Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 468
Healthy volunteers: no

Brief summary:
The goal of this clinical study is to test how well the study drug, obeldesivir (GS-5245), works and how safe it is in treating coronavirus disease 2019 (COVID-19) in participants that have a higher risk of getting a serious illness.

Detailed description:

Arms:
arm 1: Participants will receive obeldesivir 350 mg orally twice daily for 5 days. arm 2: Participants will receive placebo-to-match obeldesivir orally twice daily for 5 days.

Interventions: intervention 1: Obeldesivir intervention 2: Obeldesivir Placebo
Intervention descriptions: intervention 1: Tablets administered orally without regard to food. intervention 2: Placebo tablets administered orally without regard to food.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of GS-5245 for the Treatment 
of COVID-19 in Participants With High-Risk for Disease 
Progression
Short Title:
Study of GS-5245 in Participants With COVID-19 Who Have a 
High Risk of Developing Serious or Severe Illness
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
This is a non-IND study
EudraCT Number:
2022-002741-18
ClinicalTrials.gov 
Identifier:
NCT05603143
Indication:
COVID-19 
Protocol ID:
GS-US-611-6273
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol 
Version/Date:
Amendment 1:
29 March 2023
Amendment History:
Original:
01 August 2022
Admin Amendment 0.0.1:  22 August 2022
Amendment 0.1:
05 December 2022
Amendment 0.2:
20 January 2023
High-level summaries of the history of amendments are provided in 
Appendix 11.5.
Country-Specific 
Requirements:
Country-specific requirements, as applicable, are listed in 
Appendix 11.4.
GILEAU 


This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................6
LIST OF IN-TEXT FIGURES........................................................................................................................................6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................................7
PROTOCOL SYNOPSIS................................................................................................................................................9
STUDY SCHEMA........................................................................................................................................................15
STUDY PROCEDURES TABLE ................................................................................................................................16
1.
INTRODUCTION................................................................................................................................................19
1.1.
Background..............................................................................................................................................19
1.2.
Background on Study Interventions ........................................................................................................20
1.2.1.
GS-5245.................................................................................................................................20
1.3.
Rationale for This Study..........................................................................................................................29
1.4.
Rationale for Dose Selection of GS-5245 ...............................................................................................29
1.4.1.
Participants with Compensated Cirrhosis..............................................................................31
1.5.
Risk/Benefit Assessment for the Study ...................................................................................................31
1.6.
Compliance..............................................................................................................................................32
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................33
3.
STUDY DESIGN.................................................................................................................................................35
3.1.
Study Design Overview...........................................................................................................................35
3.2.
Duration of Intervention..........................................................................................................................35
3.3.
Protocol-Specific Discontinuation Criteria .............................................................................................35
3.3.1.
Criteria for Early Discontinuation for the Individual Participants ........................................35
3.3.2.
Criteria for Early Discontinuation of the Study ....................................................................36
3.3.3.
Loss to Follow-up..................................................................................................................36
3.4.
Definitions for Time of Primary Endpoint and End of Study .................................................................36
3.4.1.
Primary Endpoint...................................................................................................................36
3.4.2.
End of Study..........................................................................................................................37
3.5.
Source Data .............................................................................................................................................37
4.
PARTICIPANT POPULATION..........................................................................................................................38
4.1.
Number of Participants and Participant Selection...................................................................................38
4.1.1.
Participant Replacement........................................................................................................38
4.2.
Inclusion Criteria.....................................................................................................................................38
4.3.
Exclusion Criteria....................................................................................................................................40
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................42
5.1.
Randomization, Blinding, and Treatment Code Access..........................................................................42
5.1.1.
Randomization.......................................................................................................................42
5.1.2.
Blinding .................................................................................................................................42
5.1.3.
Planned Interim Internal Unblinding.....................................................................................42
5.1.4.
Procedures for Breaking the Blind on Treatment Codes.......................................................43
5.2.
Description and Handling........................................................................................................................43
5.2.1.
Formulation ...........................................................................................................................43
5.2.2.
Packaging and Labeling ........................................................................................................43
5.2.3.
Storage and Handling ............................................................................................................44
5.3.
Dosage and Administration .....................................................................................................................44


