Additional COVID-19 Related Assessments.......................... 54
4.5.7
Optional Blood Samples for Whole Genome 
Sequencing (Patients at Participating Sites).......................... 55
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 56
4.6.1
Study Treatment Discontinuation........................................... 56
4.6.2
Patient Discontinuation from the Study.................................. 56
4.6.3
Study Discontinuation............................................................ 57
4.6.4
Site Discontinuation............................................................... 57
5.
ASSESSMENT OF SAFETY....................................................................... 58
5.1
Safety Plan ............................................................................ 58


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
7/Protocol CV43043, Version 3
5.1.1
Risks Associated with RO7496998 (AT-527)......................... 58
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 59
5.1.2.1
Dose Modifications ................................................................ 59
5.1.2.2
Treatment Interruption ........................................................... 59
5.2
Safety Parameters and Definitions ........................................ 59
5.2.1
Adverse Events ..................................................................... 59
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 59
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 60
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 61
5.3.1
Adverse Event Reporting Period ........................................... 61
5.3.2
Eliciting Adverse Event Information....................................... 61
5.3.3
Assessment of Severity of Adverse Events ........................... 61
5.3.4
Assessment of Causality of Adverse Events ......................... 62
5.3.5
Procedures for Recording Adverse Events............................ 63
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 63
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 63
5.3.5.3
Persistent or Recurrent Adverse Events................................ 64
5.3.5.4
Abnormal Laboratory Values ................................................. 64
5.3.5.5
Abnormal Vital Sign Values ................................................... 65
5.3.5.6
Abnormal Liver Function Tests.............................................. 65
5.3.5.7
Deaths ................................................................................... 66
5.3.5.8
Preexisting Medical Conditions.............................................. 66
5.3.5.9
Lack of Efficacy or Worsening of COVID-19.......................... 66
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 67
5.3.5.11
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse .......................................................... 67
5.3.5.12
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 69
5.3.5.13
Safety Biomarker Data........................................................... 69


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
8/Protocol CV43043, Version 3
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 69
5.4.1
Medical Monitors and Emergency Medical 
Contacts ................................................................................ 70
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 70
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 70
5.4.2.2
Events That Occur after Study Drug Initiation........................ 71
5.4.3
Reporting Requirements for Pregnancies.............................. 71
5.4.3.1
Pregnancies in Female Patients............................................ 71
5.4.3.2
Abortions ............................................................................... 71
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 72
5.5
Follow-Up of Patients after Adverse Events .......................... 72
5.5.1
Investigator Follow-Up........................................................... 72
5.5.2
Sponsor Follow-Up ................................................................ 72
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 72
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 73
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 73
6.1
Determination of Sample Size ............................................... 74
6.2
Summaries of Conduct of Study............................................ 74
6.3
Summaries of Treatment group comparability....................... 74
6.4
Efficacy Analyses .................................................................. 75
6.4.1
Primary Efficacy Endpoint...................................................... 75
6.4.2
Secondary Efficacy Endpoints............................................... 77
6.4.3
Secondary Virology Endpoints............................................... 78
6.4.4
Exploratory Virology Endpoints.............................................. 79
6.4.5
Exploratory Patient Reported Outcome and 
Health Utility Endpoints.......................................................... 80
6.5
Safety Analyses..................................................................... 80
6.6
Pharmacokinetic Analyses..................................................... 81
6.7
Biomarker Analyses............................................................... 82
6.8
Interim Analysis ..................................................................... 82


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9/Protocol CV43043, Version 3
6.8.1
Planned Interim Analysis ....................................................... 82
6.8.2
Optional Interim Analysis....................................................... 82
7.
DATA COLLECTION AND MANAGEMENT ............................................... 83
7.1
Data Quality Assurance......................................................... 83
7.2
Electronic Case Report Forms............................................... 84
7.3
Electronic Patient Reported Outcome Data........................... 84
7.4
Source Data Documentation.................................................. 84
7.5
Use of Computerized Systems .............................................. 85
7.6
Retention of Records............................................................. 85
8.
ETHICAL CONSIDERATIONS.................................................................... 86
8.1
Compliance with Laws and Regulations ................................ 86
8.2
Informed Consent.................................................................. 86
8.3
Institutional Review Board or Ethics Committee.................... 87
8.4
Confidentiality........................................................................ 88
8.5
Financial Disclosure .............................................................. 88
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 89
9.1
Study Documentation ............................................................ 89
9.2
Protocol Deviations................................................................ 89
9.3
Management of Study Quality ............................................... 89
9.4
Site Inspections ..................................................................... 89
9.5
Administrative Structure......................................................... 89
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 90
9.7
Protocol Amendments ........................................................... 91
10. REFERENCES ........................................................................................... 92
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 29
Table 2
Priority Order for Blood Samples for Adolescents....................... 52
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 62
Table 4
Causal Attribution Guidance ....................................................... 63


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
10/Protocol CV43043, Version 3
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 34
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 95
Appendix 2
Schedule of Pharmacokinetic Samples (for Adults and 
Adolescents) ............................................................................... 99
Appendix 3
Temperature ............................................................................. 100
Appendix 4
COVID-19 Symptom Diary........................................................ 101
Appendix 5
Patient Global Impression of Severity....................................... 103
Appendix 6
EuroQol 5-Dimension, 5-Level Questionnaire........................... 104
Appendix 7
Update on AT-527 Reproductive Toxicity and Non-Clinical In 
Vitro Drug-Drug Interaction Data............................................... 107


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
11/Protocol CV43043, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTICENTER, PHASE III RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
OUTPATIENT STUDY TO EVALUATE THE
EFFICACY, SAFETY, AND ANTIVIRAL ACTIVITY
OF RO7496998 (AT-527) IN PATIENTS WITH MILD 
OR MODERATE COVID-19
PROTOCOL NUMBER:
CV43043
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-005759-18
IND NUMBER:
149508
NCT NUMBER:
To be determined 
TEST PRODUCT:
RO7496998 (AT-527)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSORS:
F. Hoffmann-La Roche Ltd (Ex-United States)
Atea Pharmaceuticals, Inc. (United States)
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
12/Protocol CV43043, Version 3
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, OUTPATIENT STUDY TO EVALUATE
THE EFFICACY, SAFETY, AND ANTIVIRAL ACTIVITY OF 
RO7496998 (AT-527) IN PATIENTS WITH MILD OR MODERATE 
COVID-19
PROTOCOL NUMBER:
CV43043
VERSION NUMBER:
3
EUDRACT NUMBER:
2020-005759-18
IND NUMBER:
149508
NCT NUMBER:
To be determined
TEST PRODUCT:
RO7496998 (AT-527)
PHASE:
Phase III
INDICATION:
COVID-19
SPONSORS:
F. Hoffmann-La Roche Ltd (Ex-United States)
Atea Pharmaceuticals, Inc. (United States)
Objectives and Endpoints
This study will evaluate the efficacy, safety, antiviral activity, and pharmacokinetics of 
RO7496998 (AT-527) compared with placebo in non-hospitalized adults and adolescents with 
mild to moderate coronavirus disease 2019 (COVID-19).  Specific objectives and corresponding 
endpoints are outlined below.
Primary Objective
Corresponding Endpoint
To evaluate the efficacy 
of RO7496998 (AT-527)
compared with placebo
The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 symptom diary) maintained for a 
duration of 21.5 hours, defined as follows:
For new symptoms:  time from randomization to the alleviation 
of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on 
the COVID-19 Symptom Diary) 
For preexisting symptoms:  time from randomization to when a 
patient’s symptoms have been maintained or improved (Note:  
Improved requires at least a single category improvement from 
baseline on the COVID-19 Symptom Diary Likert scale.)
COVID-19coronavirus disease 2019.


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
13/Protocol CV43043, Version 3
Secondary Objectives
Corresponding Endpoints
To evaluate the efficacy 
of RO7496998 (AT-527)
compared with placebo
The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 Symptom Diary) maintained for 
a duration of 43 hours, defined as follows:
For new symptoms:  time from randomization to the 
alleviation of COVID-19 symptoms (i.e., a score of 0 [none] 
or 1 [mild] on the COVID-19 Symptom Diary) 
For preexisting symptoms:  time from randomization to when 
a patient’s symptoms have been maintained or improved 
(Note:  Improved requires at least a single category 
improvement from baseline on the COVID-19 Symptom Diary 
Likert scale.)
Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion is 
met and maintained for at least 21.5 hours:
Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary
Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion 
is met and maintained for at least 43 hours: 
Score of 0 or 1 for Items 112 of the COVID-19 Symptom 
Diary
Time to one-category improvement of baseline presenting 
COVID-19 symptoms (Items 1-12 of the COVID-19 Symptom 
Diary) maintained for a duration of 21.5 hours defined as time 
from randomization to when the symptoms have improved by at 
least one category from baseline on the COVID-19 Symptom 
Diary Likert scale
Time to alleviation of individual symptoms, defined as the time 
from randomization to the point at which the following criterion is 
met and maintained (for each individual symptom) for at least 
21.5 hours:
Score of 0 or 1 for Items 114 of the COVID-19 Symptom Diary
Proportion of patients requiring hospitalization for COVID-19
Proportion of patients with 1 COVID-19 related medically 
attended visit through to study end (defined as hospitalization, 
emergency room visit, urgent care visit, physician’s office visit, or 
telemedicine visit, with the primary reason for the visit being 
COVID-19)
Duration of fever (time to return to afebrile state [temperature 
37.5C] and remaining so for at least 21.5 hours)
Frequency of COVID-19 related complications (e.g., death, 
hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, 
pericarditis/myocarditis, cardiac failure)
Proportion of patients with any post-treatment infection
Proportion of patients with all-cause mortality
COVID-19coronavirus disease 2019


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
14/Protocol CV43043, Version 3
Secondary Objectives 
(cont.)
Corresponding Endpoints
To evaluate the antiviral 
activity of RO7496998 
(AT-527) compared with 
placebo
Change from baseline in amount of SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by RT-qPCR
Proportion of patients positive for SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at specified timepoints
AUC in the amount of SARS-CoV-2 virus RNA, as measured by 
RT-qPCR
To evaluate the safety of 
RO7496998 (AT-527)
compared with placebo
Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0
Incidence of serious adverse events
Change from baseline in vital signs, including SpO2
Change from baseline in targeted clinical laboratory test results
To characterize the PK 
profile of AT-511 and 
major metabolites in 
plasma
Plasma concentration of AT-511 (the free base form of 
RO7496998 [AT-527]), AT-551, AT-229, and AT-273 (a surrogate 
for the intracellular concentration of the active triphosphate 
metabolite AT-9010) at specified timepoints
AUCarea under the concentrationtime curve; NCI CTCAE v5.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; RT-qPCRreverse-transcriptase 
quantitative polymerase chain reaction; SARS-CoV-2 severe acute respiratory syndrome 
coronavirus-2; SpO2peripheral capillary oxygen saturation.


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15/Protocol CV43043, Version 3
Exploratory Objectives
Corresponding Endpoints
To evaluate the antiviral 
activity of RO7496998 
(AT-527) compared with 
placebo
Treatment-emergent amino acid substitutions in SARS-CoV-2 
viral genes (nsp12 and potentially other genes)
Anti-SARS-CoV-2 antibody status/titer at specified timepoints
Change from baseline in amount of SARS-CoV-2 virus titer at 
each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by virus titer
Proportion of patients with positive SARS-CoV-2 virus titer at 
specified timepoints
AUC of SARS-CoV-2 virus titer
Drug susceptibility in patients with evaluable virus at specified 
timepoints
To identify and/or 
evaluate biomarkers that 
are predictive of 
response to RO7496998 
(AT-527) (i.e., predictive 
biomarkers), are early 
surrogates of efficacy, 
are associated with 
progression to a more 
severe disease state 
(i.e., prognostic 
biomarkers), can provide 
evidence of RO7496998 
(AT-527) activity 
(i.e., pharmacodynamic 
biomarkers), or can 
increase the knowledge 
and understanding of 
disease biology and drug 
safety
Relationship between biomarkers in blood, nasopharyngeal 
swab, Nasosorption, and saliva samples and efficacy, safety, 
PK, or other biomarker endpoints
To evaluate health status 
utility, and PGIS scores 
of patients treated with 
RO7496998 (AT-527) as 
compared with placebo
Patient’s global impression of severity of COVID-19 symptoms as 
assessed through the use of PGIS at Day 14 and Day 29
Change from baseline in EQ-5D-5L health utility index-based and 
VAS scores at specified timepoints
To support content 
validity of COVID-19 
Symptom Diary
Optional exit interviews at Day 33 (or within 14 days) in a 
subset of study patients to gather qualitative data to support 
content validity and inform interpretation of COVID-19 
Symptom Diary scores observed during the study
AUCarea under the concentrationtime curve; COVID-19coronavirus disease 2019; EQ-5D-
5LEuroQol 5-Dimension, 5-Level Questionnaire; PGISPatient Global Impression of Severity; 
PKpharmacokinetic; SARS-CoV-2severe acute respiratory syndrome coronavirus-2; 
VASVisual Analog Scale.
Study Design
This is a Phase III, placebo-controlled, double-blind, multicenter study to assess the efficacy, 
safety, antiviral activity, and pharmacokinetics of RO7496998 (AT-527) compared with placebo 


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in non-hospitalized adult and adolescent patients with mild to moderate COVID-19 in the 
outpatient setting.
The study will enroll approximately 1386 patients (including approximately 100 adolescents, up 
to a maximum of 150, with the remaining patients being adults) with confirmed severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.  Patients will be randomized within 
5 days of symptom onset.  At the time of enrollment, patients must be stable as per eligibility 
criteria and not require hospitalization.  Patients who, in the opinion of the treating physician are 
likely to experience imminent deterioration and require hospitalization will be excluded from the 
study.  Patients confirmed to have other active viral or bacterial infections at the time of 
screening will be excluded.
Patients will be randomized as soon as possible after screening and within 48 hours.  Patients 
who do not meet the criteria for participation in this study (screen failure) cannot be re-screened 
during the same illness episode.  The investigator will record the reason for screen failure in the 
interactive voice or web-based response system. 
Eligible patients will be randomized on or prior to Day 1 in a 2:1 ratio to receive either 
RO7496998 (AT-527) or matching placebo.  Patients will be orally administered 550 mg 
RO7496998 (AT-527) or matching placebo (two 275 mg tablets) two times a day (BID) for 
5 days.  Randomization will be stratified by geographic region (North America, Europe and rest 
of the world [ROW]) and presence of a high-risk factor (yes, no).  A minimum of 40% of the 
overall study population will have a high-risk factor for hospitalization because of COVID-19.  A 
minimum of 40% will also be expected for the otherwise healthy population. Patients may have 
1 risk factor for hospitalization as a result of COVID-19.
The study consists of two periods:  a 5-day treatment period and a 28-day safety and efficacy 
follow-up period, with mandatory study visits on Days 1, 2, 3, 5, 7, and 14.  Some of these visits 
may be conducted by mobile nursing or telemedicine.  In addition to mandatory study visits, 
there will be telephone calls on Day 21 (2 days) and Day 28 (2 days).  The end of study visit 
will take place on Day 33 (3 days), preferentially as a telephone consult but may by conducted 
in-person in some instances, such as if the patient is enrolling in a longer-term follow-up 
RO7496998 (AT-527) study. The total study duration for each patient will be approximately 
33 days.
At study visits, patients will be assessed through physical examination, vital signs including 
peripheral capillary oxygen saturation (SpO2), concomitant therapies, clinical laboratory tests, 
nasopharyngeal (NP) swabs, Nasosorption, and saliva samples.  In addition, pharmacokinetic 
(PK) samples will be collected from adult and adolescent patients.  A cohort of 65 adult patients 
may also undergo optional intensive sampling for pharmacokinetics and biomarkers.  Patients 
will be closely monitored for COVID-19 signs and symptoms, COVID-19-related medically 
attended visits, and adverse events; adverse events will be graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
Throughout the treatment and safety-follow-up periods, patients will record symptoms in the 
COVID-19 Symptom Diary and record body temperature.  Temperatures will be recorded four 
times daily (morning, noon, evening, and bedtime) on Days 15, BID (morning and evening) on 
Days 610, and once daily in the evening on Days 1129.  COVID-19 symptoms will be 
recorded BID (morning and bedtime) on Days 114 and once daily (bedtime) on Days 1529.
If patients are hospitalized during the study treatment period, follow-up visits should continue 
until study end if possible.
Patients in this study may be eligible to rollover to a separate observational study for 
longer-term follow-up.
This study will be conducted at approximately 220 sites globally.
An external independent Data Monitoring Committee (iDMC) will evaluate safety according to 
policies and procedures detailed in an iDMC charter.
Number of Patients
Approximately 1386 non-hospitalized patients (including approximately 100 adolescents, up to a 
maximum of 150, with the remaining patients being adults) with mild to moderate COVID-19, 
with or without high-risk factors will be enrolled in this study.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent/assent for study participation obtained from patient, parent, or 
patient’s legal guardian, with assent as appropriate by the patient, depending on the 
patient’s level of understanding

Age 18 years (regardless of weight) at the time of signing informed consent or age 
12 to 18 years (weight 40 kg) at the time of signing informed consent (and assent)

Ability to comply with all aspects of the study protocol, including providing samples for 
virology, in the opinion of the investigator

At least three of the following symptoms of at least moderate (score 2 as per COVID-19 
Symptom Diary) intensity:  nasal congestion or runny nose, sore throat, cough, shortness of 
breath, muscle or body aches, fatigue, headache, chills or sweats, feeling hot or feverish, 
nausea, vomiting, or diarrhea.

Positive SARS-CoV-2 diagnostic test (reverse-transcriptase polymerase chain reaction 
[RT-PCR] or validated rapid antigen test) 72 hours prior to randomization
A historical record of positive result (RT-PCR and validated rapid antigen test) from 
test conducted 72 hours prior to randomization is acceptable.  Note:  sites should 
record the details of a patient’s screening test in the eCRF. Home tests are not 
acceptable and would require a site confirmatory test.

Symptoms consistent with mild or moderate COVID-19, as determined by the Investigator, 
with onset 5 days before randomization 

For women of childbearing potential and girls at or beyond menarche 
(age 12 to 18 years):  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use adequate contraception during the treatment period and for 30 days 
after the final dose of RO7496998 (AT-527). 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.  Women of childbearing potential must be established on their chosen 
method of contraception at screening.
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing intrauterine 
devices; copper intrauterine devices; male or female condom with or without 
spermicide; and cap, diaphragm, or sponge with spermicide.
Hormonal contraceptive methods must be supplemented by a barrier method.
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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Clinical signs indicative of COVID-19 illness requiring hospitalization defined as any of the 
following:
–
In adults:  respiratory rate 30, heart rate 125 bpm, SpO2 93% on room air
–
In adolescents:  respiratory rate 30, heart rate 130 bpm, SpO2 93% on room air

Admitted to a hospital prior to randomization or is hospitalized (inpatient) at randomization 
due to COVID-19


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Note:  If local policy requires COVID-19 isolation or internment in a hospital or similar 
facility, such as in Japan, but those patients otherwise meet the inclusion criteria, this 
exclusion may not apply.

In the opinion of the investigator, is likely to experience imminent deterioration and require 
hospitalization

Treatment with an investigational drug within 5 half-lives or 3 months (whichever is longer) 
of randomization

Treatment with a COVID-19 therapeutic agent including, but not limited to, other direct or 
indirect acting antivirals against SARS-CoV-2 (such as remdesivir or favipiravir), systemic 
or inhaled steroids (such as dexamethasone or inhaled budesonide), colchicine, ivermectin, 
interferons, convalescent plasma, monoclonal antibodies against SARS CoV-2 or 
interleukin 6, intravenous immunoglobulin or other Emergency Use Authorization-approved 
treatments within 3 months or less than 5 drug elimination half-lives (whichever is longer)
prior to the screening visit

Concomitant use of P-glycoprotein inhibitors or inducers listed as prohibited therapy in the 
protocol

Known allergy or hypersensitivity to components of study drug

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
30 days after the final dose of RO7496998 (AT-527)
Women of childbearing potential must have a negative pregnancy test result at 
screening prior to initiation of study drug.

Abnormal laboratory test results at screening, defined as meeting any of the following sets 
of criteria:
–
ALT or AST 5 upper limit of normal (ULN)
–
Total bilirubin 1.5 ULN, unless the patient has known Gilbert disease
–
Creatinine clearance 60 mL/min
–
Total WBC 2,500/mm3 or ANC 800/mm3
–
Platelet count 80/mm3
Local laboratory test results from standard-of-care tests performed prior to obtaining written 
informed consent and 48 hours before randomization may be used; such tests do not 
need to be repeated for screening.

Requirement of any prohibited medications during the study

Other known active viral or bacterial infection at the time of screening, such as influenza
Note:  This exclusion does not apply to patients with stable chronic viral infections, 
such as chronic HCV or HIV providing other eligibility criteria are met.

Any clinically significant medical condition or laboratory abnormality that, in the opinion of 
the investigator, could jeopardize the safety of the patient or affect patient compliance or 
safety/efficacy observations during the study

COVID-19 vaccination within 40-days prior to enrollment (second dose if applicable)
End of Study
The end of this study is defined as the date when the last patient, last visit (i.e., safety follow-up 
telephone call), occurs or the date at which the last data point required for statistical analysis or 
safety follow-up is received from the last patient, whichever occurs later.  The end of the study 
is expected to occur approximately 33 days after the last patient has been enrolled.
In addition, the Sponsor may decide to terminate the study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 6 months.


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Investigational Medicinal Products
The investigational medicinal product for this study is RO7496998 (AT-527) or matching 
placebo.
Test Product (Investigational Drug)
For patients randomized to receive study drug, RO7496998 (AT-527) will be provided as 
275 mg tablets; two tablets will be administered orally BID from Day 1 to Day 5.
Comparator
For patients randomized to receive placebo, placebo will be provided as 275 mg tablets; 
two tablets will be administered orally BID from Day 1 to Day 5.
Statistical Methods
Primary Analysis
The primary efficacy objective of this study is to evaluate the efficacy of RO7496998 (AT-527)
compared with placebo in adult and adolescent patients and will be assessed based on the 
following endpoint:

The time to alleviation or improvement of COVID-19 symptoms (Items 112 of the COVID-
19 symptom diary) maintained for a duration of 21.5 hours (24 hours minus 10%, to allow 
some flexibility in the timing of assessments), defined as follows:
For new symptoms:  time from randomization to the alleviation of COVID-19 symptoms 
(i.e., a score of 0 [none] or 1 [mild] on the COVID-19 Symptom Diary) 
For pre-existing symptoms:  time from randomization to when a patient’s symptoms 
have been maintained or improved (note improved requires at least a single category 
improvement from baseline on the COVID-19 Symptom Diary Likert scale)
The primary efficacy endpoint definition includes both alleviation of new COVID-19 symptoms 
and maintenance/improvement of pre-existing COVID-19 symptoms to allow for the possibility 
that some patients may have concurrent conditions with symptoms similar to those observed 
with COVID-19 (e.g., cough in a patient with chronic obstructive pulmonary disease).  At 
screening, patients will be assessed with a 14-item COVID-19 symptom severity assessment to
identify pre-existing symptoms (within the prior 30 days), and assess if they worsened due to 
COVID-19. Symptoms that are not pre-existing are considered to be new symptoms and need 
to achieve sustained alleviation (score of 0 or 1) to meet the endpoint.
The median time to alleviation or improvement of signs and symptoms (TTAIS) will be 
compared between the RO7496998 (AT-527) and placebo arms using the stratified log-rank test 
within three regions (i.e., North America, Europe, and ROW) and high-risk factor (yes, no) 
included as the stratification factors.  Kaplan-Meier plots, median time to response, 95% CIs, 
and p-values will be presented.
The log-rank test is most powerful when the assumption of proportional hazards holds.  The 
proportional hazards assumption will be tested graphically using the log-cumulative hazard plot 
by treatment group.  Should the proportional hazards assumption not hold, the Gehan-Wilcoxon 
test will be used to analyze the data.  Full details of data investigation methods and planned 
analysis methods will be specified in the Statistical Analysis Plan (SAP).
The estimand is the median change in time from randomization to alleviation or improvement in 
signs and symptoms of COVID-19 in patients with mild or moderate COVID-19.  This absolute 
measure will be assessed during the study to Day 29 and the primary treatment effect 
comparison will be between the RO7496998 (AT-527) arm and the placebo arm.  Intercurrent 
events are those that occur after treatment initiation and either preclude observation of the 
variable or affect its interpretation.  Intercurrent events will be accounted for through censoring 
rules.  Patients who are lost to follow-up, who do not meet the primary endpoint, who die or 
discontinue for any reason prior to achieving the primary endpoint will be censored at Day 29.  
No dose reductions or treatment crossovers are anticipated.  A treatment policy approach will 
be taken whereby rescue and concomitant medications will be ignored and observations 
collected after use will be used. 
The primary efficacy analysis population will be the modified intent-to-treat infected (mITTi)
population, which consists of all patients who were randomized to treatment, received a dose of 


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study drug, and were reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR)
positive for SARS-CoV-2 at any point during the study.
Determination of Sample Size
The required sample size of the mITTi population is 1248 patients.  It is assumed that the 
RT-qPCR positive rate for SARS CoV 2 will be 90%.  Therefore, approximately 1386 patients 
will be randomized to ensure an adequate number of patients in the mITTi population.  The total 
number of randomized patients may change based on the percentage of patients who are 
RT-qPCR positive during the study.
The required sample size has been calculated to ensure at least 90% power to detect a 2 day 
difference in the median TTAIS of COVID 19 between the RO7496998 (AT-527) group and the 
placebo group, based on an assumed TTAIS in the placebo group of 10 days.  Patients will be 
randomized to a 2:1 ratio to RO7496998 (AT-527) or placebo.  The study will require 1248 
patients in the mITTi population based on an expected 90% event rate (1122 events required) in 
order for the LogRank test to have at least 90% power with a two sided significance level of 
0.025, under the assumption of an exponential distribution.  Additional patients may be enrolled 
in order to observe 1122 events, where an event is meeting the primary endpoint.
Interim Analyses
Planned Interim Analysis
No interim analysis is planned for this study.
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct one interim efficacy analysis and/or one interim virology analysis.  Full details 
will be pre-specified in a SAP prior to the interim analysis being conducted and will include 
rationale and specifications for ensuring the study maintains the highest standards of integrity.
If an interim analysis is conducted for efficacy, the Sponsor will remain blinded.  The interim 
analysis will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC charter. 
The decision to conduct the optional interim efficacy analyses, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the SAP, and the SAP will be 
submitted to relevant health authorities prior to the conduct of the interim analysis.  The iDMC 
charter will be updated to document potential recommendations the iDMC can make to the 
Sponsor as a result of the analysis (e.g., stop the study for positive efficacy, stop the study for 
futility), and the iDMC charter will also be made available to relevant health authorities.
If an interim analysis is conducted for virology, the Sponsor will be unblinded.  The interim 
analysis will be conducted by the Sponsor to confirm adequate antiviral effect. Patients that 
contribute to the virology interim analysis will be excluded from the final efficacy and virology 
analyses and will be replaced in order to maintain power of the primary endpoint analysis and 
there will therefore be no alpha adjustment for the final analysis. The interim virology analysis 
will involve an early look at virology parameters over time and may include formal statistical 
analysis of the change from baseline in viral titer. Details will be specified in a separate interim 
SAP which will be finalized prior to the interim analysis taking place.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AUC
area under the concentrationtime curve
BID
two times a day
BMI
body mass index
Cmax
maximum concentration
Cmin
minimum concentration
COVID-19
coronavirus disease 2019
CV
coefficient of variation
DSMB
Data Safety Monitoring Board
EC
Ethics Committee
EC90
90% effective concentration
eCRF
electronic Case Report Form
EDC
electronic data capture
ER
emergency room
EUA
Emergency Use Authorization
FDA
Food and Drug Administration
GLP
Good Laboratory Practice
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee 
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system 
LLOQ
lower limit of quantification
MERS
middle east respiratory syndrome
mITTi
modified intention-to-treat infected
MN
mobile nursing
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NGS
next-generation sequencing
NLME
non-linear mixed effects
NOAEL
no-observed-adverse effect level
NP
nasopharyngeal
NTI
narrow therapeutic index
P-gp
P-glycoprotein


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Abbreviation
Definition
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic 
PRO
patient-reported outcome
ROW
rest of the world
RT-PCR
reverse-transcriptase polymerase chain reaction 
RT-qPCR
reverse-transcriptase quantitative polymerase chain 
reaction 
SAP
Statistical Analysis Plan
SARS
severe acute respiratory syndrome
SARS-CoV-1/2
severe acute respiratory syndrome coronavirus-1/2
SpO2
peripheral capillary oxygen saturation
Tmax
time to maximum concentration
TTAIS
time to alleviation or improvement of signs and 
symptoms
ULN
upper limit of normal
VAS
Visual Analog Scale
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON COVID-19
Coronaviruses are positive-sense, single-stranded RNA viruses, named for the
crown-like appearance of their spike glycoproteins on the virus envelope.  They are a 
large family of viruses that can cause illness ranging from the common cold to more 
severe diseases such as Middle East respiratory syndrome (MERS) and severe acute 
respiratory syndrome (SARS). An epidemic of cases with unexplained lower respiratory 
tract infections was first detected in Wuhan, the largest metropolitan area in China’s 
Hubei province, and was reported to the WHO Country Office in China on 31 December 
2019.  The WHO subsequently declared a pandemic on 11 March 2020.  This infectious 
disease, named coronavirus disease 2019 (COVID-19) by the WHO, is caused by a 
novel coronavirus strain SARS coronavirus-2 (SARS-CoV-2).  As of 30 October 2020,
nearly 45 million cases of COVID-19 and more than1 million COVID-19related deaths
were reported in over 200 countries and territories worldwide (WHO 2020).
Infection with SARS-CoV-2 may be asymptomatic or it may cause a wide spectrum of 
illness ranging from a mild upper respiratory tract infection to severe life-threatening 
sepsis and multiorgan failure (Wiersinga et al. 2020). Commonly reported symptoms 
include fever, cough, shortness of breath, loss of taste or smell, sore throat, fatigue, 
headaches, muscle aches, and gastrointestinal disturbance. Symptoms are typically 
thought to last 23 weeks, but it is increasingly recognized that many patients continue 
to experience symptoms for many weeks, the so-called long COVID (NIHR 2020).
Approximately 10% of non-hospitalized patients with mild COVID-19 report symptoms 
lasting more than 4 weeks, and up to 87% of hospitalized patients continue to 
experience symptoms 2 months after the onset of their illness. COVID-19 affects people 
of all ages; however, people who are immunocompromised, elderly, or have certain 
underlying medical conditions (e.g., chronic heart, lung, and kidney disease; diabetes, 
obesity, and cancer) are at increased risk of poor outcomes (Carfi et al. 2020; 
Centers for Disease Control [CDC] 2020a; PHE 2020).
There are now a number of vaccines with approvals or Emergency Use Authorizations
(EUA) (or equivalent) for the prevention of SARS-CoV-2 infection. These remain in the 
early distribution phase and there are several logistical issues to be overcome in 
vaccinating large populations globally. Prevention and control of the disease remains a
focus for public health measures to slow transmission, these include social distancing, 
the use of face masks, and national or regional lockdowns. Intravenous remdesivir, an 
inhibitor of RNA-dependent, RNA polymerase, and dexamethasone have shown benefit 
in hospitalized patients with COVID-19.  However, in patients with moderate COVID-19, 
dexamethasone is not efficacious (and may be harmful), and use of remdesivir is not 
approved for non-hospitalized patients (Gandhi et al. 2020). There remains a significant 
and urgent unmet medical need for an orally administered direct acting antiviral drug 
with broad utility for the treatment of COVID-19. This will remain the case despite the 
availability of vaccinations, given that there will still be subsets of the population who will 


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24/Protocol CV43043, Version 3
refuse or not respond to the available vaccines, or individuals who have a 
contraindication and will need treatment options to be available. An antiviral therapeutic 
that could be administered to ambulatory, non-hospitalized patients has the potential to 
significantly reduce disease duration and deterioration of these patients, preventing
progression of disease or hospitalization, and will have a significant impact on the 
pandemic and public health systems globally.
1.2
BACKGROUND ON RO7496998 (AT-527)
RO7496998 (AT-527) is a phosphoramidate prodrug of a unique 6-modified purine 
nucleotide prodrug discovered by Atea Pharmaceuticals Inc. In laboratory studies, 
RO7496998 (AT-527) potently inhibits the RNA-dependent RNA polymerase of several 
single-stranded RNA viruses. RO7496998 (AT-527) is converted to its active 
intracellular triphosphate form (AT-9010) through a series of intermediate metabolites. 
RO7496998 (AT-527) has demonstrated sub-micromolar potency against a range of 
coronaviruses, including SARS-CoV-1 (90% effective concentration [EC90] = 0.34 μM) 
and SARS-CoV-2 (mean EC90 = 0.5 μM). RO7496998 (AT-527), at once daily doses up 
to 553 mg (free base), has been evaluated in two completed clinical studies in healthy 
volunteers and patients infected with hepatitis C virus (HCV).  In the recently completed 
Phase II study (AT-01B-002), RO7496998 (AT-527) in patients infected with HCV was 
well-tolerated for durations of up to 12 weeks and achieved a high rate of antiviral 
efficacy, with no safety issues.
RO7496998 (AT-527) is administered to patients orally as tablets.  In healthy volunteers 
and patients infected with HCV, RO7496998 (AT-527) exhibited a predictable and 
predictive pharmacokinetic (PK) and pharmacodynamic (PD) profile associated with the 
observed antiviral efficacy in patients infected with HCV. This supportive human PK 
profile is likely to be observed with dosing of patients with COVID-19 and is expected to 
be sufficient for achieving antiviral efficacy based on the sub-micromolar EC90 for the 
active triphosphate of RO7496998 (AT-527) against SARS-CoV-2 virus replication in 
laboratory studies.
The safety and efficacy of RO7496998 (AT-527), at doses of 550 mg twice a day (BID),
in hospitalized patients age 18 years with moderate COVID-19 who have risk factors 
for poor outcome are currently being evaluated in a Phase II study (AT-03A-001).  
The safety and pharmacokinetics of RO7496998 (AT-527) at doses of 550 mg BID, have
also been evaluated in healthy volunteers (AT-03A-002).  Summaries from these studies
are briefly outlined in the sections below.
AT-03A-002
This ongoing Phase I study AT-03A-002 is a randomized (1:1), double-blind, 
placebo-controlled study to assess the safety and pharmacokinetics of multiple doses of 
RO7496998 (AT-527) in healthy subjects.  Subjects received RO7496998 (AT-527) at 
doses of 550 mg or matching placebo, BID for 5 days.


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Twenty subjects (10 subjects in the active group and 10 subjects in the placebo group) 
were enrolled and have completed dosing and follow-up through Day 10.  No subjects
have prematurely discontinued the study drug and no serious adverse events have been 
reported.  All adverse events were mild, limited in duration, and were resolved by the 
end of the study.
There were no other clinically significant treatment-emergent laboratory abnormalities, 
ECG abnormalities, or vital sign abnormalities.  
AT-03A-001
Phase II study AT-03A-001 is an ongoing randomized (1:1), double-blind, 
placebo-controlled study to evaluate the safety and efficacy of RO7496998 (AT-527) in 
adult patients with moderate COVID-19 who are at high risk for poor outcomes.  Patients
must have either obesity (BMI 30), hypertension, diabetes, or asthma.  The study 
protocol targets enrollment of 190 patients.
Patients are treated with RO7496998 (AT-527) at doses of 550 mg or matching placebo,
BID (approximately every 12 hours) for 5 days (total of 10 doses).
Safety reviews have been performed by a Data Safety Monitoring Board (DSMB) for the 
first two 20-patient cohorts (40 patients total) with a data cutoff date of 
11 December 2020. Data remains blinded in this ongoing study. To date, pertinent 
events reviewed by the DSMB include:

Serious adverse events assessed by the investigator as unrelated to study drug
were reported in 3 patients:  2 patients experienced decreased oxygen saturation 
(1 case resulting in death due to COVID-19 pneumonia) and 1 patient experienced 
acute respiratory failure. Progression of COVID-19 is common in this clinical 
setting.

Grade 3 or 4 adverse events of laboratory abnormalities were reported in 2 patients:  
in 1 patient, one event each of isolated lipase increase and isolated triglycerides 
increase with no associated symptoms; and in another patient, one event of
hyperbilirubinemia (normal ALT/AST). 

Grade 3 and 4 laboratory abnormalities of special interest for nucleosides did not 
reveal any signals or patterns suggestive of drug toxicity. 
Cumulative blinded data review from 40 patients enrolled in the study continues to 
support a favorable safety profile of RO7496998 (AT-527). The study DSMB
recommended the study continue without modification.
Refer to the AT-527 Investigator's Brochure for details on nonclinical and clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Despite the availability of vaccines, a need for treatment options with varying modes of 
action is still required. Currently available treatments (i.e., remdesivir and 


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dexamethasone) have demonstrated benefit only in hospitalized patients with 
COVID-19. Two virus-neutralizing monoclonal antibody cocktail 
therapiesbamlanivimab plus etesevimab, and casirivimab plus imdevimabhave been 
granted EUA for the treatment of mild to moderate COVID-19 in adults and pediatric 
patients (12 years and older weighing at least 40 kg) 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. These monoclonal antibody interventions are
administered intravenously, and therefore, present challenges in the outpatient setting.
Alternative routes of administration such as orally administered COVID-19 treatments 
would be more practical for use in early disease. Eventually, it is likely multiple 
COVID-19 therapies will be required, both to address the medical needs of distinct 
patient populations and to bolster treatment supplies as caseloads continue to rise 
worldwide. Preventing hospitalizations and chronic sequelae of COVID-19 will not only 
save lives but also help restore healthcare systems and other institutions that are
currently overburdened by the effects of the COVID-19.
Extensive nonclinical safety data, Phase I and Phase II clinical safety data in healthy 
volunteers and patients infected with HCV, favorable human PK data, and the potent 
in vitro antiviral activity of RO7496998 (AT-527) against SARS-CoV-2 replication,
support further clinical evaluation of RO7496998 (AT-527) in patients with COVID-19. 
The main objective of the current study is to evaluate the efficacy and safety of 
RO7496998 (AT-527) in patients with mild or moderate COVID-19.
Nonclinical and clinical safety studies have not revealed any pattern of drug-attributable 
adverse effects or any consistent clinically significant laboratory abnormalities related to 
any body system. Repeat dose-toxicity studies of up to 13 weeks duration in rats and 
monkeys did not show target organ toxicity up to the highest tested dose levels. In rats,
the no-observed-adverse effect level (NOAEL) was the highest tested dose at
1000 mg/kg/day in these studies. In monkeys, the NOAEL in a 7-day study was 
1000 mg/kg/day, a dose that was reduced to 650 mg/kg/day on Day 8 of a 14-day study 
due to loose stools, emesis, inappetence, and weight loss. The dose level of 
650 mg/kg/day was the NOAEL and the highest tested dose in a subsequent 13-week 
monkey toxicity study.  Plasma exposures achieved in these studies either exceeded or 
approximated the anticipated clinical exposures for the different metabolites in one or 
both species, depending on the metabolite.  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. These studies have not revealed a concern for reproductive toxicity and 
achieved exposures that exceeded the anticipated clinical exposures (see Appendix 7).
Thus, the nonclinical safety data are considered to be supportive of the intended clinical 
dose levels and regimens and consistent with international guidelines, ICH Topic M3 
(R2) and associated question and answer document (ICH 2008; ICH 2012).  The 


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potential for gastrointestinal effects in humans will be monitored by means of medical 
data review and safety review on an ongoing basis in this study.
Some nucleoside analogs have been associated with mitochondrial toxicity, resulting in 
damage to the liver, muscles, heart, nerve, pancreas, and other organs. Nephrotoxicity 
has also been associated with the use of some nucleoside analogues (e.g., tenofovir), 
but this is not a broad class effect. The completed nonclinical assessments of 
RO7496998 (AT-527) indicate no potential for mitochondrial toxicity. The active 
triphosphate of RO7496998 (AT-527), AT-9010, did not inhibit the in vitro enzyme
activities of human cellular DNA-dependent DNA polymerases (, , or ) and was 
poorly incorporated by human mitochondrial RNA polymerase.  Additionally, using 
cell-based assays, RO7496998 (AT-527) had no effect on mitochondrial cell membrane 
integrity, mitochondrial-dependent adenosine triphosphate production or mitochondrial 
biogenesis. To date, there have been no clinical signs of adverse effects suggesting 
mitochondrial toxicity for RO7496998 (AT-527) in animal toxicology studies or in 
completed clinical studies.
Current medically used nucleoside analogs are primarily metabolized in the kidney, and 
dose adjustments are generally not needed for patients with creatinine clearance values 
60 mL/min.  Therefore, this study excludes patients with creatinine clearance 
60 mL/min.
RO7496998 (AT-527) has not been associated with hepatotoxicity in nonclinical or 
clinical experience to date.  A total of 82 subjects (30 healthy volunteers and 52 patients 
infected with HCV, including patients with cirrhosis), have received RO7496998
(AT-527) at various dose levels in completed clinical studies. In patients infected with
HCV, liver function test values tend to normalize with RO7496998 (AT-527) treatment.  
No hepatotoxicity was observed in animal models (multiple species).
In the ongoing Phase I study AT-03A-002, 20 healthy subjects (10 treated with 
RO7496998 [AT-527] 550 mg two times a day (BID) and 10 treated with placebo) were 
enrolled and have completed dosing and follow-up through Day 10.  No subjects have
prematurely discontinued study drug.  No serious adverse events have been reported 
and all adverse events have been mild in intensity, limited in duration, and resolved by 
the end of the study.  There have been no other clinically significant treatment-emergent 
laboratory abnormalities or vital sign abnormalities.  All 12-lead safety ECGs (taken 
Days 1, 3, and 5 prior to each dose and at 0.5 and 4 hours after each dose) were 
normal.  In addition to these safety ECGs, continuous cardiodynamic monitoring was
also performed using a Holter.  This recording was performed, read, and extracted by a 
central ECG laboratory (ERT).  Continuous Holter ECG recordings were performed from 
approximately 1 hour prior to the first study drug administration on Day 1 until 
approximately 24 hours following Day 1 a.m. dose and approximately 1 hour prior to the 
Day 5 a.m. dose until approximately 24 hours following Day 5 a.m. dose.  ECGs were 
extracted at pre-determined time points, and were read centrally by ERT. Although 


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analysis of Holter extracted ECG data from this study is ongoing, approximately 40% of 
the planned ECG time points have been analyzed.  To date, no significant QTcF outliers 
or change from baseline abnormalities have been seen.  No clinically relevant changes 
in HR, PR, or QRS post-baseline were observed, and no clinically relevant morphologic 
findings were seen.  Specifically, no notable conduction abnormalities, arrhythmias, ST/T 
wave changes, or new myocardial infarction patterns were seen.  The data overall are 
unremarkable and consistent with expected findings within a healthy volunteer 
population. 
In the Phase II study (AT-03A-001) evaluating RO7496998 (AT-527) 550 mg BID 
(compared with placebo) in hospitalized patients with moderate COVID-19 and risk
factors for poor outcomes, data for the first 40 patients as of the data cutoff date of 
11 December 2020 have not revealed any safety concerns.  
Although it is reasonable to expect that a SARS-CoV-2 direct acting antiviral with potent 
in vitro antiviral activity will result in clinical benefit in patients infected with SARS-CoV-2, 
RO7496998 (AT-527) has not yet been proven to be efficacious in patients with 
COVID-19. Thus, it is possible that patients will not receive any benefit from 
participation in this study. However, the high unmet medical need for the treatment of 
COVID-19, the nonclinical and clinical data for RO7496998 (AT-527) summarized in this 
protocol, and the risk mitigation outlined for this study support the conduct of a 
placebo-controlled study to evaluate the clinical efficacy of RO7496998 (AT-527) in 
non-hospitalized adult and adolescent patients with mild or moderate COVID-19.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, antiviral activity, and pharmacokinetics of 
RO7496998 (AT-527) compared with placebo in non-hospitalized adults and 
adolescents with mild to moderate COVID-19.  Specific objectives and corresponding 
endpoints (see Table 1) are outlined below.


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
 To evaluate the efficacy 
of RO7496998 (AT-527) 
compared with placebo 
 The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 Symptom Diary) maintained for a 
duration of 21.5 hours, defined as follows: 
 For new symptoms:  time from randomization to the alleviation 
of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on 
the COVID-19 Symptom Diary)  
 For preexisting symptoms:  time from randomization to when a 
patient’s symptoms have been maintained or improved (Note:  
Improved requires at least a single category improvement from 
baseline on the COVID-19 Symptom Diary Likert scale.) 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy 
of RO7496998 (AT-527) 
compared with placebo 
 The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 Symptom Diary) maintained for 
a duration of 43 hours, defined as follows: 
 For new symptoms:  time from randomization to the 
alleviation of COVID-19 symptoms (i.e., a score of 0 [none] 
or 1 [mild] on the COVID-19 Symptom Diary)  
 For preexisting symptoms:  time from randomization to when 
a patient’s symptoms have been maintained or improved 
(Note:  Improved requires at least a single category 
improvement from baseline on the COVID-19 Symptom Diary 
Likert scale.) 
 Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion is 
met and maintained for at least 21.5 hours:  
 Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary 
 Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion 
is met and maintained for at least 43 hours:  
 Score of 0 or 1 for Items 112 of the COVID-19 Symptom 
Diary 
 Time to one-category improvement of baseline presenting 
COVID-19 symptoms (Items 1-12 of the COVID-19 Symptom 
Diary) maintained for a duration of 21.5 hours defined as time 
from randomization to when the symptoms have improved by at 
least one category from baseline on the COVID-19 Symptom 
Diary Likert scale 
 Time to alleviation of individual symptoms, defined as the time 
from randomization to the point at which the following criterion is 
met and maintained (for each individual symptom) for at least 
21.5 hours:  
 Score of 0 or 1 for Items 114 of the COVID-19 Symptom Diary 
 Proportion of patients requiring hospitalization for COVID-19 


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Proportion of patients with 1 COVID-19 related medically 
attended visit through to study end (defined as hospitalization, 
emergency room [ER] visit, urgent care visit, physician’s office 
visit, or telemedicine visit, with the primary reason for the visit 
being COVID-19)
Duration of fever (time to return to afebrile state [temperature 
37.5C] and remaining so for at least 21.5 hours)
(see Section 6.4.1)
Frequency of COVID-19 related complications (e.g., death, 
hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, 
pericarditis/myocarditis, cardiac failure)
Proportion of patients with any post-treatment infection
Proportion of patients with all-cause mortality
To evaluate the antiviral 
activity of RO7496998
(AT-527) compared with 
placebo
Change from baseline in amount of SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by RT-qPCR
Proportion of patients positive for SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at specified timepoints
AUC in the amount of SARS-CoV-2 virus RNA, as measured by 
RT-qPCR
To evaluate the safety of 
RO7496998 (AT-527)
compared with placebo
Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0
Incidence of serious adverse events
Change from baseline in vital signs, including SpO2
Change from baseline in targeted clinical laboratory test results
To characterize the PK 
profile of AT-511 and 
major metabolites in 
plasma
Plasma concentration of AT-511 (the free base form of 
RO7496998 [AT-527]), AT-551, AT-229, and AT-273 (a surrogate 
for the intracellular concentration of the active triphosphate 
metabolite AT-9010) at specified timepoints


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Exploratory Objectives
Corresponding Endpoints
To evaluate the antiviral 
activity of RO7496998
(AT-527) compared with 
placebo
Treatment-emergent amino acid substitutions in SARS-CoV-2 
viral genes (nsp12 and potentially other genes)
Anti-SARS-CoV-2 antibody status/titer at specified timepoints
Change from baseline in amount of SARS-CoV-2 virus titer at 
each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by virus titer
Proportion of patients with positive SARS-CoV-2 virus titer at 
specified timepoints
AUC of SARS-CoV-2 virus titer
Drug susceptibility in patients with evaluable virus at specified 
timepoints
To identify and/or 
evaluate biomarkers that 
are predictive of 
response to RO7496998
(AT-527) (i.e., predictive 
biomarkers), are early 
surrogates of efficacy, 
are associated with 
progression to a more 
severe disease state 
(i.e., prognostic 
biomarkers), can provide 
evidence of RO7496998
(AT-527) activity 
(i.e., pharmacodynamic 
biomarkers), or can 
increase the knowledge 
and understanding of 
disease biology and drug 
safety
Relationship between biomarkers in blood, nasopharyngeal
swab, Nasosorption, and saliva samples (listed in 
Section 4.5.5) and efficacy, safety, PK, or other biomarker 
endpoints
To evaluate health status 
utility, and PGIS scores 
of patients treated with 
RO7496998 (AT-527) as 
compared with placebo
Patient’s global impression of severity of COVID-19 symptoms as 
assessed through the use of PGIS at Day 14 and Day 29
Change from baseline in EQ-5D-5L health utility index-based and 
VAS scores at specified timepoints
To support content 
validity of COVID-19 
Symptom Diary
Optional exit interviews at Day 33 (or within 14 days) in a 
subset of study patients to gather qualitative data to support 
content validity and inform interpretation of COVID-19 
Symptom Diary scores observed during the study


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AUCarea under the concentrationtime curve; COVID-19coronavirus disease 2019; 
EQ-5D-5LEuroQol 5-Dimension, 5-Level Questionnaire; NCI CTCAE v5.0National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; PKpharmacokinetic; 
PGISPatient Global Impression of Severity; RT-qPCRreverse-transcriptase quantitative 
polymerase chain reaction; SARS-CoV-2severe acute respiratory syndrome coronavirus-2; 
SpO2peripheral capillary oxygen saturation; VASVisual Analog Scale.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, placebo-controlled, double-blind, multicenter study to assess the
efficacy, safety, antiviral activity, and pharmacokinetics of RO7496998 (AT-527)
compared with placebo in non-hospitalized adult and adolescent patients with mild to 
moderate COVID-19 in the outpatient setting.
The study will enroll approximately 1386 patients (including approximately 
100 adolescents, up to a maximum of 150, with the remaining patients being adults) with 
confirmed SARS-COV-2 infection. Patients will be randomized within 5 days of 
symptom onset. At the time of enrollment, patients must be stable as per eligibility 
criteria and not require hospitalization. Patients who, in the opinion of the treating 
physician are likely to experience imminent deterioration and require hospitalization will 
be excluded from the study. Patients confirmed to have other active viral or bacterial 
infections at the time of screening will be excluded.
Patients will be randomized as soon as possible after screening and within 48 hours. 
Patients who do not meet the criteria for participation in this study (screen failure) cannot 
be re-screened during the same illness episode. The investigator will record the reason 
for screen failure in the interactive voice or web-based response system (IxRS). 
Eligible patients will be randomized on or prior to Day 1 in a 2:1 ratio to receive either 
RO7496998 (AT-527) or matching placebo.  Patients will be orally administered 550 mg
RO7496998 (AT-527) or matching placebo (two 275 mg tablets) BID for 5 days (see 
Section 4.3.2.1).  Randomization will be stratified by geographic region (North America, 
Europe and rest of the world [ROW]) and presence of a high-risk factor (yes, no). A 
minimum of 40% of the overall study population will have a high-risk factor for 
hospitalization because of COVID-19.  A minimum of 40% will also be expected for the
otherwise healthy population. Patients may have 1 risk factor for hospitalization as a 
result of COVID-19 (see Section 3.3.2).
The study consists of two periods: a 5-day treatment period and a 28-day safety and 
efficacy follow-up period, with mandatory study visits on Days 1, 2, 3, 5, 7, and 14.
Some of these visits may be conducted by mobile nursing or telemedicine. In addition to 
mandatory study visits, there will be telephone calls on Day 21 (2 days) and Day 28
(2 days).  The end of study visit will take place on Day 33 (3 days), preferentially as a 
telephone consult but may by conducted in-person in some instances, such as if the 


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patient is enrolling in a longer-term follow-up RO7496998 (AT-527) study. The total 
study duration for each patient will be approximately 33 days.
Based on local COVID-19 isolation policies, such as those in Japan, some study visits 
may be conducted in a hospital or similar facility.  Patients in these countries will meet 
eligibility criteria as per protocol but may be hospitalized for the sole purpose of isolation 
and not for severe symptoms or inpatient treatment.
At study visits, patients will be assessed through physical examination, vital signs 
including peripheral capillary oxygen saturation (SpO2), concomitant therapies, clinical 
laboratory tests, nasopharyngeal (NP) swabs, Nasosorption, and saliva samples
(see Appendix 1 for details regarding the timing of these assessments). In addition, 
PK samples will be collected from adult and adolescent patients at the timepoints 
indicated in Appendix 2. A cohort of 65 adult patients may also undergo optional 
intensive sampling for pharmacokinetics and biomarkers. Patients will be closely 
monitored for COVID-19 signs and symptoms, COVID-19-related medically attended 
visits, and adverse events; adverse events will be graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Throughout the treatment and safety-follow-up periods, patients will record symptoms in 
the COVID-19 Symptom Diary (see Appendix 4) and record body temperature
(see Appendix 3). Temperatures will be recorded four times daily (morning, noon, 
evening, and bedtime) on Days 15, BID (morning and evening) on Days 610, and 
once daily in the evening on Days 1129. COVID-19 symptoms will be recorded BID 
(morning and bedtime) on Days 114 and once daily (bedtime) on Days 1529.
If patients are hospitalized during the study treatment period, follow-up visits should 
continue until study end if possible.
Patients in this study may be eligible to rollover to a separate observational study for 
longer-term follow-up.
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1.