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5.4.
Prior and Concomitant Medications........................................................................................................44
5.4.1.
Prior and Concomitant Medications That Are Prohibited.....................................................44
5.5.
Accountability for Study Drug(s)............................................................................................................45
5.5.1.
Study Drug Return or Disposal .............................................................................................45
6.
STUDY PROCEDURES......................................................................................................................................46
6.1.
Informed Consent ....................................................................................................................................46
46
6.2.
Screening, Participant Enrollment, and Treatment Assignment .............................................................46
6.3.
Instructions for Study Procedures ...........................................................................................................47
6.3.1.
Adverse Events......................................................................................................................47
6.3.2.
Safety Assessments ...............................................................................................................47
6.3.3.
Pharmacokinetics...................................................................................................................49
6.3.4.
SARS-CoV-2 Serology .........................................................................................................50
6.3.5.
Clinical Virology...................................................................................................................50
6.3.6.
Patient-Reported Outcomes...................................................................................................50
6.4.
Assessments for Early Discontinuation From the Study.........................................................................51
6.5.
Assessments for End of Study.................................................................................................................51
6.6.
Poststudy Care.........................................................................................................................................51
6.7.
Sample Storage........................................................................................................................................51
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................52
7.1.
Definitions of Adverse Events and Serious Adverse Events...................................................................52
7.1.1.
Adverse Events......................................................................................................................52
7.1.2.
Serious Adverse Events.........................................................................................................52
7.1.3.
Study Drugs and Gilead Concomitant Medications Special Situation 
Reports...................................................................................................................................53
7.2.
Assessment of Adverse Events and Serious Adverse Events..................................................................54
7.2.1.
Assessment of Causality for Study Drugs and Procedures ...................................................54
7.2.2.
Assessment of Severity..........................................................................................................54
7.3.
Investigator Reporting Requirements and Instructions ...........................................................................55
7.3.1.
Requirements for Collection Before Study Drug Initiation ..................................................55
7.3.2.
Adverse Events......................................................................................................................55
7.3.3.
Serious Adverse Events.........................................................................................................55
7.3.4.
Study Drug Special Situation Reports...................................................................................55
7.3.5.
Concomitant Medications Reports ........................................................................................55
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports.......................................56
7.4.1.
Serious Adverse Event Reporting Process ............................................................................56
7.4.2.
Special Situation Reporting Process......................................................................................57
7.5.
Gilead Reporting Requirements ..............................................................................................................59
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events...........................................................................................................................59
7.7.
Toxicity Management..............................................................................................................................60
7.7.1.
GS-5245.................................................................................................................................60
8.
STATISTICAL CONSIDERATIONS.................................................................................................................62
8.1.
Analysis Objectives and Endpoints.........................................................................................................62
8.2.
Planned Analyses.....................................................................................................................................62
8.2.1.
Interim Analysis ....................................................................................................................62
8.2.2.
Final Analysis........................................................................................................................62
8.3.
Analysis Conventions..............................................................................................................................63
8.3.1.
Analysis Sets .........................................................................................................................63
8.3.2.
Data Handling Conventions ..................................................................................................63
8.4.
Demographic and Baseline Characteristics Analysis..............................................................................64
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8.5.
Efficacy Analysis.....................................................................................................................................64
8.5.1.
Primary Analysis ...................................................................................................................64
8.5.2.
Secondary Analyses...............................................................................................................65
8.5.3.
Intercurrent Events ................................................................................................................66
8.6.
Safety Analysis........................................................................................................................................67
8.6.1.
Extent of Exposure ................................................................................................................67
8.6.2.
Adverse Events......................................................................................................................67
8.6.3.
Laboratory Evaluations .........................................................................................................67
8.7.
Adjustments for Multiplicity ...................................................................................................................67
8.8.
Pharmacokinetic Analysis .......................................................................................................................68
8.9.
Sample Size .............................................................................................................................................68
8.9.1.
Sample Size Re-estimation....................................................................................................68
8.10.
Data Monitoring Committee....................................................................................................................69
9.
RESPONSIBILITIES...........................................................................................................................................70
9.1.
Investigator Responsibilities ...................................................................................................................70
9.1.1.
Good Clinical Practice...........................................................................................................70
9.1.2.
Financial Disclosure ..............................................................................................................70
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval................................................................................................................................70
9.1.4.
Informed Consent ..................................................................................................................70
9.1.5.
Confidentiality.......................................................................................................................71
9.1.6.
Study Files and Retention of Records ...................................................................................71
9.1.7.
Electronic Case Report Forms...............................................................................................73
9.1.8.
Investigator Inspections.........................................................................................................73
9.1.9.
Protocol Compliance .............................................................................................................73
9.2.
Sponsor Responsibilities .........................................................................................................................73
9.2.1.
Protocol Modifications ..........................................................................................................73
9.2.2.
Study Reports and Publications.............................................................................................74
9.3.
Joint Investigator/Sponsor Responsibilities ............................................................................................74
9.3.1.
Payment Reporting ................................................................................................................74
9.3.2.
Access to Information for Monitoring...................................................................................74
9.3.3.
Access to Information for Auditing or Inspections ...............................................................74
9.3.4.
Study Discontinuation ...........................................................................................................74
10.
REFERENCES.....................................................................................................................................................75
11.
APPENDICES......................................................................................................................................................77
11.1.
Investigator Signature Page.....................................................................................................................78
11.2.
Pandemic Risk Assessment and Mitigation Plan ....................................................................................79
11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........82
11.4.
Country-Specific Requirements ..............................................................................................................85
11.4.1.
Additional Country-Specific Requirements for South Africa...............................................85
11.4.2.
Additional Country-Specific Requirements for the United Kingdom...................................86
11.5.
Amendment History ................................................................................................................................87
11.5.1.
Amendment 1 (29 March 2023) ............................................................................................87
11.5.2.
Amendment 0.2 (20 January 2023) .......................................................................................88
11.5.3.
Amendment 0.1 (05 December 2022) ...................................................................................89
11.5.4.
Administrative Amendment 0.0.1 (22 August 2022) ............................................................89