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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for RO7496998 (AT-527) Dose and Schedule
In healthy volunteers and patients infected with HCV, the pharmacokinetics of AT-511 
(the free base form of RO7496998 [AT-527]), AT-551, AT-229, and AT-273 (a major 
nucleoside metabolite of AT-511 and a surrogate for the intracellular concentration of the 
active triphosphate metabolite AT-9010) were comparable. AT-511 and metabolites 
exhibited dose-related plasma exposure in both populations. The PK parameters of 
AT-511 and its metabolites AT-551, AT-229, and AT-273 were also comparable between 
non-cirrhotic and cirrhotic patients infected with HCV.
Similar disposition characteristics of RO7496998 (AT-527) are assumed in otherwise 
healthy non-hospitalized adult patients with mild or moderate COVID-19.
The RO7496998 (AT-527) dose regimen for this study is 550 mg BID for 5 days.
This regimen is supported by the following data:

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 M AT-511 (details in the AT-527 
Investigator's Brochure). 

Predicted PK profiles for AT-9010 in the lung at the proposed 550 mg BID regimen 
(see the AT-527 Investigator's Brochure) show that, at steady state, the 550 mg BID 
regimen is predicted to deliver the following values:
–
Mean trough AT-9010 (the active triphosphate metabolite) concentrations at 
12 hours in the lung at about 0.9 M, 1.8-fold higher than the mean EC90 of 
0.5 M determined for the free base AT-511 in an in vitro antiviral activity assay 
in SARS-CoV-2-infected human airway epithelial cells (see the AT-527 
Investigator's Brochure)
–
Mean maximum lung AT-9010 concentrations at about 1.5 M (time to 
maximum concentration [Tmax] at about 4 hours postdose), 3-fold higher than 
the mean EC90 of 0.5 µM
While the 550 mg BID regimen has not been previously evaluated in otherwise healthy 
non-hospitalized adult patients with mild or moderate COVID-19, this regimen is being 
evaluated in the ongoing Phase II study (AT-03A-001) in hospitalized patients with 
moderate COVID-19 and risk factors for poor outcomes; data for the first 40 patients as 
of the data cutoff date of 11 December 2020 have not revealed any safety concerns.
This dose has also been evaluated in healthy volunteers in the AT-03A-002 study, and 
has been well-tolerated, with no safety concerns.
Data for RO7496998 (AT-527) 550 mg once daily combined with daclatasvir 60 mg once 
daily in patients infected with HCV is available from the recently completed 12-week 
study (AT-01B-002).  In this study, most patients received a cumulative total dose of 
RO7496998 (AT-527) of 30800 mg. Safety and tolerability data from the study provide a 


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safety margin of 5.6-fold for a 5-day (5500 mg cumulative dose) treatment regimen for 
patients with COVID-19.
The animal and human systemic exposure parameters summarized in 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 RO7496998 (AT-527) 550 mg BID dose in the target 
population of this study.
These considerations support an expected favorable safety profile for the evaluation of 
the 550 mg BID dose regimen in the target population of this study.
In addition, a Phase II study (WV43042) to determine the antiviral activity and 
pharmacokinetics of RO7496998 (AT-527) at 550 mg BID for 5 days has been initiated 
in a similar patient population (adults only) and will provide further data to support the 
dosing of RO7496998 (AT-527) for this Phase III study.
3.3.2
Rationale for Patient Population
The safety and efficacy of RO7496998 (AT-527) in hospitalized adult patients with 
moderate COVID-19 who have risk factors for poor outcome is currently being 
investigated in a Phase II study (AT-03A-001).  Given the significant unmet need and 
disease burden in those with mild to moderate disease in the outpatient setting, this 
Phase III study is designed to further evaluate the efficacy and safety of RO7496998
(AT-527) in this population. Using the FDA guidance for industry (FDA 2020a), mild and
moderate COVID-19 baseline severity categorization is defined as follows:

Mild COVID-19
–
Positive testing by standard reverse-transcriptase polymerase chain reaction
(RT-PCR) assay or equivalent test
–
Symptoms of mild illness with COVID-19 that could include fever, cough, sore 
throat, malaise, headache, muscle pain, gastrointestinal symptoms, without 
shortness of breath or dyspnea
–
No clinical signs indicative of Moderate, Severe, or Critical Severity

Moderate COVID-19
–
Positive testing by standard RT-PCR assay or equivalent testing
–
Symptoms of moderate illness with COVID-19, which could include any 
symptom of mild illness or shortness of breath with exertion
–
Clinical signs suggestive of moderate illness with COVID-19, such as 
respiratory rate 20 breaths per minute, SpO2 93% on room air at sea level, 
heart rate 90 beats per minute
–
No clinical signs indicative of Severe or Critical Illness Severity


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In this study, otherwise healthy adult and adolescent patients without risk factors, as well 
as adult and adolescent patients with risk factors for hospitalization, will be enrolled. 
Randomization will be stratified based on the presence of one or more risk factors for 
severe COVID-19 as well as geographic region. Although the inclusion of a risk factor 
increases the individual risk of hospitalization, the course and progression of disease in 
those with mild to moderate disease alone should be similar irrespective of the presence 
or absence of a risk factor or the specific underlying risk factor.
The true incidence of SARS-CoV-2 infection in the pediatric population is currently 
unknown, and it is unclear whether adolescents are as susceptible to infection by 
SARS-CoV-2 compared with adults. Recent evidence suggests that those aged 
18 years are likely to have the same or higher viral loads in their nasopharynx 
compared with adults and that adolescents can spread the virus effectively in 
households (Heald-Sargent et al. 2020; Park et al. 2020). Whilst children and 
adolescents infected with SARS-CoV-2 are less likely to develop severe illness 
compared with adults, they are still at risk for developing severe illness and 
complications from COVID-19 especially if they have underlying risk factors.
Adolescents in this study will need to meet the symptom severity criteria as per adults,
therefore, the benefit of RO7496998 (AT-527) is still likely to be seen in this population. 
Approximately 100 adolescents will be recruited to the study, with a maximum of
150 adolescents. Similar PK characteristics are expected for adolescents compared 
with adults and also in those who are healthy compared to those at high risk for poor 
disease outcome. It is also expected that efficacy and virological endpoints will show 
consistent results in adolescents compared with adults.
Although more severe COVID-19 illness can occur in individuals of all ages, it primarily 
occurs in older adults or those with underlying medical conditions, including 
cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, obesity 
(body mass index [BMI] 30), cancer, and chronic kidney disease (CDC 2020b; 
Lighter et al. 2020; Wu and McGoogan 2020; Zhou et al. 2020). 
The following are considered high-risk factors for hospitalization for adults and will be 
used for the purposes of stratification:

Age 65 years

Obesity, defined as BMI 30

Cardiovascular disease, including hypertension

Chronic lung disease, including moderate to severe asthma

Chronic metabolic disease, including diabetes

Chronic kidney disease 

Chronic liver disease


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
Immunocompromised (e.g., active cancer, HIV or AIDS, use of corticosteroids and 
immunosuppressants) 
The following are considered high-risk factors for hospitalization for adolescents and will 
be used for the purposes of stratification:

BMI 85th percentile for their age and gender based on CDC growth chart
Boys: https://www.cdc.gov/growthcharts/data/set1clinical/cj41l023.pdf
Girls: https://www.cdc.gov/growthcharts/data/set1clinical/cj41l024.pdf 

Sickle cell disease

Congenital or acquired heart disease

Neurodevelopmental disorders (e.g., cerebral palsy)

Asthma, reactive airway disease, chronic respiratory disease that requires daily 
medication for control

Diabetes

Immunosuppressive disease
3.3.3
Rationale for Control Group
A placebo-controlled study design for the evaluation of RO7496998 (AT-527) will allow 
unbiased evaluation of both safety and efficacy of RO7496998 (AT-527). There is a lack 
of targeted treatments for COVID-19 and none currently approved for those with 
mild-moderate disease and not requiring hospitalization. Supportive or symptomatic 
treatment is the mainstay of treatment for this patient population. Participants in this 
study will be allowed to use appropriate rescue treatment as detailed in Section 4.3.3.
Therefore, a placebo-control arm is appropriate in this study.
3.3.4
Rationale for Biomarker Assessments
COVID-19 is a heterogeneous disease, and expression of certain biomarkers has been 
shown to vary among patients, especially those that are hospitalized
(Arunachalam et al. 2020).  Therefore, all patients may not be equally likely to benefit 
from treatment with RO7496998 (AT-527).  Predictive biomarker samples collected prior 
to dosing will be assessed in an effort to identify those patients with COVID-19-driven 
pathogenesis who are most likely to respond to RO7496998 (AT-527).  PD biomarkers 
will also be assessed to demonstrate evidence of anti-viral activity of RO7496998
(AT-527) and the resulting changes in the host immune response in patients.  Given that
these biomarkers may also have prognostic value, their potential association with 
disease progression will also be explored.
3.3.5
Rationale for Non-Standard Clinical Outcome Assessments
At the onset of the global emergency, there was limited understanding of what 
constituted disease progression in COVID-19 and how the symptoms experienced by 
patients manifested themselves and affected their lives. Given the heterogeneous 
nature of COVID-19 related symptoms in outpatients, key COVID-19 related symptoms 


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should be assessed systematically to provide an accurate evaluation. Symptom 
alleviation has also been used as a registrational endpoint for influenza therapies. 
The precedent for the use of patient-reported symptoms in influenza provides key 
insights on how to apply a similar strategy to COVID-19, especially given that 
approximately 80% of patients with COVID-19 are treated in the outpatient setting and 
symptom alleviation is an important marker of clinical benefit for these patients.
Furthermore, FDA guidance (FDA 2020b), notes resolution of symptoms as an example 
of important clinical outcomes. For this reason, the example FDA COVID-19 
patient-reported outcome (PRO) instrument has been used as a basis for the COVID-19 
Symptom Diary assessing 14 key symptoms and will be used for this study.
The symptom items used in this PRO are derived from information provided by the 
Centers for Disease Control and Prevention as of 28 August 2020. Optional exit 
interviews will be conducted in a subset of patients (up to 80 patients in limited 
countries) to support content validity of the COVID-19 Symptom Diary.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 1386 non-hospitalized patients (including approximately 100 adolescents, 
up to a maximum of 150, with the remaining patients being adults) with mild to moderate 
COVID-19, with or without high-risk factors will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent/assent for study participation obtained from patient,
parent, or patient’s legal guardian, with assent as appropriate by the patient, 
depending on the patient’s level of understanding

Age 18 years (regardless of weight) at the time of signing informed consent or age 
12 to 18 years (weight 40 kg) at the time of signing informed consent (and
assent)

Ability to comply with all aspects of the study protocol, including providing samples 
for virology, in the opinion of the investigator

At least three of the following symptoms of at least moderate (score 2 as per 
COVID-19 Symptom Diary) intensity: nasal congestion or runny nose, sore throat, 
cough, shortness of breath, muscle or body aches, fatigue, headache, chills or 
sweats, feeling hot or feverish, nausea, vomiting, or diarrhea.

Positive SARS-CoV-2 diagnostic test (RT-PCR or validated rapid antigen test) 
72 hours prior to randomization
A historical record of positive result (RT-PCR and validated rapid antigen test) 
from test conducted 72 hours prior to randomization is acceptable. Note:  
sites should record the details of a patient’s screening test in the eCRF. Home 
tests are not acceptable and would require a site confirmatory test. 


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
Symptoms consistent with mild or moderate COVID-19, as determined by the 
Investigator, with onset 5 days before randomization 

For women of childbearing potential and girls at or beyond menarche 
(age 12 to 18 years):  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use adequate contraception during the treatment period and for
30 days after the final dose of RO7496998 (AT-527).
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes,
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.  Women of 
childbearing potential must be established on their chosen method of 
contraception at screening.
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; male or female condom with 
or without spermicide; and cap, diaphragm, or sponge with spermicide.
Hormonal contraceptive methods must be supplemented by a barrier method.
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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Clinical signs indicative of COVID-19 illness requiring hospitalization defined as any 
of the following:
–
In adults: respiratory rate 30, heart rate 125 bpm, SpO2 93% on room air
–
In adolescents: respiratory rate 30, heart rate 130 bpm, SpO2 93% on 
room air

Admitted to a hospital prior to randomization or is hospitalized (inpatient) at 
randomization due to COVID-19
Note:  If local policy requires COVID-19 isolation or internment in a hospital or 
similar facility, such as in Japan, but those patients otherwise meet the 
inclusion criteria, this exclusion may not apply.


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
In the opinion of the investigator, is likely to experience imminent deterioration and 
require hospitalization

Treatment with an investigational drug within 5 half-lives or 3 months (whichever is 
longer) of randomization

Treatment with a COVID-19 therapeutic agent including, but not limited to, other 
direct or indirect acting antivirals against SARS-CoV-2 (such as remdesivir or 
favipiravir), systemic or inhaled steroids (such as dexamethasone or inhaled 
budesonide), colchicine, ivermectin, interferons, convalescent plasma, monoclonal 
antibodies against SARS CoV-2 or interleukin 6 (IL-6), intravenous 
immunoglobulin or other EUA-approved treatments within 3 months or less than 5 
drug elimination half-lives (whichever is longer) prior to the screening visit

Concomitant use of P-glycoprotein (P-gp) inhibitors or inducers listed in
Section 4.4.3

Known allergy or hypersensitivity to components of study drug

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 30 days after the final dose of RO7496998 (AT-527)
Women of childbearing potential must have a negative pregnancy test result at 
screening prior to initiation of study drug.

Abnormal laboratory test results at screening, defined as meeting any of the 
following sets of criteria:
–
ALT or AST 5upper limit of normal (ULN)
–
Total bilirubin 1.5ULN, unless the patient has known Gilbert disease
–
Creatinine clearance 60 mL/min
–
Total WBC 2,500/mm3 or ANC 800/mm3
–
Platelet count 80/mm3
Local laboratory test results from standard-of-care tests performed prior to obtaining 
written informed consent and 48 hours before randomization may be used; such 
tests do not need to be repeated for screening

Requirement of any prohibited medications during the study

Other known active viral or bacterial infection at the time of screening, such as 
influenza
Note: This exclusion does not apply to patients with stable chronic viral 
infections, such as chronic HCV or HIV providing other eligibility criteria are 
met.

Any clinically significant medical condition or laboratory abnormality that, in the 
opinion of the investigator, could jeopardize the safety of the patient or affect patient
compliance or safety/efficacy observations during the study

COVID-19 vaccination within 40-days prior to enrollment (second dose if 
applicable); see Section 4.5.2 for documentation requirements pertaining to vaccine 
type and date of dosing


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
4.2.1
Treatment Assignment
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an IxRS.
Patients will be randomly assigned to one of two treatment arms:  RO7496998 (AT-527)
or matching placebo.  Randomization will occur in a 2:1 ratio of RO7496998 (AT-527) to 
placebo through use of a permuted-block randomization method to ensure a balanced 
assignment to each treatment arm.  Randomization will be stratified by region and 
high-risk factor for hospitalization due to COVID-19 for (see Sections 3.1 and 3.3.2 for 
details).
4.2.2
Blinding
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and iDMC members.
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK results for these patients are 
generally not needed for the safe conduct or proper interpretation of the study data.  
Laboratories responsible for performing study drug PK will be unblinded to patient 
treatment assignments to identify appropriate samples for analysis.  PK samples from 
patients assigned to the comparator arm will not be analyzed for study drug PK 
concentration except by request (e.g., to evaluate a possible error in dosing).
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The treatment code should not be broken except in emergency 
situations.  The investigator is not required to contact the Medical Monitor prior to 
breaking the treatment code.  However, the investigator should contact the Medical 
Monitor to discuss emergency unblinding after the treatment code has been broken.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to an 
investigational medicinal product (IMP; defined in Section 4.3).  The patient may 
continue to receive treatment, and the investigator, patient, and Sponsor personnel, with 


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the exception of the Drug Safety representative and personnel who must have access to 
patient treatment assignments to fulfill their roles (as defined above), will remain blinded 
to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The IMP for this study is RO7496998 (AT-527) or matching placebo.
4.3.1
Study Treatment Formulation and Packaging
4.3.1.1
RO7496998 (AT-527) and Placebo
RO7496998 (AT-527) will be supplied by the Sponsor as 275 mg tablets in high-density 
polyethylene bottles with child-resistant closures.  For information on the formulation and 
handling of RO7496998 (AT-527), see the pharmacy manual.
Placebo for RO7496998 (AT-527) will be supplied by the Sponsor as matching 275 mg
tablets.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on drug preparation and 
administration.
Details regarding treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). Cases of overdose, 
medication error, drug abuse, or drug misuse, along with associated adverse events, 
should be reported as described in Section 5.3.5.11.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.
4.3.2.1
RO7496998 (AT-527) and Placebo
RO7496998 (AT-527) is provided as 275 mg tablets; two tablets will be administered 
orally BID from Day 1 to Day 5. Matching placebo is provided as 275 mg tablets; 
two tablets will be administered orally BID from Day 1 to Day 5.
RO7496998 (AT-527) (or matching placebo) should be taken orally at 12-hour intervals 
(2 hours).  If the first study dose is taken prior to 2:00 p.m. on Day 1, the next dose 
should be taken in the evening of the same day (i.e., prior to midnight on the same 
calendar day with a minimum of 10 hours between doses).  For these patients, the final 
(tenth) dose will be taken in the evening of Day 5.  However, if the first study dose is 
taken after 2:00 p.m. on Day 1, the next dose should be taken in the morning of Day 2.
For these patients, the final (tenth) dose will be taken on the morning of Day 6.


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4.3.3
Rescue Medication
If COVID-19 symptoms, such as fever and headache, are so severe, in the opinion of
the patient or investigator, that the patient needs rescue therapy between Day 1 and 
Day 29, the use of acetaminophen will be permitted only for the relief of severe 
symptoms. If acetaminophen is used, this should be recorded on the Concomitant 
Medications eCRF by the investigator, recording the dates and dosing at the next visit. 
Acetaminophen will not be provided by the Sponsor.
4.3.4
Investigational Medicinal Product Handling and Accountability
All IMPs required for completion of this study (RO7496998 [AT-527] or matching placebo 
formulations) will be provided by the Sponsor.  The study site (i.e., investigator or other 
authorized personnel [e.g., pharmacist or mobile nurse) is responsible for maintaining 
records of IMP delivery to the site, IMP inventory at the site, IMP use by each patient, 
and disposition or return of unused IMP, thus enabling reconciliation of all IMP received, 
and for ensuring that patients are provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor, using the 
IxRS.  Any damaged shipments will be replaced.  The investigator or designee must 
confirm that appropriate temperature conditions have been maintained during transit, 
either by time monitoring (shipment arrival date and time) or temperature monitoring, for 
all IMPs received and that any discrepancies have been reported and resolved before 
use of the IMPs.  All IMPs must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and AT-527 Investigator's Brochure for information on 
IMP handling, including preparation and storage, and accountability. 


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4.3.5
Continued Access to RO7496998 (AT-527)
Currently, the Sponsor does not have any plans to provide Roche IMP
(RO7496998 [AT-527]) or any other study treatments to patients who have completed 
the study.  The Sponsor may evaluate whether to continue providing RO7496998
(AT-527) in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED THERAPY, AND 
ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
(12 months for COVID-19 vaccines) prior to initiation of study drug to the end of study 
visit.  All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
4.4.1
Permitted Therapy
Patients are permitted to use the following therapies during the study:

Hormonal contraceptives (see Section 4.1.1)

Acetaminophen (paracetamol)

Hormone replacement therapy

Prescribed medications for concomitant conditions as per medical history, such 
as antihypertensives, antidiabetic medications, rheumatologic medications or
respiratory medications (e.g., chronic inhaled/intranasal/oral steroids)

Low dose aspirin

COVID-19 vaccination (see Section 4.5.2 for documentation requirements pertaining
to vaccine type and date of dosing). 
Patients are not to be vaccinated during the first 2 weeks of the study.
Patients must have at least a 40-day window since their last dose of vaccination 
(second dose if applicable) prior to enrollment.
4.4.2
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 in vitro experiments, AT-511 (the free base form of RO7496998) demonstrated the 
potential for the following DDIs (see Appendix 7 for more details):


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Cytochrome P450 (CYP) 3A4 sensitive substrates

CYP3A4 induction:  weak induction at mRNA level with no increase in CYP3A4 
enzyme activity.  The clinical relevance (e.g., potential for decreased efficacy of oral 
contraceptives) of this finding has not been evaluated. As a precaution, hormonal 
contraceptive methods in women with childbearing potential must be supplemented 
by a barrier method (see Section 4.1.1).

CYP3A4 inhibition:  time-dependent and reversible inhibition by AT-511.  CYP3A4 
sensitive substrates, in particular, those with a narrow therapeutic index (NTI),
should be used with caution.  Common examples of CYP3A4 sensitive substrates 
with NTI include aminophylline, warfarin, methotrexate and amitriptyline.  A list of 
CYP3A4 substrates with NTI is available at: 
https://go.drugbank.com/categories/DBCAT004028. 
Consider substituting or stopping CYP3A4 substrates with NTI during study 
treatment and resume 2 days after the final dose.  In the event that the CYP3A4 
substrate with NTI cannot be safely discontinued or substituted, close monitoring is
required.
P-glycoprotein (P-gp) sensitive substrates

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.
Breast Cancer Resistance Protein (BCRP) sensitive substrates

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.
In in vitro experiments, the plasma circulating nucleoside metabolites AT-229 and 
AT-273 (inactive metabolites of AT-511) demonstrated potential for the following DDI
(See Appendix 7 for more details):
BCRP inhibitors or inducers

BCRP inhibitors or inducers may affect plasma levels of AT-229.  However, AT-
229 is considered an inactive metabolite, and changes in AT-229 PK are not 
expected to affect the antiviral activity of AT-527.  Consider substituting or 
stopping drugs that are major BCRP inhibitors or inducers during study treatment 


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and resume 12 hours after the final dose of study drug.  In the event that the BCRP 
inhibitors or inducers cannot be safely discontinued or substituted, they should be 
used with caution.  Common examples of BCRP inhibitors include omeprazole, 
lansoprazole and buprenorphine.  Common examples of BCRP inducers include 
venlafaxine.
For a list of BCRP inhibitors and inducers, refer to 
https://go.drugbank.com/categories/DBCAT002662 and 
https://go.drugbank.com/categories/DBCAT003986, respectively.
Organic Anion Transporter 1 and 3 (OAT1 and OAT3) inhibitors

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.
4.4.3
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:

Investigational therapy (other than protocol-mandated study treatment)

Treatment with a COVID-19 therapeutic agent including, but not limited to, other 
direct or indirect acting antivirals against SARS-CoV-2 (such as remdesivir or 
favipiravir), systemic or inhaled steroids (such as dexamethasone or inhaled 
budesonide), colchicine, ivermectin, interferons, convalescent plasma, monoclonal 
antibodies against SARS-CoV-2 or IL-6, intravenous immunoglobulin or other EUA-
approved treatments 

Sofosbuvir, for patients with active HCV

Abacavir for patients with HIV

P-glycoprotein (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 in the event the P-gp inhibitor cannot
be safely discontinued or substituted.  If an appropriate substitute cannot be 
identified, dosing of study drug and the P-gp inhibitor must be staggered by 2 hours 
(with study drug dosed first).  Patients may resume use of the substituted P-gp 
inhibitor approximately 12 hours after the final dose of study drug.
For a list of P-gp inhibitors, refer to
https://go.drugbank.com/categories/DBCAT002667


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Macrolides (including azithromycin) may be used if dosing is staggered as described 
above.

P-gp inducers, including the following:
–
Anticonvulsants:  carbamazepine, phenytoin, phenobarbital, oxcarbazepine
–
Rifamycins:  rifabutin, rifampin, rifapentine
–
St. John’s wort
–
HIV protease inhibitors (tipranavir/ritonavir)
For other P-gp inducers, study drug dosing cannot be initiated unless the 
investigator determines that the P-gp inducer can be safely discontinued or 
substituted.  Patients may resume use of the substituted P-gp inducers
approximately 12 hours after the final dose of study drug.
For a list of P-gp inducers, refer to
https://go.drugbank.com/categories/DBCAT002666
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.
Patients will be closely monitored for safety and tolerability throughout the study.
At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional at the patient's home to improve access and convenience for patients 
participating in the study.  The Sponsor will select a healthcare company that will be 
responsible for providing MN services for participating sites (the MN vendor).  The MN
vendor is responsible for ensuring that all MN professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks 
have been performed.  If the investigator at a participating site determines that MN
services are appropriate for a patient and the patient gives written informed consent to 
participate in MN visits, the MN network will communicate with the patient and the 
patient's site.  MN visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the MN professional.  The schedule of activities (see 
Appendix 1) will specify the assessments that may be performed by an MN professional.
In the event of an unscheduled visit that is not part of the schedule of activities, such as 
for follow-up of a medically-supervised visit or adverse event, all vital signs and activities 
should be documented on the unscheduled visit eCRF. As clinically indicated and where 
applicable, the investigator may obtain additional unscheduled assessments and labs 
during this visit. Examples of labs which may be appropriate include, but are not limited 
to, hematology, chemistry, nasopharyngeal swab, serum for biomarkers and virology, 
and/or blood for RNA analysis. For unscheduled visits occurring after Day 7, PK sample 
collection will not be recommended or required. 


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent/assent (where appropriate) for participation in the study must 
be obtained before performing any study-related procedures (including screening 
evaluations).
Informed Consent Forms (and Assent Forms where appropriate) for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients 
meet all eligibility criteria before enrollment.  Screened patients and screen failures will 
be tracked in IxRS.
4.5.2
Medical History, Baseline Conditions, Concomitant Medication,
and Demographic Data
Medical history, including clinical date of onset of symptoms, significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and use of alcohol and drugs of abuse, will be recorded at 
baseline.  In addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 7 days prior to screening will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
COVID-19 vaccination history for the 12 months before screening will be recorded in the 
concomitant medications eCRF, including the product or brand/trade or company 
manufacturer, if available (examples: Pfizer COVID-19 vaccine, Moderna COVID-19 
vaccine) and date administered if known. If not available, report as COVID-19 vaccine.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems; genitourinary examinations may be performed if clinically indicated.  
A neurologic examination, performed at screening and each subsequent study visit, 
should include an assessment of mental status, level of consciousness, cranial nerve 
function, motor function, sensory function, reflexes, and coordination.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 


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should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
Limited, symptom-directed physical examinations may be performed by an MN 
professional.
Height and weight will also be recorded at screening in all patients.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure and SpO2 while the patient is in a seated position, and
temperature.  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
Vital sign measurement may be performed by an MN professional.
4.5.5
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis.  Collection of hematology, chemistry, coagulation and pregnancy laboratory 
samples will be performed locally as per schedule of activities. Historical
standard-of-care laboratory tests performed locally, prior to obtaining written informed 
consent, may be used as the screening labs as indicated below; such tests do not need 
to be repeated for screening.  If standard-of-care laboratory tests are conducted prior to 
obtaining written informed consent, documentation of results must be available.
Blood sample collection may be performed by a MN professional.

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells).  If using a historical standard-of-care test, it must be performed 
48 hours prior to randomization.

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct 
bilirubin, ALP, ALT, AST, triglycerides, CK, CRP, ferritin, cholesterol, amylase, 
lipase, urate, procalcitonin, and LDH.  If using a historical standard-of-care test, it 
must be performed 48 hours prior to randomization.

Pregnancy test
All women of childbearing potential will have a pregnancy test at screening.
This will be a urine or serum test depending on local guidelines. If a historical 
serum test is conducted, it must be performed 48 hours prior to 
randomization.


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
SARS-CoV-2 approved diagnostic test (RT-PCR or validated rapid antigen test) for
screening by an NP swab.  If using a historical test, it must be performed 72 hours 
prior to randomization.

Coagulation:  INR, aPTT, PT, D-dimer, and fibrinogen. If using a historical
standard-of-care test, it must be performed 48 hours prior to randomization.
Samples for the following laboratory tests will be sent to designated central laboratories 
or the Sponsor or a designee for analysis:

Plasma samples for PK analysis

Serum samples for SARS-CoV-2 antibody titer and virology tests

NP or nasal swabs and saliva samples for SARS-CoV-2 virology tests

NP or nasal swabs for respiratory pathogen co-infections panel (multiplex BioFire
assay)

Serum samples for exploratory biomarker research

Blood PAXgene RNA for RNA sequencing or quantitative PCR

Cryopreserved peripheral blood mononuclear cells (PBMCs) for high dimensional
cytometry analysis

Plasma obtained during PBMC processing will be retained for further exploratory 
research

Nasosorption samples for exploratory research on biomarkers
Consent for optional supplementary PK, PBMC and biomarker sampling (intensive 
sampling schedule) will be obtained at the time of study entry (see Appendix 1 and 
Appendix 2).
Exploratory biomarker research and virology tests may include, but will not be limited to,
analysis of inflammatory mediators and/or cytokines, immune cells, virological 
assessment, SARS-COV-2 antibody titer, virus drug susceptibility and virus genotypic
analysis (e.g., next-generation sequencing [NGS]). Research may involve extraction of 
DNA, cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, 
and other genomic variants; and genomic profiling through use of NGS of a 
comprehensive panel of genes.  Genomic research will be aimed at exploring inherited 
characteristics.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions:

Plasma samples collected for PK analysis may be needed for additional PK assay 
development and validation, and biomarker measurements; therefore, these 
samples will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.


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
Serum, blood PAXgene RNA, PBMCs, plasma (from PBMC processing),
Nasosorption, saliva, and NP swab samples collected for virology or biomarker 
research will be destroyed no later than 15 years after the final Clinical Study Report 
has been completed.  However, the storage period will be in accordance with the 
Institutional Review Board/ Ethics Committee (IRB/EC)approved Informed Consent 
Form and applicable laws (e.g., health authority requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.5.1
Priority Order for Blood Samples for Adolescents
Timepoints for blood samples are indicated in Appendix 1 and Appendix 2. However, in 
adolescents, should the total blood volume to be collected at any timepoint according to 
the schedule of activities exceed 0.8 mL/kg or the total blood volume per 30 day period 
exceed 2.4 mL/kg (adolescent patients ages 12 to 18 years and weighing 4080 kg)
the priority order for blood samples indicated in Table 2 should be followed. Note: blood 
volumes are based on 2008 E.U. recommendations on blood limits (EC 2020). 
Table 2
Priority Order for Blood Samples for Adolescents
Order
Samples
1
Any safety laboratory samples (scheduled or unscheduled hematology, 
chemistry and coagulation samples and any samples performed at the 
discretion of the investigator)
2
Plasma PK samples
3
Serum virology/biomarker samples
4
Blood sample for RNA
5
Blood sample for WGS (optional)
PKpharmacokinetic; WGSwhole genome sequencing.
4.5.6
Clinical Outcome Assessments
PRO instruments will be completed to assess the clinical efficacy of RO7496998
(AT-527) compared with placebo.  In addition, PRO instruments will enable capture of 
the direct experience with RO7496998 (AT-527) for each patient.


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PRO data will be collected through use of the following instruments: COVID-19 
Symptom Diary, Patient Global Impression of Severity (PGIS), and EQ-5D-5L.
4.5.6.1
Data Collection Methods for Clinical Outcome Assessments
PRO instruments will be self-administered-at the clinic at screening and at specified 
timepoints during the study (see schedule of activities in Appendix 1) and at home 
according to prespecified timepoints.  At the clinic, instruments will be administered 
before the patient or observer receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment.
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor.  The device will be 
pre-programmed to enable the instrument to be administered at each specified 
timepoint.  The electronic device and instructions for completing the instrument 
electronically will be provided by the site staff.  The data will be transmitted to a 
centralized database maintained by the electronic device vendor.  The data will be 
available for access by appropriate study personnel.
Patients and observers should be given the following instructions for completing PRO 
instruments at home:

Patients and observers should complete the instruments in a quiet area with minimal 
distractions and disruptions.

Patients and observers should answer questions to the best of their ability; there are 
no right or wrong answers.

Patients and observers should not obtain advice or help from others (e.g., family 
members or friends) when completing the instruments.
During study visits and designated timepoints, PRO instruments should be administered 
as outlined below:

Patients' health status should not be discussed prior to administration of the 
instruments.

Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol.

Sites should allow sufficient time for patients and observers to complete the 
instruments

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions.

Patients and observers should be instructed to answer questions to the best of their 
ability; there are no right or wrong answers.

Site staff should not interpret or explain questions, but may read questions verbatim 
upon request.


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
Patients and observers should not obtain advice or help from others (e.g., family 
members or friends) when completing the instruments.
4.5.6.2
Description of Clinical Outcome Assessment Instruments
COVID-19 Symptom Diary
A COVID-19 Symptom Diary (see Appendix 4) will be used to characterize key 
symptoms recognized as part of COVID-19 illness based on FDA guidance (FDA 2020b) 
and document the treatment benefit of RO7496998 (AT-527).  The COVID-19 Symptom 
Diary is composed of 14 individual symptom item questions, each with a 3- or 4-point 
Likert response option. 
The COVID-19 Symptom Diary will be completed in its entirety by the patient twice daily 
(morning and bedtime) on Days 114 and once daily (bedtime) on Days 1529
(see Appendix 1).  To ensure that data standards meet health authority requirements, 
the COVID-19 Symptom Diary will be completed as per schedule of assessment during 
the treatment and monitoring follow-up period.
Patient Global Impression of Severity
The PGIS (see Appendix 5) is a single item assessment of a patient’s impression of the 
severity of his or her COVID-19 symptoms during the course of the study. Change in 
COVID-19 symptoms is rated on a 4-point Likert scale from “none” (0) to “severe” (3).
The PGIS will be completed by the patient once a day at bedtime for the duration of the 
study.
EuroQol EQ-5D-5L
The EQ-5D-5L, is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) 
(see Appendix 6).  There are two components to the EQ-5D-5L:  a 5-item health state 
profile that assesses mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale (VAS) that measures health state.  
The EQ-5D-5L is designed to capture the patient's current health status.  Published 
weighting systems allow for creation of a single composite score of the patient's health 
status.  The EQ-5D-5L takes approximately 3 minutes to complete.  It will be used in this 
study for informing pharmacoeconomic evaluations.
4.5.6.3
Additional COVID-19 Related Assessments
Self-Reported Temperature
Patients will measure temperature four times a day between Days 1 and 5, BID between 
Days 6 and 10, and once daily between Days 11 and 29 (see Appendix 3).


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COVID-19 Related Medically-Attended Visit(s) Assessment
A COVID-19-related medically-attended visit will be defined as follows:  hospitalization, 
emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, 
with the primary reason for the visit being COVID-19. 
Only medically-attended visits related to COVID-19, as determined by the investigator, 
will be recorded in the eCRF. Details will include at minimum:

Type of visit (hospitalization, ER, urgent care, physician’s office visit, telemedicine)

Date of visit

Primary reason for COVID-19 related medically-attended visit 

Treatments given for COVID-19 (including, but not limited to, concomitant 
medications and supplemental oxygen) 

If hospitalization due to COVID-19 was required, include length of visit, whether ICU 
care was given, or whether mechanical ventilation was required
Any adverse events or concomitant therapies reported to the investigator should be
recorded on the respective Adverse Events eCRF or Concomitant Medications eCRF.
4.5.7
Optional Blood Samples for Whole Genome Sequencing 
(Patients at Participating Sites)
At participating sites, optional blood samples will be collected from consenting patients 
for DNA extraction to enable whole genome sequencing (WGS) to identify variants that 
are predictive of response to study drug, are associated with progression to a more 
severe disease state, are associated with susceptibility to developing adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  Research will be 
aimed at exploring inherited characteristics.  The samples may be sent to one or more 
laboratories for analysis.
Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS, this 
section of the protocol (Section 4.5.7 ) will not be applicable at that site. 
The Informed Consent Form will contain a separate section that addresses optional 
blood samples for WGS.  A separate, specific signature will be required to document a 
patient's agreement to provide optional blood samples.  The investigator should 
document whether or not the patient has given consent to participate and (if applicable) 
the date(s) of consent, by completing the Optional Whole Genome Sequencing Informed 
Consent/Withdrawal eCRF. 
Genomics is increasingly informing researchers understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 


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data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Refer to Section 4.5.5 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients who discontinue study drug prematurely will complete assessments as 
indicated in the schedule of activities (see Appendix 1). If a patient requests to be 
withdrawn from treatment or follow-up assessments, this request must be documented in 
the source documents and signed by the investigator.
4.6.2
Patient Discontinuation from the Study
Patients who discontinue from study participation will return to the clinic for an early 
termination visit 7 (2) days after their final dose of study drug. Patients who 
discontinue from the study after Day 14 will not be required to complete an early 
termination visit.


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Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  
Patients who withdraw from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
RO7496998 (AT-527) is not approved, and clinical development is ongoing.  The safety 
plan for patients in this study is based on clinical experience with RO7496998 (AT-527)
in completed and ongoing studies.  The anticipated important safety risks for
RO7496998 (AT-527) are outlined below.  Please refer to the AT-527 Investigator's 
Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for treatment interruption or 
discontinuation, are provided below.
5.1.1
Risks Associated with RO7496998 (AT-527)
RO7496998 (AT-527), at once daily doses up to 553 mg (free base), has been evaluated 
in two clinical studies (AT-01B-001 and AT-01B-002) in healthy volunteers and patients 
infected with HCV.  In the first study, 88 subjects were dosed with blinded study drug 
(RO7496998 [AT-527] or placebo), with 72 of the 88 subjects receiving active study 
drug.  RO7496998 (AT-527) was well tolerated in both healthy volunteers and patients 
infected with HCV as either single or multiple doses (seven daily doses) up to 600 mg
RO7496998 (AT-527) (equivalent to 553 mg AT-511 free base).  In the second study, 
10 patients infected with HCV received RO7496998 (AT-527) 550 mg in combination
with 60 mg daclatasvir once daily for 812 weeks. There were no serious adverse 
events, dose-limiting toxicities, or premature discontinuations. RO7496998 (AT-527) is 
currently being evaluated in a Phase II study (AT-03A-001) at 550 mg BID in 
hospitalized patients with moderate COVID-19 and risk factors for poor outcomes. 
Safety data from the first 40 patients has not revealed any safety concerns
(see Section 1.3).  This dose has also been evaluated in healthy volunteers in the 
AT-03A-002 study, and has been well-tolerated, with no safety concerns
(see Section 1.2).
To date, there have been no appreciable patterns of treatment-related or dose-related 
clinical adverse events or laboratory abnormalities from nonclinical or clinical studies.
Some nucleoside analogues have been associated with mitochondrial 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 broad class effect.  The completed nonclinical assessments of RO7496998
(AT-527) indicate no potential for mitochondrial toxicity.  To date, there have been no 
clinical signs of adverse events suggesting mitochondrial toxicity for RO7496998
(AT-527) dosing.


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5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose Modifications
There will be no dose modification for RO7496998 (AT-527) in this study.
5.1.2.2
Treatment Interruption
Treatment interruptions will not be permitted for RO7496998 (AT-527) in this study.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8
and 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)


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
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last study visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see Table 4):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness,
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.


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
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., hypertension) should be recorded 
on the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of COVID-19.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of COVID-19, "COVID-19 progression" 
should be recorded on the Adverse Event eCRF.
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of COVID-19
Medical occurrences or symptoms of deterioration that are anticipated as part of 
COVID-19, such as fluctuations in symptoms, should not be recorded as adverse 
events. However, deterioration that is judged by the investigator to have unexpectedly 
worsened in severity or frequency or changed in nature at any time during the study 
should be recorded as an adverse event.  When recording an unanticipated worsening 


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of COVID-19 on the Adverse Event eCRF, it is important to convey the concept that the 
condition has changed by including applicable descriptors (e.g., accelerated worsening 
of COVID-19). Any COVID-19-related medically attended visits (defined as 
hospitalization, ER visit, urgent care visit, physician’s office visit, or telemedicine visit, 
with the primary reason for the visit being COVID-19) should be reported in the eCRF 
(see Section 4.5.6.3).
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization based on local COVID19 isolation policies, such as those in Japan: 
patients in these countries may be hospitalized for the sole purpose of isolation and 
not for severe symptoms or inpatient treatment. If deterioration that is judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during isolation, it should be recorded as an adverse event. 
5.3.5.11
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
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In cases where drug is to be self administered by the patient, drug misuse could 
involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For RO7496998 (AT-527) (or matching placebo), adverse 
events associated with special situations should be recorded as described below for 
each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with RO7496998 (AT-527) (or matching 
placebo), regardless of whether they result in an adverse event, should be recorded on 
the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.12
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review the PRO data for adverse events.
5.3.5.13
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor,
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 


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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Medical Monitors and Emergency Medical Contacts
PPD 24-Hour Safety Hotline:

North America:
1 888 483 7729

EMEA/APAC:
44 (0) 1223 374 240

Latin America:
55 11 4504 4801
Roche Medical Monitor/ Medical Responsible:
 M.D., Ph.D.
Mobile Telephone No.:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.


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5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 24 days after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 30 days after the final dose of RO7496998 (AT-527). A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).


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If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported.
During the adverse event reporting period (defined in Section 5.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient's 
medical record to facilitate source data verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
exposure to study drug.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 


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these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
AT-527
AT-527 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Efficacy analyses will be conducted for the modified intent-to-treat infected (mITTi) 
population. This is defined as all randomized patients who received at least one dose of 
study drug and were centrally assessed as reverse-transcriptase quantitative 
polymerase chain reaction (RT-qPCR) positive for SARS-CoV-2 at any point during the 
study, with patients grouped according to the treatment assigned at randomization.
Safety analyses will be conducted for the safety population. This is defined as all 
randomized patients who received at least one dose of study drug, with patients grouped 
according to the treatment received.
The analysis will occur at the end of the study (as defined in Section 3.2).


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The method for controlling type I error among primary and secondary endpoints will be 
described in the Statistical Analysis Plan (SAP), as well as detailed specifications of the 
statistical methods to be implemented. The SAP will be signed off prior to unblinding.
6.1
DETERMINATION OF SAMPLE SIZE
The required sample size of the mITTi population is 1248 patients.  It is assumed that 
the RT-qPCR positive rate for SARS-CoV-2 will be 90%. Therefore, approximately 
1386 patients will be randomized to ensure an adequate number of patients in the mITTi 
population. The total number of randomized patients may change based on the 
percentage of patients who are RT-qPCR positive during the study.
Rationale for the Target Sample Size
The required sample size has been calculated to ensure at least 90% power to detect a
2-day difference in the median time to alleviation or improvement of signs and symptoms 
(TTAIS) of COVID-19 between the RO7496998 (AT-527) group and the placebo group, 
based on an assumed TTAIS in the placebo group of 10 days (Regeneron 2020). 
Patients will be randomized to a 2:1 ratio to RO7496998 (AT-527) or placebo,
respectively, and the fixed follow-up period will be 29 days.  The study will require 
1248 patients in the mITTi population based on an expected 90% event rate 
(1122 events required) in order for the LogRank test to have at least 90% power with a 
two-sided significance level of 0.025, under the assumption of an exponential 
distribution. Additional patients may be enrolled in order to observe 1122 events, where 
an event is meeting the primary endpoint. The minimal detectable difference is a 
hazard ratio of approximately 1.15, which equates to a difference in medians of 
approximately 1.33 days under the assumption of a 10-day placebo response.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who are randomized, enrolled, discontinued, or completed the 
study will be summarized. Reasons for premature study discontinuation will be listed 
and summarized.
Eligibility criteria and other major protocol deviations will be listed and summarized by 
treatment group.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including age, sex, race, region, RT-PCR 
status, time from symptom onset to study treatment, presence of high-risk factors, 
pre-existing symptoms, and seropositive status at baseline) will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate. Summaries will be presented by 
treatment group. These will be summarized for the mITTi population and may also be 
summarized for the safety population.


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Medical history data, including surgery and procedures, and baseline conditions, will be 
summarized descriptively by treatment group using the safety population. 
Previous and concomitant treatments will be summarized descriptively by treatment 
group, details will be specified in the SAP. 
Exposure to study drug will be summarized, including number of doses. A listing of 
patients by treatment group, detailing dosing of study drug, will be prepared.
6.4
EFFICACY ANALYSES
Efficacy analyses will use the mITTi population, which includes all patients randomized
who received at least one dose of study drug with patients grouped according to the
treatment assigned at randomization and are centrally assessed RT-qPCR positive for
SARS-CoV-2 at any point during the study.
In addition to the analyses described in Sections 6.4.1 and 6.4.2, the following analyses 
may be performed for the primary efficacy endpoint and the key secondary efficacy 
endpoints, as appropriate; details of these analyses will be specified in the SAP:

Sensitivity analyses to evaluate the robustness of results to the primary analysis 
methods (e.g., handling of dropouts)

Descriptive subgroup analyses to evaluate the consistency of results across 
pre-specified subgroups (e.g., based on age, sex, race/ethnicity, stratification 
factors, seropositive status at baseline, vaccination status, and other subgroups 
which may be of clinical relevance)
Hypothesis tests will be two-sided at the 2.5% significance level, unless stated 
otherwise.
To manage the overall type I error rate, a multiplicity strategy will be implemented, 
details of which will be included in the SAP prior to unblinding.
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective of this study is to evaluate the efficacy of RO7496998
(AT-527) compared with placebo in adult and adolescent patients and will be assessed 
based on the following endpoint:

The time to alleviation or improvement of COVID-19 symptoms (Items 112 of the 
COVID-19 symptom diary) maintained for a duration of 21.5 hours (24 hours minus 
10%, to allow some flexibility in the timing of assessments), defined as follows:
–
For new symptoms:  time from randomization to the alleviation of COVID-19 
symptoms (i.e., a score of 0 [none] or 1 [mild] on the COVID-19 Symptom 
Diary) 
–
For pre-existing symptoms: time from randomization to when a patient’s 
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least a single category improvement from baseline on the COVID-19 Symptom 
Diary Likert scale)
The primary efficacy endpoint definition includes both alleviation of new COVID-19 
symptoms and maintenance/improvement of pre-existing COVID-19 symptoms to allow 
for the possibility that some patients may have concurrent conditions with symptoms 
similar to those observed with COVID-19 (e.g., cough in a patient with chronic 
obstructive pulmonary disease). At screening, patients will be assessed with a 14-item 
COVID-19 symptom severity assessment to identify pre-existing symptoms (within the 
prior 30 days), and assess if they worsened due to COVID-19. Symptoms that are not 
pre-existing are considered to be new symptoms and need to achieve sustained 
alleviation (score of 0 or 1) to meet the endpoint.
If a symptom is pre-existing, the patient is asked if the severity at screening is worse 
than what was experienced within the last 30 days prior to COVID-19:

If the severity is not worse, the symptom must be maintained (no worsening) or 
improved to meet the endpoint.

If the severity is worse, then a sustained improvement of at least one grade must be 
achieved to meet the endpoint. For example, a symptom classed as severe at 
screening must improve to moderate, mild, or none, and a symptom classed as 
moderate at screening must improve to mild or none.
The median TTAIS will be compared between the RO7496998 (AT-527) and placebo 
arms using the stratified log-rank test within three regions (i.e., North America, Europe, 
and ROW) and high-risk factor (yes, no) included as the stratification factors. 
Kaplan-Meier plots, median time to response, 95% CIs, and p-values will be presented.
The log-rank test is most powerful when the assumption of proportional hazards holds. 
The proportional hazards assumption will be tested graphically using the log-cumulative 
hazard plot by treatment group. Should the proportional hazards assumption not hold, 
the Gehan-Wilcoxon test will be used to analyze the data. Full details of data 
investigation methods and planned analysis methods will be specified in the SAP.
The estimand is the median change in time from randomization to alleviation or 
improvement in signs and symptoms of COVID-19 in patients with mild or moderate 
COVID-19. This absolute measure will be assessed during the study to Day 29 and the 
primary treatment effect comparison will be between the RO7496998 (AT-527) arm and 
the placebo arm. Intercurrent events are those that occur after treatment initiation and 
either preclude observation of the variable or affect its interpretation. Intercurrent events 
will be accounted for through censoring rules. Patients who are lost to follow-up, who do 
not meet the primary endpoint, who die or discontinue for any reason prior to achieving
the primary endpoint will be censored at Day 29. No dose reductions or treatment 
crossovers are anticipated. A treatment policy approach will be taken whereby rescue 


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and concomitant medications will be ignored and observations collected after use will be 
used. 
As specified in Section 6.4, the primary efficacy analysis population will be the mITTi 
population, which consists of all patients who were randomized to treatment, received a 
dose of study drug, and were RT-qPCR positive for SARS-CoV-2 at any point during the 
study.
Sensitivity analyses evaluating different censoring rules will be specified in the SAP.
Alternative methods for evaluating TTAIS under non-proportional hazards will be 
specified in the SAP if required.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study are as follows:

Time to alleviation or improvement of COVID-19 symptoms (Items 112 of the 
COVID-19 Symptom Diary) maintained for a duration of 43 hours, defined as 
follows:
–
For new symptoms:  time from randomization to the alleviation of COVID-19 
symptoms (i.e., a score of 0 [none] or 1 [mild] on the COVID-19 Symptom 
Diary) 
–
For preexisting symptoms:  time from randomization to when a patient’s 
symptoms have been maintained or improved (Note:  Improved requires at least 
a single category improvement from baseline on the COVID-19 Symptom 
Diary Likert scale.)

Time to alleviation of COVID-19 symptoms defined as the time from randomization
to the point at which the following criterion is met and maintained for at least 
21.5 hours:
–
Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary

Time to alleviation of COVID-19 symptoms defined as the time from 
randomization to the point at which the following criterion is met and maintained 
for at least 43 hours: 
–
Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary

Time to one-category improvement of baseline presenting COVID-19 symptoms 
(Items 1-12 of the COVID-19 Symptom Diary) maintained for a duration of 
21.5 hours defined as time from randomization to when the symptoms have 
improved by at least one category from baseline on the COVID-19 Symptom Diary 
Likert scale

Time to alleviation of individual symptoms, defined as the time from randomization
to the point at which the following criterion is met and maintained (for each individual 
symptom) for at least 21.5 hours:
–
Score of 0 or 1 for Items 114 of the COVID-19 Symptom Diary

Proportion of patients requiring hospitalization for COVID-19


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
Proportion of patients with 1 COVID-19 related medically attended visit through to 
study end (defined as hospitalization, ER visit, urgent care visit, physician’s office 
visit, or telemedicine visit, with the primary reason for the visit being COVID-19)
(see Section 4.5.6.3 for assessments to be done at weekly visits)

Duration of fever (time to return to afebrile state [temperature 37.5C] and 
remaining so for at least 21.5 hours) (see Section 6.4.1)

Frequency of COVID-19 related complications (e.g., death, hospitalization, 
radiologically confirmed pneumonia, acute respiratory failure, sepsis, coagulopathy, 
pericarditis/myocarditis, cardiac failure)

Proportion of patients with any post-treatment infection

Proportion of patients with all-cause mortality
Duration and time to event secondary efficacy endpoints will be analyzed using similar 
methods as specified for the primary endpoint. Patients who are lost to follow-up, who 
do not have a response, or who die will be censored at their last contact date or date of 
death, whichever is applicable. Kaplan-Meier plots, median time to response, 95% CIs, 
and p-values will be presented.
Frequency and proportion secondary efficacy endpoints will be analyzed using a 
Cochran-Mantel-Haenszel test adjusted by the stratification factors at baseline, region 
(North America, Europe, ROW) and high-risk factor (yes, no), unless stated otherwise. 
The proportions and difference in proportions, together with a 95% CI and p-values will 
be presented.
COVID-19 related complications (i.e., radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, and cardiac failure) will 
be adjudicated per blinded manual medical review of events, together with other related 
eCRF data (e.g., Adverse Event forms as applicable and medical history) by an internal 
adjudication team before the study readout. Further details will be provided in an
internal adjudication charter.
6.4.3
Secondary Virology Endpoints
The secondary virology endpoints for this study are as follows:

Change from baseline in amount of SARS-CoV-2 virus RNA as measured by 
RT-qPCR at each timepoint

Time to cessation of SARS-CoV-2 viral shedding as measured by RT-qPCR

Proportion of patients positive for SARS-CoV-2 virus RNA by RT-qPCR at specified 
timepoints

Area under the concentration curve (AUC) in the amount of SARS-CoV-2 virus RNA 
as measured by RT-qPCR


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Continuous secondary virology endpoints, such as change from baseline endpoints, will 
be analyzed using an analysis of covariance (ANCOVA) model with region 
(North America, Europe, ROW), high-risk factor (yes, no) as stratification variables, and 
the baseline value of the studied measure as a covariate. The treatment group means, 
difference in means, along with 95% CI and p-value will be presented.
Time to event secondary virology endpoints will be analyzed using similar methods as 
specified for the primary endpoint. Patients who are lost to follow-up, who do not have a 
response, or who die will be censored at their last contact date or date of death, 
whichever is applicable. Kaplan-Meier plots, median time to response, 95% CIs, and 
p-values will be presented.
Frequency and proportion secondary virology endpoints will be analyzed using a 
Cochran-Mantel-Haenszel test adjusted by the stratification factors at baseline, region 
(North America, Europe, ROW) and high-risk factor (yes, no), unless stated otherwise. 
The proportions and difference in proportions, together with a 95% CI and p-values will 
be presented.
6.4.4
Exploratory Virology Endpoints
The exploratory virology endpoints for this study are as follows:

Treatment-emergent amino acid substitutions in SARS-CoV-2 viral genes 
(nsp12 and potentially other genes) 

Anti-SARS-CoV-2 antibody status/titer at specified timepoints

Change from baseline in amount of SARS-CoV-2 virus titer at each timepoint

Time to cessation of SARS-CoV-2 viral shedding as measured by virus titer

Proportion of patients with positive SARS-CoV-2 virus titer at specified timepoints

AUC of SARS-CoV-2 virus titer

Drug susceptibility in patients with evaluable virus at specified timepoints
Time to event, incidence, proportion and change from baseline endpoints will be 
analyzed using the same approach as described for secondary virology endpoints.
AUC endpoints will be analyzed using the van Elteren test where AUC is calculated 
using the trapezoidal method.  Descriptive summary statistics of the AUC will be 
presented for each treatment group along with the p-value from the van Elteren test for 
each RO7496998 (AT-527) vs placebo comparison. Additional analyses adjusting by 
baseline amount of virus RNA may also be conducted and will be specified in the 
statistical analysis plan.
Other virology endpoints will be summarized descriptively. Any further analysis methods 
will be specified in the SAP.


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6.4.5
Exploratory Patient Reported Outcome and Health Utility
Endpoints
Data from the PGIS and EQ-5D-5L will be used in separate analysis to explore 
psychometric properties of COVID-19 Symptom Diary and health utilities. The patient 
reported outcomes and health utility endpoints for this study are as follows:

Patient’s global impression of severity of COVID-19 symptoms as assessed through 
the use of the PGIS at Day 14 and Day 29

Change from baseline in EQ-5D-5L health utility index-based and VAS scores at 
specified timepoints
The EQ-5D-5L will be scored according to its manual, and results will be 
reported separately from the clinical study report.
PRO and health utility endpoints will be summarized descriptively. Any exploratory 
statistical analysis to be conducted on these endpoints will be documented in the SAP.
Optional Exit Interview
Data from optional exit interview responses will be used to gather and explore 
qualitative data.  The exit interview endpoint for this study is: 

Establishing content validity of the COVID-19 Symptom Diary and meaning of 
change scores observed during the study
Exit interviews will be conducted by an external vendor. The qualitative analysis will 
be reported separately from the clinical study report.
6.5
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population, which will consist of 
all randomized patients who received at least one dose of study drug, with patients 
grouped according to treatment received. Safety analyses will include adult and 
adolescent patients.  Additional safety analyses divided by age subgroup may also be 
produced and will be specified in the SAP.
Safety will be assessed through descriptive summaries of treatment emergent adverse 
events (nature, frequency, severity, and causality). Adverse events will be listed.  
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to the NCI CTCAE v5.0 scale.  
Safety will be assessed through descriptive summaries of adverse events, vital sign 
measurements (including SpO2), and laboratory test results (serum chemistry and 
hematology including complete blood count with differential and platelet counts).
A treatment-emergent adverse event is defined as any new adverse event reported or 
any worsening of an existing condition on or after the first dose of study drug.
Separate summaries will be generated for serious adverse events, deaths, adverse 
events leading to discontinuation of study drug, and adverse events of special interest.


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Adverse events will be summarized by MedDRA term, appropriate thesaurus level, and 
toxicity grade.
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated by treatment arm. For selected parameters, changes from baseline and the 
proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm.
Values, along with change from baseline, will be summarized using descriptive statistics 
for each vital sign parameter.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters (e.g. maximum concentration [Cmax] and minimum
concentration [Cmin]).
Samples taken for pharmacokinetic analysis will be processed and concentrations 
of AT-511 (free base form of AT-527) and its major metabolites will be quantified by a 
validated liquid chromatography-tandem mass spectrometry method.  Descriptive 
summary statistics for PK concentration data will be provided by visit/sampling time 
point. Summary statistics will include mean (arithmetic and geometric), SD, coefficient 
of variation (CV) (arithmetic and geometric), median, minimum, and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics and for PK 
parameter calculations. Individual and mean plasma concentration versus time data for 
AT-511, AT-551, AT-229, and AT-273 will be tabulated and plotted.
The following pharmacokinetic parameters will be determined on Day 1: Cmax, Tmax after 
the first dose from the plasma concentration-time data. At steady state on Day 5 the 
following PK parameters will be determined: Cmax,ss, Tmax,ss and Ctrough,ss. All PK analysis 
will be performed using the actual recorded sampling times for AT-511, AT-551, AT-229, 
and AT-273. Descriptive summary statistics for PK parameters will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, and 
maximum. An exception to this is Tmax where median, minimum, and maximum will be 
presented. Inter-patient variability and drug accumulation will be evaluated.
Nonlinear mixed effects (NLME) modeling will be used to analyze the 
dose-concentration-time data of AT-511 and AT-273 in plasma. Population and 
individual PK parameters (e.g., apparent clearance [CL/F] and apparent steady-state 
volume of distribution [Vss/F]) will be estimated and the influence of various covariates 
(e.g., age, gender, and body weight) on these parameters will be investigated.  The data 
collected during this study may be pooled with data collected in other clinical studies 
(previous Phase I and/or Phase II study in healthy volunteers and patients infected with 
HCV, COVID-19) as appropriate, to build the population PK model.  Secondary PK 


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parameters may be derived from the individual post-hoc predictions. NLME modeling 
results will be reported in a standalone document distinct from the clinical study report.
Additional PK analyses may be conducted as appropriate. The PK data and parameters 
derived from these analyses may be used for exploratory graphical analyses of the PD 
data and parameters.
6.7
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.
6.8
INTERIM ANALYSIS
6.8.1
Planned Interim Analysis
No interim analysis is planned for this study.
6.8.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis and/or one interim virology 
analysis. Full details will be pre-specified in a SAP prior to the interim analysis being 
conducted and will include rationale and specifications for ensuring the study maintains 
the highest standards of integrity.
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.
If an interim analysis is conducted for efficacy, the Sponsor will remain blinded.  The 
interim analysis will be conducted by an external statistical group and reviewed by the 
iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified in 
the iDMC charter. 
The decision to conduct the optional interim efficacy analyses, along with the rationale, 
timing, and statistical details for the analysis, will be documented in the SAP, and the 
SAP will be submitted to relevant health authorities prior to the conduct of the interim 
analysis.  The iDMC charter will be updated to document potential recommendations the 
iDMC can make to the Sponsor as a result of the analysis (e.g., stop the study for 
positive efficacy, stop the study for futility), and the iDMC charter will also be made 
available to relevant health authorities.
If there is a potential for the study to be stopped for positive efficacy as a result of the 
efficacy interim analysis, the type I error rate will be controlled to ensure statistical 
validity is maintained.  Specifically, the Lan-DeMets -spending function that 
approximates the O'Brien-Fleming boundary will be applied to determine the critical 
value for stopping for positive efficacy at the interim analysis (DeMets and Lan 1994).  


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Additional criteria for recommending that the study be stopped for positive efficacy may 
be added to the iDMC charter.  If the study continues beyond the interim analysis, the 
critical value at the final analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will include an assessment of the predictive 
probability that the specified endpoint will achieve statistical significance.
If an interim analysis is conducted for virology, the Sponsor will be unblinded.  The 
interim analysis will be conducted by the Sponsor to confirm adequate antiviral effect.  
Patients that contribute to the virology interim analysis will be excluded from the final 
efficacy and virology analyses, and will be replaced in order to maintain power of the 
primary endpoint analysis and there will therefore be no alpha adjustment for the final 
analysis. The interim virology analysis will involve an early look at virology parameters 
over time and may include formal statistical analysis of the change from baseline in viral 
titer. Details will be specified in a separate interim SAP which will be finalized prior to 
the interim analysis taking place.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data, electronic PRO 
data, and IxRS data will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PRO data will be collected through the use of an electronic device provided by a vendor
(see Section 7.3 for details).


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT REPORTED OUTCOME DATA
An electronic device or application installed on the patient’s personal device will be used 
to capture PRO data.  The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. FDA regulations for electronic 
records (21 CFR Part 11).  The data will be transmitted to a centralized database 
maintained by the electronic device vendor.
The electronic data will be available for view access only, via a secure web server.  
Only identified and trained users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will have view access only.  System backups for data stored 
by the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.
7.4
SOURCE DATA DOCUMENTATION
Where permitted, study monitors will perform targeted source data verification and 
review to confirm that critical protocol data as defined in the Monitoring Plan and entered 
into the eCRFs by authorized site personnel are accurate, complete, and verifiable from
source documents.
Due to the COVID-19 pandemic, access to clinical trial sites may be restricted. In such 
cases, remote source data verification (if permitted by the site and by local law) and 
remote data review will be performed. Study monitors will perform ongoing remote data 
review to confirm that critical protocol data (i.e., source data) entered on the eCRFs by 
authorized site personnel are accurate and complete. 


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Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
In addition to source data verification (SDV) or remote SDV on targeted critical data, 
ongoing remote data monitoring will be performed for this study. Study monitors will 
perform ongoing remote data review (defined in the Monitoring Plan and Centralized 
Monitoring Plan) to confirm that critical protocol data are entered into the eCRF by 
authorized site personnel are accurate and complete. Centralized monitoring tools will 
be implemented in order to support the remote data monitoring activity.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, and images, must be 


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retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.


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The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on genomic variants, may be submitted to
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports
and other summary reports will be provided upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. 
Prior to study initiation, the Sponsor identified potential risks associated with critical trial 
processes and data and implemented plans for evaluating and controlling these risks. 
Risk evaluation and control included the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation. Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed. 
Details on the establishment and monitoring of quality tolerance limits are provided in a 
Centralized Monitoring Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored by F. Hoffmann-La Roche Ltd (outside the United States) and 
Atea Pharmaceuticals, Inc. (in the United States).  F. Hoffmann-La Roche Ltd will 


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provide clinical operations management and data management, and both, F. 
Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc. will provide medical monitoring.
Approximately 220 sites globally will participate to enroll approximately 1386 patients
(including approximately 100 adolescents, up to a maximum of 150, with the remaining 
patients being adults).  Enrollment will occur through an IxRS.
A contract research organization will be used for site management and monitoring, 
medical monitoring, and select regulatory submissions. 
An MN vendor will be used to facilitate study visits being performed within the patient’s 
home.
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, virology, biomarker and PK analyses), as specified in 
Section 4.5.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An iDMC will be established to monitor and evaluate patient safety throughout the study.  
Its composition and a description of its responsibilities will be provided in an iDMC 
charter.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.


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The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372.
Carfi A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute 
COVID-19. JAMA 2020;324:6035.
[CDC] Centers for Disease Control and Prevention. People with certain medical 
conditions [resource on the internet]. 2020a [updated 16 October 2020; cited 
1 November 2020]. Available from: 
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medical-conditions.html.
[CDC] Centers for Disease Control and Prevention COVID-19 Response Team. 
Preliminary estimates of the prevalence of selected underlying health 
conditions among patients with coronavirus disease 2019—United States, 
February 12March 28, 2020. Morb Mortal Wkly Rep 2020b;69:3826.
DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
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[EC] European Commission. Ethical considerations for clinical trials on medicinal 
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[published 2008; cited 20 January 2021]. Available from: 
https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-
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EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208.
[FDA] U.S. Food and Drug Administration. COVID-19: Developing drugs and biological 
products for treatment or prevention: Guidance for Industry [resource on the 
internet]. 2020a [published May 2020; cited 11 February 2021]. Available from: 
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19-developing-drugs-and-biological-products-treatment-or-prevention.
[FDA] U.S. Food and Drug Administration. Assessing COVID-19related symptoms in 
outpatient adult and adolescent subjects in clinical trials of drugs and biological 
products for COVID-19 prevention or treatment: Guidance for Industry [resource 
on the internet]. 2020b [published September 2020; cited 1 November 2020]. 
Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/asses
sing-covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-t
rials-drugs. 


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Gandhi RT, Lynch JB, Del Rio C. Mild to moderate Covid-19. N Engl J Med 
2020;383:175766.
Heald-Sargent T, Muller WJ, Zheng X, et al. Age-related differences in nasopharyngeal 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) levels in patients 
with mild to moderate coronavirus disease 2019 (COVID-19). JAMA Pediatr 
2020;174:9023.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Hoang A, Chorath K, Moreira A, et al. COVID-19 in 7780 pediatric patients: A systematic 
review. EClinMed 2020;24:100433.
[ICH] International Council for Harmonisation Topic M3 (R2) Non-clinical safety studies 
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9 November 2020]. Available from: 
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Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727.
Lighter J, Phillips M, Hochman S, et al. Obesity in patients younger than 60 years is a 
risk factor for Covid-19 hospital admission. Clin Infect Dis 2020;71:8967.
[NIHR] National Institute for Health Research. Living with Covid19 [resource on the 
Internet]. 2020 [published 15 October 2020; cited 1 November 2020]. Available 
from: https://evidence.nihr.ac.uk/themedreview/living-with-covid19/.
Park YJ, Choe YJ, Park O, et al. Contact tracing during coronavirus disease outbreak, 
South Korea, 2020. Emerg Infect Dis 2020;26:246568.
[PHE] Public Health England. Guidance: COVID-19: long-term health effects [resource 
on the Internet]. 2020 [published 7 September 2020; cited 1 November 2020]. 
Available from: https://www.gov.uk/government/publications/covid-19-long-term-
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Regeneron Pharmaceuticals, Inc. “REGN-COV2 antibody cocktail program update” 
Regeneron COVID-19 Program Update. 28 September 2020. Accessed: 
16 November 2020. Available from: https://investor.regeneron.com/static-
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[WHO] World Health Organization. Weekly operational update on COVID-19 
30 October 2020 [resource on the Internet]. 2020 [published 30 October 2020; 
cited: 1 November 2020]. Available from:
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2020.
Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, 
and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 
2020;324:78293.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases 
from the Chinese Center for Disease Control and Prevention. JAMA 
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with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 
2020;395:105462.


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Appendix 1
Schedule of Activities
Day 
Screening
Treatment a
Monitoring
UV
ET b, e
(2 days)
–2 to –1
1 b
2 b
3 b
4
5 b
7 a, b 14 a, b
21
(2 days)
(TC)
28
(2 days)
(TC)
33 c, d
(3 days)
(TC)
Informed consent
x f
Demographic data
x
Medical history and baseline conditions
x
Symptom severity assessment
x g
Pre-existing symptom assessment 
x g
Vital signs, including temperature and 
SpO2 h
x
x
x
x
x
x
x
x
Height and weight
x
Complete physical examination i
x
Limited physical examination j
x
x
x
x
x
x
x
Medically attended visit(s) assessment k
x
x
x
x
x
x
x
COVID-19 Symptom Diary l
BID on Days 114
Daily on Days 1529
x
PGIS
Daily on Days 129
x
EQ-5D-5L
x
x
x
x
x
x
Self-reported temperature m
QID on Days 15, BID on Days 610, Daily on Days 1129
x
Hematology n, o
x
x
(x)
x
Chemistry p, o
x
x
(x)
x
Coagulation (INR, aPTT, PT, D-dimer, and 
fibrinogen) o
x
x
(x)
x
Pregnancy test q
x


Appendix 1:
Schedule of Activities
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Day 
Screening
Treatment a
Monitoring
UV
ET b, e
(2 days)
–2 to –1
1 b
2 b
3 b
4
5 b
7 a, b 14 a, b
21
(2 days)
(TC)
28
(2 days)
(TC)
33 c, d
(3 days)
(TC)
Nasopharyngeal swab using a 
SARS-CoV-2 approved diagnostic test 
(RT-PCR or validated rapid antigen test)
x r
Nasopharyngeal swab s
x s
x
x
x
x
(x)
x
Saliva sample s
x s
x t
x
x
x
x
(x)
x
Plasma PK sample
Refer to Appendix 2 for PK sampling schedule.
(x)
Serum sample for biomarkers and virology
x
x
x
x
(x)
x
Serum sample for biomarkers (optional 
intensive sampling group only) u
x
x
x
x
x
(x)
x
Blood sample for RNA analysis
x
x
x
x
(x)
x
Blood sample for RNA analysis (optional 
intensive sampling group only) u
x
x
x
x
x
(x)
x
Blood sample for cryopreserved PBMCs 
(optional intensive sampling group only) u, v
x
x
x
x
x
Nasosorptionsample
x w
x w
x w
(x)
x w
Blood sample for WGS (optional) x
x
RO7496998 (AT-527) administration y
x
x
x
x
x
Concomitant medications z
Adverse events aa
BIDtwo times a day; COVID-19coronavirus disease 2019; ET early termination; PBMCperipheral blood mononuclear cell; 
PKpharmacokinetic; PGISPatient Global Impression of Severity; QIDfour times a day; RT-PCRreverse-transcriptase polymerase chain 
reaction; SARS-CoV-2Severe Acute Respiratory Syndrome coronavirus-2; SpO2peripheral capillary oxygen saturation; TCtelephone call; 
UVunscheduled visit; WGSwhole genome sequencing.
Notes:
On treatment Day1, all assessments should be performed prior to dosing and on treatment Days 25, where possible all assessments 
should be performed prior to dosing, unless otherwise specified.


Appendix 1:
Schedule of Activities
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Assessments in parentheses (x) should be performed as needed.
a For patients at participating sites who have provided written informed consent to participate in mobile nursing visits, select assessments or 
procedures may be performed by a trained nursing professional at the patient's home for visits after Day 1. For patients who have provided 
written informed consent, procedures may be performed by a physician at the patient’s home at any visit.
b All assessments (except sample collection) for these visits can be conducted remotely (e.g., via telephone or telemedicine), in clinic or at home.
c End of study visit can either be in person, telephone call or telemedicine call.
d Optional exit interviews in a subset of patients to be conducted within 14 days after the Day 33 visit.
e Patients who complete study treatment or discontinue study drug prematurely should continue to complete assessments as indicated until the 
end of the study.  Patients who discontinue from study participation will return to the clinic for an early termination visit 7 (2) days after their final 
dose of study drug. Patients who discontinue from the study after Day 14 will not be required to complete an early termination visit.  COVID-19 
Symptom Diary, PGIS, EQ-5D-5L and self-reported temperature assessments should be completed at the ET visit; one single entry will be 
assessed.
f
Informed consent must be documented before any study-specific screening procedure is performed.
g At screening, symptom severity assessment and pre-existing symptom assessment to be done together to confirm patient eligibility. 
h Includes SpO2, temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position.
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary (as clinically indicated), and neurologic systems.
j
Perform a limited, symptom-directed examination or assessment as clinically indicated.
k For patients who have provided written informed consent, the Medically Attended Visit(s) assessment can be completed by a physician/trained 
nursing professional at the patient’s home.  This assessment can also be completed via telemedicine with a physician or at site.  All details to be 
recorded in the eCRF at all visits.  For details of the assessment see Section 4.5.6.3.
l
The COVID-19 Symptom Diary will be completed by the patient twice daily on Days 114, this questionnaire should be completed in the morning 
and bedtime. On Day 1, the first diary questionnaire should be completed prior to the first dose.  Then on Days 1529, the COVID-19 Symptom 
Diary will be completed once daily at bedtime.
m Body temperature should be assessed and recorded by the patient four times daily (morning, noon, evening, and bedtime) on Days 15, BID 
(morning and evening) on Days 610, and once daily (evening) on Days 1129.
n Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).


Appendix 1: 
Schedule of Activities 
  
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o Safety samples (hematology, chemistry and coagulation) will be analyzed locally.  Refer to Section 4.5.5 for information regarding the 
acceptability of historical standard-of-care tests.  
p Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, triglycerides, CK, 
CRP, ferritin, cholesterol, amylase, lipase, urate, procalcitonin, and LDH. 
q All women of childbearing potential will have a pregnancy test at screening.  This will be performed locally and will be a urine or serum test, 
depending on local guidelines.  Refer to Section 4.5.5 for information regarding the acceptability of historical standard-of-care tests. 
r Performed at or prior to Screening, nasopharyngeal swabs will be analyzed for the SARS-CoV-2 by approved diagnostic test (RT-PCR or 
validated rapid antigen test) locally. 
s Swab samples and saliva samples should be collected at approximately the same time every day where possible.  The sample on Day 1 should 
be collected prior to dosing.  At least two nasopharyngeal swabs, one from each nostril, will be taken at each visit.  Should the patient decline a 
nasopharyngeal swab, a nasal swab from each nostril may be collected instead. 
t For saliva sample at Day 2 only:  patients can take the sample at home and bring to site on Day 3 (if they are having on-site visits) or the mobile 
nurse/physician can pick the sample up at Day 3 (if they have consented to home visits). 
u Optional samples collected in adult patients only and who have consented to PK and biomarker intensive sampling. 
v A plasma sample will be generated from the blood sample obtained following PBMC processing and will be stored for biomarker research.  No 
additional blood draw is needed.  Samples for PBMC may not be collected at some timepoints if sample stability requirements for processing will 
not be met.  Please refer to the laboratory manual for more details. 
w At Day 1, Day 5, Day 14 and ET, Nasosorption sample to be taken after the nasopharyngeal swabs.   
x Not applicable for a site that has not been granted approval for WGS.  Performed only for patients at participating sites who have provided 
written informed consent to participate.  If the sample is not collected at the Day 1 visit for any reason, it may be collected at any later timepoint. 
y Study treatment will be administered BID to be taken 12 hours apart for a total of 10 doses.  See Section 4.3.2.1 for details. 
z Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) and 
supplemental oxygen used by a patient in addition to protocol-mandated treatment from 7 days (12 months for COVID-19 vaccines) prior to 
initiation of study drug until the end of study follow-up on Day 33, will be recorded.  Any COVID-19 vaccination which has occurred before the 
patient enrolls into the study or during the study will be recorded in the concomitant medications eCRF, including the product or brand/trade or 
company manufacturer, if available (examples: Pfizer COVID-19 vaccine, Moderna COVID-19 vaccine) and date administered if known. If not 
available, report as COVID-19 vaccine. 
aa After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until the end of study follow-up telephone call on 
Day 33. 


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
99/Protocol CV43043, Version 3
Appendix 2
Schedule of Pharmacokinetic Samples (for Adults and 
Adolescents)
Visit
Timepoint
Sample Type
PK sparse sampling a
Day 1 (with reference to 
1st dose)
Predose (30 min)
RO7496998 (AT-527) PK (plasma)
1 hour postdose (30 min)
RO7496998 (AT-527) PK (plasma)
Day 5 (with reference to 
the morning dose)
Predose (30 min)
RO7496998 (AT-527) PK (plasma)
1 hour postdose (30 min)
RO7496998 (AT-527) PK (plasma)
Day 7
Anytime c
RO7496998 (AT-527) PK (plasma)
Optional PK intensive sampling b
Day 1 (with reference to 
the 1st dose)
Predose (30 min)
RO7496998 (AT-527) PK (plasma)
1 hour postdose (30 min)
RO7496998 (AT-527) PK (plasma)
2 hours postdose (30 min)
RO7496998 (AT-527) PK (plasma)
4 hours postdose (30 min)
RO7496998 (AT-527) PK (plasma)
Day 5 (with reference to 
the morning dose)
Predose (30 min)
RO7496998 (AT-527) PK (plasma)
1 hour postdose (30 min)
RO7496998 (AT-527) PK (plasma)
2 hours postdose (30 min)
RO7496998 (AT-527) PK (plasma)
4 hours postdose (30 min)
RO7496998 (AT-527) PK (plasma)
8 hours postdose (30 min)
RO7496998 (AT-527) PK (plasma)
Day 7
Anytime c
RO7496998 (AT-527) PK (plasma)
PKpharmacokinetic.
a PK samples to be collected in adult and adolescent patients. Samples can be collected and 
processed in clinic/at site or at home (if patients consented to home visits).
b Optional PK samples to be collected in adult patients only, and who have consented to PK 
intensive sampling. Samples to be collected and processed at site only.
c The exact sampling time will be captured in relation to the time of last (10th) dose.


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
100/Protocol CV43043, Version 3
Appendix 3
Temperature
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.
Temperature:
Please take your temperature now. 
What is your temperature right now? (Measure before taking fever medication): 
_____ (Choose °C or °F)


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
101/Protocol CV43043, Version 3
Appendix 4
COVID-19 Symptom Diary
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.
Note that the following is a sample.  Sites will be provided with separate versions of the 
diary, reflecting appropriate recall periods.
COVID-19 Symptom Diary (Morning)
This diary will keep track of your COVID-19 symptoms and temperature during 
the study. Please complete this diary when you first wake up in the morning 
(before getting out of bed). Remember to take your temperature before you take 
any medicines to help your COVID-19 symptoms. 
Please rate the severity of each symptom at its worst since you went to bed last 
night.
None
0
Mild
1
Moderate
2
Severe
3
1. Nasal Congestion or runny nose
2. Sore Throat
3. Cough
4. Shortness of breath (difficulty 
breathing)
5. Muscle or body aches
6. Fatigue (tiredness)
7. Headache
8. Chills/Sweats 
9. Feeling hot or feverish
10. Nausea (wanting to throw up)
11. Vomiting (thrown up)
12. Diarrhea (mostly or completely 
liquid bowel movements)


Appendix 4:
COVID-19 Symptom Diary
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
102/Protocol CV43043, Version 3
Same as usual
0
Less than usual
1
No sense 
2
13. Rate your sense of 
smell since you went to 
bed last night.
14. Rate your sense of 
taste since you went to 
bed last night.


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
103/Protocol CV43043, Version 3
Appendix 5
Patient Global Impression of Severity
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.
Patient Global Impression of Severity (Bedtime)
Please rate your overall COVID-19 symptoms at their worst in the past 24 hours.
☐None
☐Mild
☐Moderate 
☐Severe 


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
104/Protocol CV43043, Version 3
Appendix 6
EuroQol 5-Dimension, 5-Level Questionnaire
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.


Appendix 6:
EuroQol 5-Dimension, 5-Level Questionnaire
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
105/Protocol CV43043, Version 3


Appendix 6:
EuroQol 5-Dimension, 5-Level Questionnaire
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
106/Protocol CV43043, Version 3


RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
107/Protocol CV43043, Version 3
Appendix 7
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 including the planned Phase 3 clinical trial. 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 


Appendix 7:Update on AT-527 Reproductive Toxicity and Non-Clinical In Vitro Drug-Drug 
Interaction Data
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
108/Protocol CV43043, Version 3
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. 
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.


Appendix 7:Update on AT-527 Reproductive Toxicity and Non-Clinical In Vitro Drug-Drug 
Interaction Data
RO7496998 (AT-527)—F. Hoffmann-La Roche Ltd and Atea Pharmaceuticals, Inc.
109/Protocol CV43043, Version 3
IN VITRO 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 AT-511 is not 
CYP450 dependent, and several 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.

SAP_001.pdf: 
 
Official Title:  A Multicenter, Phase III Randomized, Double-Blind, Placebo-
Controlled, Outpatient Study to Evaluate the Efficacy, Safety, Antiviral 
Activity of RO7496998 (AT-527) in Patients With Mild or Moderate 
COVID-19 
NCT Number: 
NCT04889040 
Document Date: 
SAP Version 1: 22-June-2021  
 
 
 




AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
2
STATISTICAL ANALYSIS PLAN VERSION HISTORY
This SAP was developed based on Roche SAP model document Version 2, 
26 October 2020.
SAP Version
Approval Date
Based on Protocol 
(Version, Approval Date)
1
see electronic date stamp 
on title page
Version 3, 2 June 2021


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
3
TABLE OF CONTENTS
1.
INTRODUCTION .......................................................................................... 9
1.1
Objectives, Endpoints, and Estimands .................................... 9
1.2
Study Design ......................................................................... 18
1.2.1
Treatment Assignment and Blinding...................................... 19
1.2.2
Sponsor Review and Adjudication......................................... 20
1.2.3
Data Monitoring ..................................................................... 20
2.
STATISTICAL HYPOTHESES.................................................................... 20
2.1
Primary Endpoint................................................................... 20
2.2
Multiplicity Adjustment ........................................................... 21
3.
SAMPLE SIZE DETERMINATION.............................................................. 22
4.
ANALYSIS SETS ........................................................................................ 23
5.
STATISTICAL ANALYSES ......................................................................... 23
5.1
General Consideration........................................................... 24
5.1.1
COVID-19 Symptom Diary..................................................... 26
5.2
Participant Disposition ........................................................... 27
5.3
Primary Endpoint(s) Analysis................................................. 27
5.3.1
Definition of Primary Endpoint ............................................... 28
5.3.2
Main Analytical Approach for Primary Endpoint(s) ................ 29
5.3.3
Sensitivity Analyses for Primary Endpoint(s) ......................... 30
5.3.4
Supplementary Analyses for Primary Endpoint(s) ................. 30
5.3.4.1
Subgroup Analyses for Primary Endpoint(s).......................... 30
5.3.4.2
Supplementary Analyses for Primary Endpoint(s) ................. 31
5.4
Secondary Endpoint(s) Analysis(ses).................................... 31
5.4.1
Key/Confirmatory Secondary Endpoint(s).............................. 31
5.4.1.1
Proportion of Patients with 1 COVID-19-Related 
Medically Attended Visit......................................................... 31
5.4.1.2
Time to Alleviation of Symptoms Maintained for a 
Duration of 21.5 Hours........................................................... 31
5.4.1.3
Frequency (Proportion) of Medically Confirmed 
COVID-19-Related Complications......................................... 32


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
4
5.4.1.4
Time to One-Category Improvement of Baseline 
Presenting Symptoms Maintained for 21.5 Hours ................. 32
5.4.1.5
Time to Cessation of SARS-CoV-2 Viral 
Shedding as Measured by RT-qPCR .................................... 33
5.4.1.6
Proportion of Patients with All-Cause Mortality...................... 33
5.4.2
Supportive Secondary Efficacy Endpoint(s)........................... 33
5.4.2.1
Time to Alleviation or Improvement of COVID-19 
Symptoms (Items 112 of the COVID-19 
Symptom Diary) Maintained for a Duration of 
43 Hours................................................................................ 33
5.4.2.2
Time to alleviation of individual symptoms 
maintained for a duration of 21.5 hours ................................. 34
5.4.2.3
Time to Alleviation of Symptoms Maintained for a 
Duration of 43 Hours ............................................................. 35
5.4.2.4
Proportion of Patients Requiring Hospitalization 
for COVID-19......................................................................... 35
5.4.2.5
Time to Return to Afebrile State Maintained for at 
least 21.5 Hours (Duration of Fever) ..................................... 35
5.4.2.6
Proportion of Patients with Any Post-Treatment 
Infection................................................................................. 36
5.4.3
Supportive Secondary Virology Endpoints............................. 36
5.4.3.1
Change from Baseline in Amount of SARS-CoV-
2 Virus RNA as Measured by RT-qPCR at Each 
Timepoint............................................................................... 36
5.4.3.2
Proportion of Patients Positive for SARS-Cov-2 
Virus RNA by RT-qPCR at Specified Timepoints .................. 36
5.4.3.3
Area Under the Concentration Curve (AUC) in 
the Amount of SARS-CoV-2 Virus RNA as 
Measured by RT-qPCR ......................................................... 36
5.4.4
Supportive Secondary Safety Endpoints ............................... 36
5.4.4.1
Incidence of Adverse Events ................................................. 36
5.4.4.2
Severity of Adverse Events.................................................... 36
5.4.4.3
Change from Baseline in Vital Signs ..................................... 36
5.4.4.4
Change from Baseline in Targeted Laboratory 
Results................................................................................... 37
5.4.5
Supportive Secondary PK Endpoints..................................... 37
5.5
Exploratory Endpoint(s) Analysis........................................... 38
5.5.1
Exploratory Efficacy Endpoints.............................................. 38


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
5
5.5.2
Exploratory Virology Endpoints.............................................. 38
5.5.3
Exploratory Patient Reported Outcome and 
Health Utility Endpoints.......................................................... 38
5.6
Other Safety Analyses........................................................... 39
5.6.1
Extent of Exposure ................................................................ 39
5.6.2
Adverse Events ..................................................................... 39
5.6.3
Laboratory Data..................................................................... 39
5.6.4
Vital Signs.............................................................................. 40
5.6.5
Medical History...................................................................... 40
5.6.6
Previous and Concomitant Medications................................. 40
5.7
Other Analyses...................................................................... 40
5.7.1
Summaries of Conduct of Study............................................ 40
5.7.2
Summaries of Treatment Group Comparability ..................... 41
5.7.2.1
Demographics and Baseline Characteristics ......................... 41
5.7.2.2
Baseline Disease Characteristics .......................................... 41
5.7.3
Pharmacokinetic Analyses..................................................... 41
5.8
Interim Analyses .................................................................... 42
5.8.1
Planned Interim Analyses...................................................... 42
5.8.2
Optional Interim Analyses...................................................... 42
6.
SUPPORTING DOCUMENTATION............................................................ 43
7.
REFERENCES ........................................................................................... 48
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints..................................... 9
Table 2
Estimands ................................................................................... 12
Table 3
Vital Signs (including SpO2) Time Windows............................... 37
Table 4
Laboratory Time Windows .......................................................... 37
Table 5
Pre-specified Treatment-Emergent Abnormal Laboratory 
Criteria ........................................................................................ 40
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 19
Figure 2
Multiple Testing Procedure for Endpoints ................................... 22


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
6
LIST OF APPENDICES
Appendix 1
Changes To Protocol-Planned Analyses .................................... 44
Appendix 2
COVID-19 Symptom Diary.......................................................... 45
Appendix 3
Patient Global Impression of Severity......................................... 47


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or Term
Description
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
CL/F
apparent clearance
Vss/F
apparent steady-state volume of distribution
AUC
area under the concentration curve
AST
aspartate aminotransferase
BLQ
below the limit of quantification 
COVID-19
coronavirus disease 2019
Ct
cycle threshold
eCRF
electronic Case Report Form
EQ-5D-5L
EuroQol 5-Dimension 5-Level
HR
hazard ratio
iDMC
independent Data Monitoring Committee
iDMC
independent Data Monitoring Committee
IxRS
interactive voice or web-based response system
IxRS
interactive voice/web-based response system
iSAP
interim Statistical Analysis Plan
ICH
International Council on Harmonization
IMP
investigational medicinal product
LSM
least squares mean
LOQ
limit of quantification
LLoQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NLME
Nonlinear mixed effects
PGIS
Patient Global Impression of Severity
PRO
patient-reported outcomes
SpO2
peripheral capillary oxygen saturation
PK
Pharmacokinetic
ROW
rest of the world
RT-PCR
reverse transcriptase polymerase chain reaction
RT-qPCR
reverse-transcriptase quantitative polymerase chain reaction
SAE
serious adverse event
SARS-COV-2
severe acute respiratory syndrome coronavirus-2
SE
standard error
SAP
Statistical Analysis Plan


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
8
TTAIS
time to alleviation or improvement of signs and symptoms
VAS
Visual Analog Scale
WBC
white blood cells


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
9
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for the efficacy, safety, antiviral activity, and pharmacokinetic (PK) 
data for Study CV43043 (MORNINGSKY). Table, listing, and figure specifications are 
contained within a separate document.
This SAP will be updated or a separate interim SAP (iSAP) will be written if an interim 
analysis for efficacy and/or virology is carried out. 
1.1
OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Table 1
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoint
To evaluate the efficacy 
of RO7496998 (AT-527)
compared with placebo
The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 Symptom Diary) maintained for a 
duration of 21.5 hours, defined as follows:
For new symptoms:  time from randomization to the alleviation 
of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on 
the COVID-19 Symptom Diary) 
For preexisting symptoms:  time from randomization to when a 
patient’s symptoms have been maintained or improved (Note:  
Improved requires at least a single category improvement from 
baseline on the COVID-19 Symptom Diary Likert scale.)
Secondary Objectives
Corresponding Endpoints
To evaluate the efficacy 
of RO7496998 (AT-527)
compared with placebo
The time to alleviation or improvement of COVID-19 symptoms 
(Items 112 of the COVID-19 Symptom Diary) maintained for a 
duration of 43 hours, defined as follows:
For new symptoms:  time from randomization to the alleviation 
of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on 
the COVID-19 Symptom Diary) 
For preexisting symptoms:  time from randomization to when a 
patient’s symptoms have been maintained or improved (Note:  
Improved requires at least a single category improvement from 
baseline on the COVID-19 Symptom Diary Likert scale.)
Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion is 
met and maintained for at least 21.5 hours: 
Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary
Time to alleviation of COVID-19 symptoms defined as the time 
from randomization to the point at which the following criterion is 
met and maintained for at least 43 hours: 
Score of 0 or 1 for Items 112 of the COVID-19 Symptom Diary
Time to one-category improvement of baseline presenting 
COVID-19 symptoms (Items 1-12 of the COVID-19 Symptom 
Diary) maintained for a duration of 21.5 hours defined as time 
from randomization to when the symptoms have improved by at 
least one category from baseline on the COVID-19 Symptom 
Diary Likert scale


AT-527—F. Hoffmann-La Roche Ltd. and Atea Pharmaceuticals, Inc.
Statistical Analysis Plan CV43043
10
Table 1
Objectives and Corresponding Endpoints (cont.)
Secondary Objectives
Corresponding Endpoints
To evaluate the efficacy 
of RO7496998 (AT-527)
compared with placebo
(cont.)
Time to alleviation of individual symptoms, defined as the time 
from randomization to the point at which the following criterion is
met and maintained (for each individual symptom) for at least 
21.5 hours:
Score of 0 or 1 for Items 114 of the COVID-19 Symptom Diary
Proportion of patients requiring hospitalization for COVID-19
Proportion of patients with 1 COVID-19 related medically 
attended visit through to study end (defined as hospitalization, 
emergency room [ER] visit, urgent care visit, physician’s office 
visit, or telemedicine visit, with the primary reason for the visit 
being COVID-19)
Duration of fever (time to return to afebrile state [temperature 
37.5C] and remaining so for at least 21.5 hours) (see
Protocol Section 6.4.1)
Frequency of COVID-19 related complications (e.g., death, 
hospitalization, radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, 
cardiac failure)
Proportion of patients with any post-treatment infection
Proportion of patients with all-cause mortality
To evaluate the antiviral 
activity of RO7496998
(AT-527) compared with 
placebo
Change from baseline in amount of SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by RT-qPCR
Proportion of patients positive for SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at specified timepoints
AUC in the amount of SARS-CoV-2 virus RNA, as measured by 
RT-qPCR
To evaluate the safety of 
RO7496998 (AT-527)
compared with placebo
Incidence and severity of adverse events, with severity 
determined according to NCI CTCAE v5.0
Incidence of serious adverse events
Change from baseline in vital signs, including SpO2
Change from baseline in targeted clinical laboratory test results
To characterize the PK 
profile of AT-511 and 
major metabolites in 
plasma
Plasma concentration of AT-511 (the free base form of 
RO7496998 [AT-527]), AT-551, AT-229, and AT-273 (a surrogate 
for the intracellular concentration of the active triphosphate 
metabolite AT-9010) at specified timepoints
Exploratory Objectives
Corresponding Endpoints
To evaluate the antiviral 
activity of RO7496998
(AT-527) compared with 
placebo
Treatment-emergent amino acid substitutions in SARS-CoV-2 
viral genes (nsp12 and potentially other genes)
Anti-SARS-CoV-2 antibody status/titer at specified timepoints
Change from baseline in amount of SARS-CoV-2 virus titer at 
each timepoint
Time to cessation of SARS-CoV-2 viral shedding, as measured 
by virus titer


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Table 1
Objectives and Corresponding Endpoints (cont.)
Exploratory Objectives
Corresponding Endpoints
To evaluate the antiviral 
activity of RO7496998
(AT-527) compared with 
placebo (contd.)
Proportion of patients with positive SARS-CoV-2 virus titer at 
specified timepoints
AUC of SARS-CoV-2 virus titer
Drug susceptibility in patients with evaluable virus at specified 
timepoints
To identify and/or 
evaluate biomarkers that 
are predictive of 
response to RO7496998
(AT-527) (i.e., predictive 
biomarkers), are early 
surrogates of efficacy, 
are associated with 
progression to a more 
severe disease state 
(i.e., prognostic 
biomarkers), can provide 
evidence of RO7496998
(AT-527) activity 
(i.e., pharmacodynamic 
biomarkers), or can 
increase the knowledge 
and understanding of 
disease biology and drug 
safety
Relationship between biomarkers in blood, nasopharyngeal
swab, Nasosorption, and saliva samples (listed in Protocol 
Section 4.5.5) and efficacy, safety, PK, or other biomarker 
endpoints
To evaluate health status 
utility, and PGIS scores 
of patients treated with 
RO7496998 (AT-527) as 
compared with placebo
Patient’s global impression of severity of COVID-19 symptoms as 
assessed through the use of PGIS at Day 14 and Day 29
Change from baseline in EQ-5D-5L health utility index-based and 
VAS scores at specified timepoints
To support content 
validity of COVID-19 
Symptom Diary
Optional exit interviews at Day 33 (or within 14 days) in a subset 
of study patients to gather qualitative data to support content 
validity and inform interpretation of COVID-19 Symptom Diary 
scores observed during the study
AUCarea under the concentrationtime curve; COVID-19coronavirus disease 2019; EQ-5D-
5LEuroQol 5-Dimension, 5-Level Questionnaire; NCI CTCAE v5.0National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 5.0; PKpharmacokinetic; 
PGISPatient Global Impression of Severity; RT-qPCRreverse-transcriptase quantitative 
polymerase chain reaction; SARS-CoVsevere acute respiratory syndrome coronavirus; 
SpO2peripheral capillary oxygen saturation; VASVisual Analog Scale.


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Table 2
Estimands
Endpoint
Variable or Outcome 
Measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/ 
Concomitant 
Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Primary: TTAIS for 21.5 
hours
Time from randomization to 
alleviation or improvement of 
COVID-19 symptoms maintained 
for a duration of 21.5 hours, right 
censored at day 29 if the patient 
doesn't meet criteria
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy.
Hypothetical approach 
where patient censored 
at Day 29 if intercurrent 
event prior to achieving 
the endpoint
Hazard ratio
Patient 
censored at 
Day 29 if study 
withdrawal is 
prior to 
achieving the 
endpoint
Secondary: TTAIS for 
43 hours
Time from randomization to 
alleviation or improvement of 
COVID-19 symptoms maintained 
for a duration of 43 hours, right 
censored at day 29 if the patient 
doesn't meet criteria
Key Secondary: Time 
to alleviation of 
symptoms (TTAS) for 
21.5 hours
Time from randomization to 
alleviation of COVID-19 
symptoms maintained for a 
duration of 21.5 hours, right 
censored at day 29 if the patient 
doesn't meet criteria
Secondary: TTAS for 
43 hours
Time from randomization to 
alleviation of COVID-19 
symptoms maintained for a 
duration of 43 hours, right 
censored at day 29 if the patient 
doesn't meet criteria


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Table 2
Estimands (cont.)
Endpoint
Variable or Outcome 
Measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/ 
Concomitant 
Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Key Secondary: Time 
to one-category 
improvement of 
symptoms
Time from randomization to one-
category improvement of baseline 
presenting COVID-19 symptoms 
maintained for a duration of 21.5 
hours, right censored at day 29 if 
the patient doesn't meet criteria
Treatment-policy 
strategy approach 
will be taken.  
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of
rescue and 
concomitant 
therapy (contd.)
Hypothetical approach 
where patient censored 
at Day 29 if intercurrent 
event prior to achieving 
the endpoint (contd.)
Hazard ratio
(contd.)
Patient 
censored at 
Day 29 if study 
withdrawal is 
prior to 
achieving the 
endpoint
(contd.)
Secondary: Time to 
alleviation of individual 
symptoms
Time from randomization to 
alleviation an individual COVID-19 
symptoms maintained for a 
duration of 21.5 hours, right 
censored at day 29 if the patient 
doesn't meet criteria
Secondary: Time to 
return to afebrile state 
[temperature 37.5C]
Time from randomization to return 
to afebrile state 
[temperature 37.5C] 
maintained for a duration of 21.5 
hours for a patient with fever at 
baseline, right censored at day 29 
if the patient doesn't meet criteria
Secondary: Proportion 
of patients requiring 
hospitalization for 
COVID-19
Patients requiring hospitalization 
for COVID-19 through to study 
end (including early termination 
visits)
Composite strategy 
where patient 
considered as having 
the event if they die
Difference in 
proportion of 
patients 
between 
treatments
The outcome 
measure up to 
point of study 
withdrawal will 
be used


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Table 2
Estimands (cont.)
Endpoint
Variable or Outcome 
measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/ 
Concomitant 
Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Key Secondary: 
Proportion of patients 
with 1 COVID-19 
related medically 
attended visit
Patients with 1 COVID-19 
related medically attended visit 
through to study end (including 
early termination visits)
Treatment-policy 
strategy approach 
will be taken. 
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of
rescue and 
concomitant 
therapy (contd.)
Composite strategy 
where patient 
considered as having 
the event if they die
(contd.)
Difference in 
proportion of 
patients 
between 
treatments
(contd.)
The outcome 
measure up to 
point of study 
withdrawal will 
be used
(contd.)
Secondary: Proportion 
of patients with any 
post treatment infection
Patients with any post treatment 
infection through to study end 
(including early termination visits)
Key Secondary: 
Frequency (Proportion) 
of COVID-19 related 
complications 
(including 
hospitalizations and 
deaths) 
Patients with a medically 
confirmed COVID-19 related 
complication through to study end 
(including early termination visits)
Not an intercurrent 
event as it is the 
outcome measure
Key Secondary: 
Proportion of patients 
with all-cause mortality
Patients with all-cause mortality 
through to study end (including 
early termination visits)


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Table 2
Estimands (cont.)
Endpoint
Variable or Outcome 
Measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/ 
Concomitant 
Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Secondary (Virology): 
Change from baseline 
in amount of SARS-
CoV-2 virus RNA
Amount of SARS-CoV-2 virus 
RNA, as measured by RT-qPCR 
at Day 3, Day 5, Day 7 and Day 
14 
Treatment-policy 
strategy approach 
will be taken. 
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy.
While on treatment 
approach where the 
outcome measure up 
to point of intercurrent 
event will be used
Difference in 
mean change 
from baseline
between 
treatments
The outcome 
measure up to 
point of study 
withdrawal will 
be used
Secondary (Virology): 
AUC in amount of 
SARS-CoV-2 virus 
RNA
Amount of SARS-CoV-2 virus 
RNA, as measured by RT-qPCR 
to Day 14
AUC for each 
treatment
Key Secondary 
(Virology): Time to 
cessation of SARS-
CoV-2 viral shedding, 
as measured by RT-
qPCR
Time from randomization to 
cessation of SARS-CoV-2 viral 
shedding, right censored at Day 
14 if the patient doesn't meet 
criteria
Hypothetical approach 
where patient censored 
at Day 14 if the patient 
doesn't meet criteria if 
intercurrent event prior 
to achieving the 
endpoint
Hazard ratio
Patient 
censored at 
Day 14 if the 
patient doesn't 
meet criteria if 
study 
withdrawal is 
prior to 
achieving the 
endpoint
Secondary (Virology): 
Proportion of patients 
positive for SARS-Cov-
2 virus RNA
Patients who are positive for 
SARS-CoV-2 virus RNA, as 
measured by RT-qPCR at Day 3, 
Day 5, Day 7 and Day 14 
While on treatment 
approach where the 
outcome measure up 
to point of intercurrent 
event will be used
Difference in 
proportion of 
patients 
between 
treatments
The outcome 
measure up to 
point of study 
withdrawal will 
be used


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Table 2
Estimands (cont.)
Endpoint
Variable or Outcome 
Measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/ 
Concomitant 
Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Secondary (Safety): 
Incidence of adverse 
events
Patients with an adverse event
Treatment-policy 
strategy approach 
will be taken. 
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of 
rescue and 
concomitant 
therapy.
Not an intercurrent 
event as it is the 
outcome measure
Proportion of 
patients for 
each 
treatment
The outcome 
measure up to 
point of study 
withdrawal will 
be used
(contd.)
Secondary (Safety): 
Severity of adverse 
events
Severity of adverse events 
determined according to 
NCI CTCAE v5.0
Proportion of 
patients for 
each 
treatment for 
each severity 
grade
Secondary (Safety): 
Incidence of serious 
adverse events
Patients with a serious adverse 
event
Proportion of 
patients for 
each 
treatment
Secondary (Safety): 
Change from baseline 
in vital signs
Vital signs, including SpO2
While on treatment 
approach where the 
outcome measure up 
to point of intercurrent 
event will be used
Means for 
each 
treatment
Secondary (Safety): 
Change from baseline 
in targeted laboratory 
results
Targeted laboratory results


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Table 2
Estimands (cont.)
Endpoint
Variable or Outcome 
Measurement
Intercurrent Events
Population-
Level 
Summary for 
the Variable
Handling of 
Missing Data
Treatment 
Withdrawal/ 
Rescue/Concomita
nt Medications
Death
Study 
Withdrawal/ 
Lost to 
Follow-Up
Secondary (PK): 
Plasma concentration 
of AT-511, AT-551, 
AT-229, and AT-273 
Plasma concentration of AT-511, 
AT-551, AT-229, and AT-273 
Treatment-policy 
strategy approach 
will be taken. 
Patients are 
followed, assessed 
and analyzed 
irrespective of their 
completion of the 
planned course of 
the study treatment 
and irrespective of
rescue and 
concomitant therapy 
(contd.)
While on treatment 
approach where the 
outcome measure up 
to point of intercurrent 
event will be used
(contd.)
Means for 
each 
treatment
(contd.)
The outcome 
measure up to 
point of study 
withdrawal will 
be used
(contd.)
AUCarea under the concentrationtime curve; COVID-19coronavirus disease 2019; NCI CTCAENational Cancer Institute Common 
Terminology Criteria for Adverse Event; PKpharmacokinetic; RT-qPCRreverse-transcriptase quantitative polymerase chain reaction ;
SARS-CoV-2severe acute respiratory syndrome-corona virus-2; SpO2peripheral capillary oxygen saturation TTAStime to alleviation of 
symptoms TTAIStime to alleviation or improvement of symptoms.
Target Population: Adult and adolescent patients with mild or moderate COVID-19 defined through inclusion/exclusion criteria.
Treatment: Primary treatment effect comparison will be between the RO7496998 (AT-527) arm and the placebo arm regardless of other therapies.


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1.2
STUDY DESIGN
This is a Phase III, placebo-controlled, double-blind, multicenter study to assess the 
efficacy, safety, antiviral activity, and pharmacokinetics of RO7496998 (AT-527) 
compared with placebo in non-hospitalized adult and adolescent patients with mild to 
moderate coronavirus disease 2019 (COVID-19) in the outpatient setting.
The study will enroll approximately 1386 patients (including approximately 
100 adolescents, up to a maximum of 150, with the remaining patients being adults) with 
confirmed severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection.
The study consists of two periods:  a 5-day treatment period and a 28-day safety and 
efficacy follow-up period, with mandatory study visits on Days 1, 2, 3, 5, 7, and 14.  
Some of these visits may be conducted by mobile nursing or telemedicine.  In addition to 
mandatory study visits, there will be telephone calls on Day 21 (2 days) and Day 28 
(2 days).  The end of study visit will take place on Day 33 (3 days), preferentially as a 
telephone consult but may by conducted in-person in some instances, such as if the 
patient is enrolling in a longer-term follow-up RO7496998 (AT-527) study.  The total 
study duration for each patient will be approximately 33 days.
The primary analysis will be performed once the data from the last patient’s last visit has 
been collected in the database and all data has been cleaned and verified.
The study schema is shown in Figure 1.




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treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Protocol Section 5.7) that are considered by the investigator or Sponsor to be 
related to an investigational medicinal product (IMP; defined in Protocol Section 4.3).
1.2.2
Sponsor Review and Adjudication
Sponsor representatives from clinical science who are independent of the study team 
will review data from the study for the purposes of adjudicating adverse events (AEs)
identified by the investigator as COVID-19-related complications. This adjudication will 
determine medically confirmed COVID-19-related complications, which will be used for 
the frequency of COVID-19-related complications endpoint.  These complications and 
the role and process of Sponsor review and adjudication will be specified in a separate 
charter.
1.2.3
Data Monitoring
An external independent Data Monitoring Committee (iDMC) will evaluate safety 
according to policies and procedures detailed in the iDMC charter.
If an interim analysis is conducted for efficacy, the Sponsor will remain blinded.  The 
interim analysis will be conducted by an external statistical group and reviewed by the 
iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified in 
the iDMC charter.
2.
STATISTICAL HYPOTHESES
2.1
PRIMARY ENDPOINT
The primary efficacy analysis for this study will evaluate the time to alleviation or 
improvement of COVID-19 symptoms maintained for a duration of 21.5 hours of 
RO7496998 (AT-527) compared with placebo to demonstrate superiority of RO7496998 
(AT-527) over placebo.
Let ℎ	
() be the hazard function for RO7496998 (AT-527) and ℎ() be the 
hazard function for placebo, then the statistical hypothesis tested at a two-
sided 0.025 significance level is:
Null hypothesis: The hazard functions for the time to alleviation or improvement of 
COVID-19 symptoms maintained for a duration of 21.5 hours are the same for 
RO7496998 (AT-527) arm and placebo arm:
:ℎ	
() = ℎ()


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Alternative hypothesis: The hazard functions for the time to alleviation or 
improvement of COVID-19 symptoms maintained for a duration of 21.5 hours are not the 
same for RO7496998 (AT-527) arm and placebo arm:
: ℎ	
() ≠ℎ()
2.2
MULTIPLICITY ADJUSTMENT
The primary and key secondary endpoints (Figure 2) will be evaluated in a hierarchical 
manner with multiplicity control via multistage gatekeeping under the truncated Holm 
multiple testing procedure (Dmitrienko et al. 2008).  In Families 1 and 2 of key secondary 
endpoints, the same truncation parameter value of 0.7 will be applied; no truncation is 
applied in Family 3, since it is prioritized lowest in the hierarchy and imposes no 
gatekeeping restrictions on subsequent families.  The truncation parameter and the 
relative effect sizes of the endpoints influence how power is balanced over the 
secondary endpoint families.  Truncation parameter values close to 1 should generally 
be chosen when the effect sizes in high-priority endpoints are relatively large in order to 
maximize overall power.  In other settings where the effect sizes might be smaller or 
mixed, a truncation parameter value closer to 0 could improve overall power.  A 
parameter value strictly less than 1 in testing families that impose parallel gatekeeping 
(i.e., at least one endpoint is considered statistically significant after multiplicity 
adjustment in order to test the next family) is needed to achieve strong overall type I 
error control (Dmitrienko et al. 2009).
Under this multistage gatekeeping approach, multiplicity-adjusted p-values will reflect the 
gatekeeping restrictions depicted in Figure 2.  In particular, the adjusted p-values for all 
key secondary endpoints in Families 1, 2, and 3 will be no smaller than the p-value for 
the primary endpoint.  Similarly, the smallest adjusted p-value in Family 2 (3) will be no 
smaller than the smallest adjusted p-value in Family 1 (2).  Endpoints for which the 
multiplicity-adjusted p-value is greater than 0.025 will not be considered statistically 
significant.  These endpoints and all endpoints not under multiplicity control will be 
considered to provide supportive information.  By repeated application of Proposition 4.1 
of Dmitrienko et al. (2008), this testing strategy ensures that the overall type I error is no 
greater than 2.5%.


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Figure 2
Multiple Testing Procedure for Endpoints
COVID-19coronavirus disease 2019; RT-qPCRreverse-transcriptase quantitative polymerase 
chain reaction; SARS-CoV-2severe acute respiratory syndrome coronavirus-2.
3.
SAMPLE SIZE DETERMINATION
The required sample size of the efficacy-evaluable set is 1248 patients.  It is assumed 
that the reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR)
positive rate for SARS-CoV-2 will be 90%.  Therefore, approximately 1386 patients will 
be randomized to ensure an adequate number of patients in the efficacy-evaluable set.  
The total number of randomized patients may change based on the percentage of 
patients who are RT-qPCR positive during the study.
Rationale for the Target Sample Size
The required sample size has been calculated to ensure at least 90% power to detect a 
hazard ratio of 1.25 in the TTAIS of COVID-19 between the RO7496998 (AT-527) group 
and the placebo group. This corresponds to a 2-day improvement in the median TTAIS, 
assuming a median in the placebo group of 10 days (Regeneron 2020).  Patients will be 
randomized to a 2:1 ratio to RO7496998 (AT-527) or placebo, respectively, and the fixed 
follow-up period will be 29 days.  The study will require 1248 patients in the efficacy-
evaluable set based on an expected 90% event rate (1122 events required) in order for 
the log-rank test to have at least 90% power with a two-sided significance level of 0.025, 
under the assumption of an exponential distribution.  Additional patients may be enrolled 


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in order to observe 1122 events, where an event is meeting the primary endpoint.  The
minimal detectable difference is a hazard ratio of approximately 1.15, which equates to a 
difference in medians of approximately 1.33 days under the assumption of a 10-day 
placebo response.
4.
ANALYSIS SETS
The following analysis sets are defined:
Analysis Set
Definition
Efficacy-evaluable
All randomized patients who received at least one dose of study 
treatment and were centrally assessed as reverse transcriptase 
quantitative polymerase chain reaction (RT-qPCR) positive for 
SARS-CoV-2 (by nasopharyngeal swab) at any point during the 
study, with patients grouped according to randomized treatment.
All patients
All randomized patients, with patients grouped according to 
randomized treatment.
Safety-evaluable
All randomized patients who received at least one dose of study 
treatment, with patients grouped to placebo if all doses received 
were placebo and to AT-527 if at least one dose of AT-527 was 
received.
PK-evaluable
All randomized patients who received at least one dose of study 
treatment and have sufficient data to enable estimation of key 
parameters (e.g., maximum concentration [Cmax] and minimum 
concentration [Cmin]), with patients grouped according to 
treatment received.
PKpharmacokinetic; RT-qPCRreverse transcriptase quantitative polymerase chain 
reaction; SARS-CoV-2severe acute respiratory syndrome coronavirus-2.
The efficacy-evaluable set will be used for the primary efficacy analysis. In addition 
to having been randomized, patients are also required to have received at least one 
dose of study treatment, so that patients who drop out of the study after 
randomization but prior to first dose of study treatment will not be included in the 
analysis.  As this is a double-blind study, patients will not know their randomized 
treatment therefore this cannot influence their decision to take study treatment.  
Additionally, patients are also required to be centrally assessed as RT-qPCR 
positive for SARS-CoV-2 (by nasopharyngeal swab) at any point during the study.  
This cannot be required prior to randomization as this would extend the time 
between first symptom onset and first dose of study treatment.
In addition, data will be listed for patients who do not receive the treatment they are 
assigned to at any timepoint.
5.
STATISTICAL ANALYSES
Estimands for the primary and secondary endpoints are presented in Table 2.


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5.1
GENERAL CONSIDERATION
All statistical tests will be performed at a 0.025 significance level using two-sided tests, 
unless otherwise noted.  As specified in Section 2.2, key secondary endpoints for which 
the multiplicity-adjusted p-value is greater than 0.025 will not be considered statistically 
significant. These endpoints and all endpoints not under multiplicity control will be 
considered to provide supportive information.
Statistical tests will use stratification factors according to IxRS unless there is 
considerable imbalance in IxRS and electronic Case Report Form (eCRF) stratum 
classification. Stratification factors may need to be removed or have their levels 
combined so that low or zero counts in one stratum do not invalidate relevant statistical 
tests.
Unless otherwise specified, continuous variables will be summarized by using the 
number of non-missing observations, arithmetic mean, standard deviation (SD), median, 
minimum, and maximum values as summary statistics; categorical variables will be 
summarized by using the frequency count and the percentage of subjects in each 
category as summary statistics. Descriptive summaries will be tabulated by treatment 
group.
All efficacy and virology analyses will be performed on the efficacy-evaluable set, all 
patient disposition and study conduct analyses will be performed on the All Patients set, 
and all safety analyses will be performed on the safety-evaluable set, unless otherwise 
specified.
Missing data due to study withdrawal or lost to follow up will be handed as described in 
Table 2. Any other missing data will not be imputed unless otherwise specified in the 
specific section describing an endpoint.
Time to event secondary efficacy and virology endpoints will use the same statistical 
methods as used for the primary endpoint as described in Section 5.3.2, and will be 
measured in days unless otherwise stated.
For time to event efficacy endpoints, once the first instance of the criteria has been met 
at an assessment, assessments with endpoint data present prior to the assessment that 
demonstrates the criteria is maintained for the required duration (either ≥21.5 hours or 
≥43 hours as appropriate), must also meet the criteria to meet the endpoint i.e.,
subsequent assessments after a patient first meets the criteria but prior to the 
assessment showing maintenance of that criteria for 21.5 hours (or 43 hours if
appropriate) must also meet the criteria if there is non-missing data at these 
assessments.
In addition, for time to event efficacy endpoints, once the endpoint has been met, 
subsequent data for a patient that does not meet the efficacy criteria will not result in a 


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null endpoint.  Due to this, these endpoints can also be thought of as the time to first 
instance of a maintained defined criteria (such as alleviation) where maintained here 
refers to the required duration.  
Secondary efficacy and virology endpoints that evaluate proportion of patients will be 
analyzed using a Cochran-Mantel-Haenszel test adjusted by the stratification factors for 
region (North America, Europe, ROW) and high-risk factor (yes, no), unless stated 
otherwise.  The proportion in each treatment arm together with the difference in 
proportions, odds ratio and accompanying 97.5% CIs will be presented along with the 
p-value.
Continuous secondary virology endpoints, such as change from baseline endpoints, will 
be analyzed using an analysis of covariance (ANCOVA) model with region (North 
America, Europe, and ROW), high-risk factor (yes, no) as stratification variables, and the 
baseline value of the studied measure as a covariate.  The least squares mean (LSM) 
change and its standard error (SE) of means in each group, the difference between two 
groups in least squares mean (LSM change), SE, and 97.5% CI, and p-values will be 
presented.  Additionally, descriptive summaries for the change from baseline will also be 
presented by treatment group.
Area under the concentration curve (AUC) for secondary and exploratory endpoints will 
be analyzed using the van Elteren test where AUC is calculated using the trapezoidal 
method. AUC of change from time 0 () to time K () is given by the formula:
 ( + )( −)
2


,
where  (hours) represents the date of the  !" virus RNA (reverse-transcriptase polymerase 
chain reaction [RT-PCR]) assessment ( = 0, . . . , %) and  represents the log10 value of the  !"
virus RNA (RT-PCR) assessment. 24-hours of time will be converted into one day.
Descriptive summary statistics of the AUC will be presented for each treatment group 
along with the p-value from the van Elteren test.
All secondary virology endpoints will be evaluated on the nasopharyngeal swab 
samples.  Additional descriptive analyses for saliva and serum samples will be 
performed on an exploratory basis for the secondary virology endpoints, as required.
The qualitative result of the SARS-CoV-2 reverse-transcriptase polymerase chain 
reaction (RT-PCR) test is determined using cycle threshold (Ct) values.  If the qualitative 
result is positive, then an associated quantitative result is also provided. The 
quantitative result is either numerical or below the limit of quantification (BLQ). The limit 
of quantification (LOQ) for the virus RNA is 120 copies/ml. If the virus RNA sample has a 


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positive qualitative result, but a quantitative result BLQ, virus RNA will be imputed as 
LOQ – 1 (119 copies/mL). Negative qualitative samples will be imputed as LOQ/2 (60 
copies/ml) before being transformed to the log10 scale.
Baseline is defined as the last available assessment prior to first dose of study 
treatment.  For efficacy analyses, if there is no such assessment available then baseline 
can be up to 4 hours post first dose, with the earliest assessment used as baseline in the 
case of multiple assessments within this time.
Secondary safety endpoints and other AE analyses will be assessed through descriptive 
summaries of treatment-emergent adverse events unless otherwise stated.  A treatment-
emergent adverse event is defined as any new adverse event reported or any worsening 
of an existing condition on or after the first dose of study treatment.  Data reported will 
include data from baseline up until the patient completes/discontinues from the study 
and including data from the early termination visit, if applicable. All verbatim adverse 
event terms will be mapped to Medical Dictionary for Regulatory Activities (MedDRA)
Preferred Terms, and adverse event severity will be graded according to the NCI 
CTCAE v5.0 scale.  Adverse events will be tabulated by system organ class (in 
decreasing order of overall incidence) and by MedDRA Preferred Term (in decreasing 
order of overall incidence), unless otherwise stated.
Data will be analyzed per the reported assessment; time windows will not be 
implemented unless otherwise specified.
5.1.1
COVID-19 Symptom Diary
Patients complete the COVID-19 Symptom Diary up to three times on Day 1, twice per 
day on Days 214 and once per day on Days 1529. Expectation for assessments is as 
follows:

Day 1, up to two of the following:
–
Prior to first dose assessment
–
Bedtime assessment

Days 214:
–
Morning assessment
–
Bedtime assessment

Days 1529:
–
Bedtime assessment
Data will be analyzed as it was captured per the expected assessments above; time 
windows will not be implemented.


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Missing data for individual symptoms at an assessment where data for other symptoms 
from the COVID-19 Symptom Diary are present will be set to the highest score on the 
Likert scale.
Missing data due to a missing assessment (i.e., all symptoms missing) where the 
assessment would be the first expected assessment to show efficacy criteria maintained 
for 21.5 hours (or 43 hours as appropriate) will be assumed to have met the efficacy 
criteria as long as the data at the next expected assessment following the missed 
assessment also has met the efficacy criteria.
5.2
PARTICIPANT DISPOSITION
Summaries of patient disposition, including the number and percentage of patients who 
are randomized, receive treatment, complete treatment, discontinue treatment, complete 
study, discontinue study, and the associated reasons for discontinuing treatment and
study will be created. Summaries of study duration (in days) defined as the date of the 
study completion/discontinuation minus the date of first study treatment plus one, and 
visit disposition will also be created.  Patient disposition summaries will be created using 
the efficacy-evaluable and the All Patients set, and will be tabulated by treatment group 
separately as well as combined.
5.3
PRIMARY ENDPOINT(S) ANALYSIS
The primary efficacy objective of this study is to evaluate the efficacy of RO7496998 
(AT-527) compared with placebo in adult and adolescent patients and will be assessed 
based on the following endpoint:

The time to alleviation or improvement of COVID-19 symptoms (Items 112 of the 
COVID-19 Symptom Diary) maintained for a duration of 21.5 hours (24 hours minus 
10%, to allow some flexibility in the timing of assessments), defined as follows:
–
For new symptoms:  time from randomization to the alleviation of COVID-19 
symptoms (i.e., a score of 0 [none] or 1 [mild] on the COVID-19 Symptom 
Diary) 
–
For pre-existing symptoms:  time from randomization to when a patient’s symptoms 
have been maintained or improved (note improved requires at least a single 
category improvement from baseline on the COVID-19 Symptom Diary Likert scale)
The primary efficacy endpoint definition includes both alleviation of new COVID-19 
symptoms and maintenance/improvement of pre-existing COVID-19 symptoms to allow 
for the possibility that some patients may have concurrent conditions with symptoms 
similar to those observed with COVID-19 (e.g., cough in a patient with chronic 
obstructive pulmonary disease).  At screening, patients will be assessed with a 14-item 
COVID-19 symptom severity assessment to identify pre-existing symptoms (within the 
prior 30 days), and assess if they worsened due to COVID-19.  Symptoms that are not 
pre-existing are considered to be new symptoms and need to achieve sustained 
alleviation (score of 0 or 1) to meet the endpoint.


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If a symptom is pre-existing, the patient is asked if the severity at screening is worse 
than what was experienced within the last 30 days prior to COVID-19:

If the severity is not worse, the symptom must be maintained (no worsening) or 
improved to meet the endpoint.

If the severity is worse, then a sustained improvement of at least one grade must be 
achieved to meet the endpoint.  For example, a symptom classed as severe at 
screening must improve to moderate, mild, or none, and a symptom classed as 
moderate at screening must improve to mild or none.
The hazard ratio for TTAIS for RO7496998 (AT-527) and placebo arms will be tested
using the stratified log-rank test with three regions (i.e., North America, Europe, and 
ROW) and high-risk factor (yes, no) included as the stratification factors.  Kaplan-Meier 
plots, median time to response, 97.5% CIs, and p-values will be presented.
The log-rank test is most powerful when the assumption of proportional hazards holds.  
The proportional hazards assumption will be tested graphically using the log-cumulative 
hazard plot by treatment group.  Should the proportional hazards assumption not hold, 
the Gehan-Wilcoxon test will be used to analyze the data.
The primary estimand is defined in Table 2.  The primary efficacy analysis population will 
be the efficacy-evaluable set, which consists of all patients who were randomized to 
treatment, received a dose of study treatment, and were RT-qPCR positive for 
SARS-CoV-2 at any point during the study.
5.3.1
Definition of Primary Endpoint
The time to alleviation or improvement of COVID-19 symptoms is defined as the time 
from randomization to the first time at which all COVID-19 symptoms from Items 1-12 of 
the COVID-19 Symptom Diary were either alleviated, maintained or improved for a 
minimum duration of 21.5 hours (24 hours minus 10%, to allow some flexibility in the 
timing of assessments). Alleviation, maintenance, or improvement of symptoms is 
defined as the time when all 12 COVID-19 symptoms from Items 1-12 of the COVID-19 
Symptom Diary have been assessed by the patient as follows:

For pre-existing symptoms (i.e., symptoms that existed prior to developing 
COVID-19) judged by the patient to be worse at screening: 
–
Improvement of at least one grade on the Likert scale from baseline if the 
severity at baseline is graded moderate or severe:

Severe to moderate, mild, or none

Moderate to mild or none

Mild to mild or none

None to mild or none


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Note:  At screening, patients will only be asked if preexisting symptoms existed (within 
the last 30 days) and if they were worsened by COVID-19. Patients will be asked to rate 
the severity at baseline that needs to improve. To avoid recall bias, patients will not be 
asked to rate the severity of preexisting symptoms prior to COVID-19.

For pre-existing symptoms (i.e., symptoms that existed prior to developing 
COVID-19) judged by the patient NOT to be worse at screening:
–
Maintained (no worsening) baseline severity if the severity at baseline is graded 
moderate or severe:

Severe to severe, moderate, mild, or none

Moderate to moderate, mild or none

Mild to mild or none

None to mild or none

For new symptoms (i.e., symptoms that develop due to COVID-19 which present 
prior to or post baseline): 
–
Alleviation of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on the 
COVID-19 Symptom Diary):

Severe to mild, or none

Moderate to mild, or none

Mild to mild or none

None to mild or none
Where the baseline assessment for COVID-19 symptom severity is missing, the 
COVID-19 symptoms for a patient will be treated as new symptoms and therefore must 
meet the alleviation criteria even if symptoms had been identified as existing prior to 
developing COVID-19.
The primary endpoint will be tested using a two-sided significance level of 0.025.
5.3.2
Main Analytical Approach for Primary Endpoint(s)
The hazard ratio (HR) for TTAIS for RO7496998 (AT-527) and placebo arms will be 
tested using the stratified log-rank test with the following stratification factors: Region 
(North America, Europe, and ROW) and high-risk factor (yes, no), unless otherwise 
required as detailed in Section 5.1 .  Kaplan-Meier plots, median time to response with 
97.5% CIs as estimated from the Kaplan-Meier curve, and difference in median time 
between treatment groups with 97.5% CIs using bootstrap method will be presented.  In 
addition, the treatment groups will be compared descriptively using a Cox proportional 
hazards model adjusting for the stratification factors and a hazard ratio with a 97.5% CI 
will be produced.


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The log-rank test is most powerful when the assumption of proportional hazards holds.  
The proportional hazards assumption will be tested graphically using the log-cumulative 
hazard plot by treatment group, where the plots for each treatment group will be parallel 
if the proportional hazard assumption holds.  Should the proportional hazards 
assumption not hold, the Gehan-Wilcoxon test stratified by Region and high-risk factor 
will be used to analyze the data.
The primary estimand is defined in Table 2. Summaries of the proportion of patients 
experiencing an intercurrent event and the time to the intercurrent event will be created. 
The WHO Drug Global B3 Format dictionary will be used for concomitant medications 
including rescue medication. 
The statistical hypotheses for the primary endpoint is defined in Section 2.1.
5.3.3
Sensitivity Analyses for Primary Endpoint(s)
To support the primary analyses, the following sensitivity analyses will be conducted:

To test the sensitivity of the results to the special case of handling missing data, all 
missed assessments will be assumed not to have met the efficacy criteria.

To test the sensitivity of the results to the COVID-19 symptoms followed, only 
baseline presenting symptoms are required to meet the relevant criteria.

To test the sensitivity of the results to the statistical test performed, the stratified 
Gehan-Wilcoxon test will be used.

To test the sensitivity of the results to adjustment by the stratification factors, an 
unstratified log-rank test will be performed.
5.3.4
Supplementary Analyses for Primary Endpoint(s)
5.3.4.1
Subgroup Analyses for Primary Endpoint(s)
The generalizability of primary endpoint results when comparing RO7496998 (AT-527) 
to placebo will be investigated by estimating the treatment effect in subgroups.  
Summaries of primary endpoint by the following subgroups will be provided:

Stratification factors:
–
Region (North America, Europe, and ROW)
–
Presence of a high risk factor for hospitalization due to COVID-19 (yes, no)

Key baseline demographics:
–
Age (Adolescent 1218 years, Adult 65 years, Adult 65 years)
–
Sex (Female, Male)
–
Race/Ethnicity

Disease characteristics:
–
Time from symptom onset to study treatment in days (≤3, >3)
–
Vaccinated for COVID-19 (Yes, No)


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–
Baseline viral load (high, low; based on median baseline viral load)
–
Seropositive status at baseline (Yes, No)
–
Presence of a high-risk factor:  Obesity (Yes, No)
–
Presence of a high-risk factor:  Cardiovascular disease (Yes, No)
–
Presence of a high-risk factor: Chronic lung disease (Yes, No)
–
Presence of a high-risk factor:  Chronic metabolic disease (Yes, No)
–
Presence of a high-risk factor:  Immunocompromised (Yes, No)
–
Presence of a high-risk factor:  Chronic liver disease (Yes, No)
–
Presence of a high-risk factor:  Chronic kidney disease (Yes, No)
5.3.4.2
Supplementary Analyses for Primary Endpoint(s)
To support the primary analyses, the following supplementary analyses will be 
conducted:

For intercurrent events of study withdrawal, lost to follow-up, and death where 
censoring is planned for Day 29, censor at the time associated with the intercurrent 
event.
5.4
SECONDARY ENDPOINT(S) ANALYSIS(SES)
Estimands for all secondary endpoints are defined in Table 2.
5.4.1
Key/Confirmatory Secondary Endpoint(s)
5.4.1.1
Proportion of Patients with 1 COVID-19-Related Medically 
Attended Visit
COVID-19-related medically attended visits are defined as hospitalization, emergency 
room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with the 
primary reason for the visit being COVID-19.  The statistical method is detailed in 
Section 5.1.
5.4.1.2
Time to Alleviation of Symptoms Maintained for a Duration of 
21.5 Hours
Time to alleviation of symptoms defined as the time from randomization to the point at 
which a score of 0 or 1 for all Items 1-12 of the COVID-19 Symptom Diary is met and 
maintained for at least 21.5 hours.
For new symptoms (i.e., symptoms that develop due COVID-19 which present prior to or 
post baseline) and pre-existing symptoms (i.e., symptoms that existed prior to 
developing COVID-19) regardless of whether judged to be worse at screening: 

Alleviation of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on the 
COVID-19 Symptom Diary):
–
Severe to mild, or none
–
Moderate to mild, or none


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–
Mild to mild or none
–
None to mild or none
The same statistical methods as for the primary endpoint will be used as described in 
Section 5.3.2.
5.4.1.3
Frequency (Proportion) of Medically Confirmed 
COVID-19-Related Complications
COVID-19-related complications are defined as deaths and hospitalizations that are 
reported as COVID-19-related complications by the investigator, and medically 
confirmed COVID-19-related complications of radiologically confirmed pneumonia, acute 
respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, cardiac failure etc.  
The process of medical confirmation of certain events is briefly described in 
Section 1.2.2.  The statistical method is detailed in Section 5.1.  A sensitivity analysis of 
this endpoint using COVID-19-related complications as reported by the investigator will 
also be produced.
5.4.1.4
Time to One-Category Improvement of Baseline Presenting 
Symptoms Maintained for 21.5 Hours
Time to one-category improvement of baseline presenting COVID-19 for Items 1-12 of 
the COVID-19 Symptom Diary maintained for a duration of 21.5 hours defined as time 
from randomization to when the symptoms have improved by at least one category from 
baseline on the Likert scale, where improvement is defined as:

For pre-existing symptoms (i.e., symptoms that existed prior to developing 
COVID-19) judged by the patient to be worse at screening OR for new symptoms 
(i.e., symptoms that develop due COVID-19 which present prior to or post baseline): 
–
Improvement of at least one grade on the Likert scale from baseline if the 
severity at baseline is graded moderate or severe:

Severe to moderate, mild, or none

Moderate to mild or none

Mild to mild or none

None to mild or none

For pre-existing symptoms (i.e., symptoms that existed prior to developing COVID-
19) judged by the patient NOT to be worse at screening:
–
Maintained (no worsening) baseline severity:

Severe to severe, moderate, mild, or none

Moderate to moderate, mild or none

Mild to mild or none

None to none


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Where the baseline assessment for COVID-19 symptom severity is missing, the patient 
will be excluded from the analysis.
The same statistical methods as for the primary endpoint will be used as described in 
Section 5.3.2.
5.4.1.5
Time to Cessation of SARS-CoV-2 Viral Shedding as Measured 
by RT-qPCR
Time to cessation of viral shedding by RT-PCR is defined as the time from 
randomization to the first time when a negative qualitative virus RNA by RT-PCR test 
result is obtained.  The same statistical methods as for the primary endpoint will be used 
as described in Section 5.3.2.
5.4.1.6
Proportion of Patients with All-Cause Mortality
All-cause mortality is defined as an adverse event captured within the clinical database 
for which there is a non-missing death date (partial date of death will be considered as a 
death).  The statistical method is detailed in Section 5.1.
5.4.2
Supportive Secondary Efficacy Endpoint(s)
5.4.2.1
Time to Alleviation or Improvement of COVID-19 Symptoms 
(Items 112 of the COVID-19 Symptom Diary) Maintained for a 
Duration of 43 Hours
The time to alleviation or improvement of COVID-19 symptoms is defined as the time 
from randomization to the first time at which all COVID-19 symptoms from Items 1-12 of 
the COVID-19 Symptom Diary were either alleviated, maintained or improved for a 
duration of 43 hours. Alleviation, maintenance or improvement of symptoms is defined 
as the time when all 12 COVID-19 symptoms from Items 1-12 of the COVID-19 
Symptom Diary have been assessed by the patient as follows:

For pre-existing symptoms (i.e., symptoms that existed prior to developing 
COVID-19) judged by the patient to be worse at screening: 
–
Improvement of at least one grade on the Likert scale from baseline if the 
severity at baseline is graded moderate or severe:

Severe to moderate, mild, or none

Moderate to mild or none

Mild to mild or none

None to mild or none
Note: At screening, patients will only be asked if preexisting symptoms existed (within 
the last 30 days) and if they were worsened by COVID-19. Patients will be asked to rate 
the severity at baseline that needs to improve. To avoid recall bias, patients will not be 
asked to rate the severity of preexisting symptoms prior to COVID-19.


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
For pre-existing symptoms (i.e., symptoms that existed prior to developing 
COVID-19) judged by the patient NOT to be worse at screening:
–
Maintained (no worsening) baseline severity if the severity at baseline is graded 
moderate or severe:

Severe to severe, moderate, mild, or none

Moderate to moderate, mild or none

Mild to mild or none

None to mild or none

For new symptoms (i.e., symptoms that develop due COVID-19 which present prior 
to or post baseline): 
–
Alleviation of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on the 
COVID-19 Symptom Diary):

Severe to mild, or none

Moderate to mild, or none

Mild to mild or none

None to mild or none
Where the baseline assessment for COVID-19 symptom severity is missing, the 
COVID-19 symptoms for a patient will be treated as new symptoms and therefore must 
meet the alleviation criteria even if symptoms had been identified as existing prior to 
developing COVID-19.
5.4.2.2
Time to alleviation of individual symptoms maintained for a 
duration of 21.5 hours
Time to alleviation of individual symptoms (Items 1-14 of the COVID-19 Symptom Diary) 
is defined separately for each symptom as the time from randomization to the point at 
which a score of 0 or 1 for the individual symptom is met and maintained for at least 21.5 
hours in patients with a symptom score 2 at baseline.  The endpoints corresponding to 
each of the symptoms are as follows:

Time to alleviation of nasal congestion or runny nose

Time to alleviation of sore throat

Time to alleviation of cough

Time to alleviation of shortness of breath

Time to alleviation of muscle or body aches

Time to alleviation of fatigue

Time to alleviation of headache

Time to alleviation of chills/sweats 

Time to alleviation of feeling hot or feverish


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
Time to alleviation of nausea

Time to alleviation of vomiting

Time to alleviation of diarrhea

Time to alleviation of sense of smell

Time to alleviation of sense of taste
The same statistical methods as for the primary endpoint will be used as described in 
Section 5.3.2. 
Where a baseline assessment for COVID-19 symptom severity is missing for an 
individual symptom, the patient will be excluded from the analysis.
5.4.2.3
Time to Alleviation of Symptoms Maintained for a Duration of 
43 Hours
Time to alleviation of symptoms is defined as the time from randomization to the point at 
which a score of 0 or 1 for all Items 1-12 of the COVID-19 Symptom Diary is met and 
maintained for at least 43 hours.
For new symptoms (i.e., symptoms that develop due COVID-19 which present prior to or 
post baseline) and pre-existing symptoms (i.e., symptoms that existed prior to 
developing COVID-19) regardless of whether judged to be worse at screening: 

Alleviation of COVID-19 symptoms (i.e., a score of 0 [none] or 1 [mild] on the 
COVID-19 Symptom Diary):
–
Severe to mild, or none
–
Moderate to mild, or none
–
Mild to mild or none
–
None to mild or none
The same statistical methods as for the primary endpoint will be used as described in
Section 5.3.2.
5.4.2.4
Proportion of Patients Requiring Hospitalization for COVID-19
Hospitalizations for COVID-19 are defined as SAEs for which the investigator has cited 
that the suspected cause was the disease under study and where there is a non-missing 
hospital admission date.  The statistical method is detailed in Section 5.1.
5.4.2.5
Time to Return to Afebrile State Maintained for at least 
21.5 Hours (Duration of Fever)
Time to return to afebrile state (temperature 37.5C) is defined as the time from 
randomization to the time of afebrile state maintained for at least 21.5 hours in patients 
with a fever at baseline. The same statistical methods as for the primary endpoint will be 
used as described in Section 5.3.2.


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Where a baseline temperature assessment is missing, the patient will be excluded from 
the analysis.
5.4.2.6
Proportion of Patients with Any Post-Treatment Infection
Post-treatment infections are defined as any treatment-emergent adverse event with a 
primary system organ class of infections and infestations.  The statistical method is 
detailed in Section 5.1.
5.4.3
Supportive Secondary Virology Endpoints
5.4.3.1
Change from Baseline in Amount of SARS-CoV-2 Virus RNA as 
Measured by RT-qPCR at Each Timepoint
The change from baseline in amount of SARS-CoV 2-virus RNA as measured by 
RT-qPCR will be analyzed at Day 3, Day 5, Day 7 and Day 14 separately.  The statistical 
method is detailed in Section 5.1.
5.4.3.2
Proportion of Patients Positive for SARS-Cov-2 Virus RNA by 
RT-qPCR at Specified Timepoints
Proportion of patients positive for SARS-CoV-2 virus RNA is defined as the proportion of 
patients with a positive qualitative virus RNA by RT-PCR test result, which will be 
analyzed at Day 3, Day 5, Day 7 and Day 14 separately.  The statistical method is 
detailed in Section 5.1.
5.4.3.3
Area Under the Concentration Curve (AUC) in the Amount of 
SARS-CoV-2 Virus RNA as Measured by RT-qPCR
The statistical method is detailed in Section 5.1.
5.4.4
Supportive Secondary Safety Endpoints
5.4.4.1
Incidence of Adverse Events
Descriptive summaries of treatment-emergent adverse events will be presented.
5.4.4.2
Severity of Adverse Events
Descriptive summaries of treatment-emergent adverse events tabulated by severity will 
be presented.
5.4.4.3
Change from Baseline in Vital Signs
For each of the vital signs (pulse rate, respiratory rate, systolic and diastolic blood 
pressure, peripheral capillary oxygen saturation [SpO2], and temperature), descriptive 
statistics on absolute value and the change from baseline will be presented over time.
For vital signs, including oxygen saturation, time windows for unscheduled and early 
termination visits are given in Table 3 below.  Where multiple measurements within a 
visit window are available for a patient, the value obtained closest to the target timepoint 
will be used.


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Table 3
Vital Signs (including SpO2) Time Windows
Scheduled Timepoint
Acceptable Time Window
Baseline (Day 1 pre-dose)
Day 1 pre-dose
Day 3
Day 1 post-dose – Day 3
Day 5
Day 4 – Day 5
Day 7
Day 6 – Day 10
Day 14
Day 11 – Day 18
5.4.4.4
Change from Baseline in Targeted Laboratory Results
Laboratory data will use ranges from local laboratories and laboratory values will be 
converted to Système International units.
Summary tables will present the observed and change from baseline values of the 
laboratory chemistry parameters: alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, total bilirubin, blood urea nitrogen, creatine kinase, lactate 
dehydrogenase, C-reactive protein and creatinine, and laboratory hematology 
parameters:  hemoglobin, white blood cell count, and platelets, and laboratory 
coagulation parameter: D-dimer for baseline and Day 5 visits by treatment group.
For laboratory results, time windows for unscheduled and early termination visits are 
given in Table 4 below.  Where multiple measurements within a visit window are 
available for a patient, the value obtained closest to the target timepoint (center of the 
acceptable time window) will be used.
Table 4
Laboratory Time Windows
Scheduled Timepoint
Acceptable Time Window
Baseline (Day 1 pre-dose)
Day 1 pre-dose
Day 5
Day 4 – Day 6
5.4.5
Supportive Secondary PK Endpoints
Samples taken for PK analysis will be processed to plasma and concentrations of 
AT-511 (free base form of AT-527) and its major metabolites AT-551, AT-229, and 
AT-273, will be quantified by a validated liquid chromatography-tandem mass 
spectrometry method.
Descriptive summary statistics for PK concentration data will be provided by 
visit/sampling time point. Summary statistics will also include geometric mean and 
coefficient of variation (CV; arithmetic and geometric).  Concentrations below lower limit 
of quantification (LLOQ) will be treated as zero in summary statistics and for PK 


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parameter calculations.  Individual and mean plasma concentration versus time data for 
AT-511, AT-551, AT-229, and AT-273 will be summarized and plotted.
5.5
EXPLORATORY ENDPOINT(S) ANALYSIS
5.5.1
Exploratory Efficacy Endpoints

Proportion of patients with ≥1 COVID-19-related medically attended visit (handling 
missing data due to study withdrawal or loss of follow up with multiple imputation)

Proportion of patients requiring hospitalizations for COVID-19 (handling missing 
data due to study withdrawal or loss of follow up with multiple imputation)

Frequency (Proportion) of medically confirmed COVID-19-related complications 
(handling missing data due to study withdrawal or loss of follow up with multiple 
imputation) 
5.5.2
Exploratory Virology Endpoints
The exploratory virology endpoints for this study are as follows:

Treatment-emergent amino acid substitutions in SARS-CoV-2 viral genes (such as 
nsp12 and potentially other genes)

Anti-SARS-CoV-2 antibody status/titer for neutralizing antibodies and anti-S 
antibodies at specified timepoints

Change from baseline in amount of SARS-CoV-2 virus titer at each timepoint

Time to cessation of SARS-CoV-2 viral shedding as measured by virus titer

Proportion of patients with positive SARS-CoV-2 virus titer at specified timepoints

AUC of SARS-CoV-2 virus titer

Drug susceptibility in patients with evaluable virus at specified timepoints
Time to event, incidence, proportion and change from baseline endpoints will be 
analyzed using the same approach as described for secondary virology endpoints in 
Section 5.1.
Additional analyses adjusting by baseline amount of virus RNA may also be conducted.  
Other virology endpoints will be summarized descriptively.
5.5.3
Exploratory Patient Reported Outcome and Health Utility 
Endpoints
Data from the PGIS and EQ-5D-5L will be used in separate analysis to inform 
understanding of the COVID-19 Symptom Diary and health utilities.  The patient reported 
outcomes and health utility endpoints for this study are as follows:

Patient’s global impression of severity (PGIS) of COVID-19 symptoms as assessed 
through the use of the PGIS at Day 14 and Day 29

Change from baseline in EQ-5D-5L health utility index-based and Visual Analog 
Scale (VAS) scores at specified timepoints


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The EuroQol 5-Dimension 5-Level (EQ-5D-5L) will be scored according to its manual, 
and results will be reported separately from the clinical study report. 
Patient-reported outcomes (PRO) and health utility endpoints will be summarized 
descriptively.
5.6
OTHER SAFETY ANALYSES
5.6.1
Extent of Exposure
The number of administrations and the duration of exposure to study treatment will be 
summarized using descriptive statistics.  The duration of exposure will be calculated in 
days as the date and time of last dose of study treatment minus the date and time of first 
dose of study treatment plus 12 hours and divided by 24 to convert to days.
5.6.2
Adverse Events
Separate summaries will be generated for SAEs, deaths, adverse events leading to 
discontinuation of study treatment, adverse events leading to discontinuation of study, 
adverse events of special interest, SAEs suspected to be caused by study treatment and 
adverse events suspected to be caused by study treatment, as assessed by the 
investigator. In addition, adverse events and SAEs by time of onset according to the 
following categories will be reported: Days 1-7, Days 8-14, and Days 15. If a low 
number of events is observed, a listing may be produced in place of a summary table.  
Adverse events will also be listed.
Adverse events of special interest for this study will be identified by the relevant 
checkbox on the eCRF and are as follows:

Cases of potential drug induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy's Law (see Protocol 
Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
–
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of the study drug is suspected.
Additional safety analyses for adverse event and SAEs divided by age and vaccination 
status subgroup will also be produced.
5.6.3
Laboratory Data
Summaries of the number of patients by NCI CTCAE v5.0 grade for hematology (white 
blood cells [WBC], hemoglobin, platelets), and for chemistry (alkaline phosphatase, ALT, 


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AST, total bilirubin, creatinine), and renal function will be produced. The number of 
patients will be summarized by NCI CTCAE grade category for baseline and worst post 
baseline value.
Patients with values outside the reference will be listed, with an indication of the direction 
of the abnormality (high, low).
A listing of patients who meet the pre-specified criteria shown in Table 5 during the study 
will be presented for each treatment group.
Table 5
Pre-specified Treatment-Emergent Abnormal Laboratory Criteria
AST (U/L) or ALT (U/L) and Total bilirubin (mg/dL)
AST (U/L) or ALT (U/L) 3 Baseline
AST (U/L) or ALT (U/L) 5 Baseline
AST (U/L) or ALT (U/L) 3 Baseline in combination with total bilirubin (mg/dL) 2 ULN
ALTalanine aminotransferase; ASTaspartate aminotransferase; ULNupper limit of normal.
5.6.4
Vital Signs
A summary of the proportion of patients that have SpO2 ≤ 93% at any point in the study 
will be created. 
5.6.5
Medical History
Medical history data will be summarized descriptively by treatment group using the 
safety-evaluable set.
5.6.6
Previous and Concomitant Medications
Previous and concomitant treatments will be summarized descriptively by treatment 
group for the safety-evaluable set. Previous treatments that have been stopped prior to 
Study Day 1 will be summarized separately, where Study Day 1 is the day of 
randomization. There will be a summary of all concomitant treatments, including those 
that were initiated prior to Study Day 1. In addition, there will be summaries of previous 
and concomitant treatments with the indication given as ‘COVID-19’ as well as summary 
of the proportion of patients requiring supplemental oxygen.
5.7
OTHER ANALYSES
5.7.1
Summaries of Conduct of Study
Summary of analysis sets including numbers of patients in each set and a summary of 
major protocol deviations will be created on the All Patients set. Summaries will be 
tabulated by treatment group separately as well as combined.


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5.7.2
Summaries of Treatment Group Comparability
To review treatment group comparability within the study, a number of variables 
collected at baseline will be compared across treatment groups on the efficacy-evaluable 
set.
5.7.2.1
Demographics and Baseline Characteristics

Age

Sex

Race

Ethnicity

Region

Smoking history

Weight

BMI
5.7.2.2
Baseline Disease Characteristics

SARS-CoV-2 RT-PCR Status at Baseline

Baseline viral load

Seropositive status at baseline

Presence of a high-risk factor

Presence of individual high-risk factors

Time from symptom onset to study treatment in days

Number of symptoms present at baseline

Number of symptoms from pre-existing conditions at baseline

Number of symptoms with score 2 present at baseline

Vaccinated for COVID-19

Baseline systemic corticosteroid use

Baseline inhaled corticosteroid use
5.7.3
Pharmacokinetic Analyses
The following pharmacokinetic parameters will be determined on Day 1:  maximum 
concentration (Cmax), time to maximum concentration (Tmax) after the first dose from the 
plasma concentration-time data.  At steady state on Day 5 the following PK parameters 
will be determined:  Cmax,ss, Tmax,ss, and Ctrough,ss. All PK analysis will be performed using 
the actual recorded sampling times for AT-511, AT-551, AT-229, and AT-273.  
Descriptive summary statistics for PK parameters will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum.  
An exception to this is Tmax where median, minimum, and maximum will be presented.  
Inter-patient variability and drug accumulation will be evaluated.


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Nonlinear mixed effects (NLME) modeling will be used to analyze the dose-
concentration-time data of AT-511 and AT-273 in plasma.  Population and individual PK 
parameters (e.g., apparent clearance [CL/F] and apparent steady-state volume of 
distribution [Vss/F]) will be estimated and the influence of various covariates (e.g., age, 
sex, and weight) on these parameters will be investigated.  The data collected during 
this study may be pooled with data collected in other clinical studies (previous Phase I 
and/or Phase II study in healthy volunteers and patients infected with hepatitis C virus
[HCV], COVID-19) as appropriate, to build the population PK model.  Secondary PK 
parameters may be derived from the individual post-hoc predictions.  NLME modeling 
results will be reported in a standalone document distinct from the clinical study report.
Additional PK analyses may be conducted as appropriate.  The PK data and parameters 
derived from these analyses may be used for exploratory graphical analyses of the PD 
data and parameters.
5.8
INTERIM ANALYSES 
5.8.1
Planned Interim Analyses
No interim analysis is planned for this study.
5.8.2
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis and/or one interim virology 
analysis.  Full details will be pre-specified in a SAP (either this SAP or a separate iSAP)
prior to the interim analysis being conducted and will include rationale and specifications 
for ensuring the study maintains the highest standards of integrity.
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.
If an interim analysis is conducted for efficacy, the Sponsor will remain blinded.  The 
interim analysis will be conducted by an external statistical group and reviewed by the 
iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified in 
the iDMC charter. 
The decision to conduct the optional interim efficacy analyses, along with the rationale, 
timing, and statistical details for the analysis, will be documented in this SAP or in a 
separate iSAP, and the relevant SAP will be submitted to relevant health authorities prior 
to the conduct of the interim analysis.  The iDMC charter will be updated to document 
potential recommendations the iDMC can make to the Sponsor as a result of the 
analysis (e.g., stop the study for positive efficacy, stop the study for futility), and the 
iDMC charter will also be made available to relevant health authorities.
If there is a potential for the study to be stopped for positive efficacy as a result of the 
efficacy interim analysis, the type I error rate will be controlled to ensure statistical 


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validity is maintained.  Specifically, the Lan-DeMets -spending function that 
approximates the O'Brien-Fleming boundary will be applied to determine the critical 
value for stopping for positive efficacy at the interim analysis (DeMets and Lan 1994).  
Additional criteria for recommending that the study be stopped for positive efficacy may 
be added to the iDMC charter.  If the study continues beyond the interim analysis, the 
critical value at the final analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will include an assessment of the predictive 
probability that the specified endpoint will achieve statistical significance.
If an interim analysis is conducted for virology, the Sponsor will be unblinded.  The 
interim analysis will be conducted by the Sponsor to confirm adequate antiviral effect.  
Patients that contribute to the virology interim analysis will be excluded from the final 
efficacy and virology analyses, and will be replaced in order to maintain power of the 
primary endpoint analysis and there will therefore be no alpha adjustment for the final 
analysis.  The interim virology analysis will involve an early look at virology parameters 
over time and may include formal statistical analysis of the change from baseline in viral 
titer.  Details will be specified in a separate iSAP, or by updating this SAP which will be 
finalized prior to the interim analysis taking place.
6.
SUPPORTING DOCUMENTATION
This section is not applicable, since there is no additional supporting document.


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Appendix 1 Changes To Protocol-Planned Analyses
The modified intent-to-treat infected (mITTi) population described in the protocol has 
been renamed to the efficacy-evaluable set to more accurately describe this analysis 
set.
The rationale for the target sample size and the primary efficacy endpoint has been 
updated to remove references to comparing the median TTAIS and to include references 
to the comparison of the hazard ratio to more accurately describe the comparison to be 
made and from which the sample size was based upon.
The optional interim analysis was updated to specify that if an optional interim efficacy or 
virology analysis is conducted that this will be updated in this SAP or within a separate 
iSAP, which will be finalized prior to the interim analysis taking place.


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Appendix 2 COVID-19 Symptom Diary
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.
Note that the following is a sample.  Sites will be provided with separate versions of the 
diary, reflecting appropriate recall periods.
COVID-19 Symptom Diary (Morning)
This diary will keep track of your COVID-19 symptoms and temperature during the study.
Please complete this diary when you first wake up in the morning (before getting out of 
bed). Remember to take your temperature before you take any medicines to help your 
COVID-19 symptoms.
Please rate the severity of each symptom at its worst since you went to bed last night.
None
0
Mild
1
Moderate
2
Severe
3
1. Nasal Congestion or runny nose
2. Sore Throat
3. Cough
4. Shortness of breath (difficulty breathing)
5. Muscle or body aches
6. Fatigue (tiredness)
7. Headache
8. Chills/Sweats
9. Feeling hot or feverish
10. Nausea (wanting to throw up)
11. Vomiting (thrown up)
12. Diarrhea (mostly or completely liquid
bowel movements)


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Same as usual
0
Less than usual
1
No sense 
2
13. Rate your sense of
smell since you went to
bed last night.
14. Rate your sense of
taste since you went to
bed last night.
Appendix 2 COVID-19 Symptom Diary (Cont.) 


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Appendix 3 Patient Global Impression of Severity
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study.
Patient Global Impression of Severity (Bedtime)
Please rate your overall COVID-19 symptoms at their worst in the past 24 hours.
☐None
☐Mild
☐Moderate 
☐Severe 


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7.
REFERENCES
DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152.
Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. 
Biom J. 2008;50(5):66777.
Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple testing problems in pharmaceutical 
statistics. CRC Press 2009;16591.
Regeneron Pharmaceuticals, Inc. “REGN-COV2 antibody cocktail program update” 
Regeneron COVID-19 Program Update. 28 September 2020. Accessed: 
16 November 2020. Available from: https://investor.regeneron.com/static-
files/a596a85e-e72d-4529-8eb5-d52d87a99070.