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LIST OF IN-TEXT TABLES
Table 1.
Study Procedures Table...........................................................................................................16
Table 2.
GS-US-611-6248: Plasma Pharmacokinetic Parameters of GS-441524 in Single 
Ascending Dose Cohorts 1 Through 4 ....................................................................................24
Table 3.
GS-US-611-6248: Plasma Pharmacokinetic Parameters of GS-441524 in Multiple 
Ascending Dose Cohorts 5 and 6 ............................................................................................24
Table 4.
GS-US-611-6248: PBMC Pharmacokinetic Parameters of GS-443902 in Multiple 
Ascending Dose Cohorts 5 and 6 ............................................................................................25
Table 5.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of Midazolam in Cohort 3..............27
Table 6.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of Pitavastatin in Cohort 5..............27
Table 7.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of GS-441524 in Cohort 1..............28
Table 8.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of GS-441524 in Cohort 7..............28
Table 9.
Prior and Concomitant Medications That Are Prohibited.......................................................45
Table 10.
Laboratory Analytes ................................................................................................................49
Table 11.
Handling of Intercurrent Events ..............................................................................................66
Table 12.
Boundaries for Interim and Final Analysis..............................................................................68
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ..........................................................................................................................15


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
AGM
African green monkey
ALT
alanine aminotransferase
ARA
acid-reducing agent
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-t
partial area under the concentration versus time curve from time 0 to time t
AUCinf
area under the concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/z)
BID
twice daily 
CI
confidence interval
CLcr
creatinine clearance
CLr
renal clearance of unchanged drug in a specific interval (CLr (interval)) or 
cumulatively over all collection intervals
Cmax
maximum observed concentration of drug
COVID-19
coronavirus disease 2019
CP
conditional power
CSR
clinical study report
CYP
cytochrome P450 enzyme
DAIDS
Division of AIDS
DDI
drug-drug interaction
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EC50
effective concentration
EDC
electronic data capture
FAM
famotidine
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Gilead
Gilead Sciences
GMR
geometric mean ratio
IB
investigator’s brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IEC
institutional ethics committee
IND
investigational new drug


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IRB
institutional review board
IRT
interactive response technology
IV
intravenous
LLOQ
lower limit of quantitation
MAV
medically attended visit
MDZ
midazolam
MMRM
mixed-effects model repeated measures
NOAEL
no observed adverse effect level
OATP
organic anion transporting polypeptide
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PIT
pitavastatin
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PROMIS-29
Patient-Reported Outcomes Measurement Information System-29
QD
once daily dosing
RDV
remdesivir (Veklury®)
RNA
ribonucleic acid
RT-qPCR
reverse transcriptase-quantitative polymerase chain reaction
SAC
Safety Assessment Committee
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SSR
special situation report
t1/2 
terminal elimination half-life
TEAE
treatment-emergent adverse event
TK
toxicokinetic(s)
ULN
upper limit of normal
UK
United Kingdom
US
United States
WPAI + CIQ: COVID-19
Work Productivity and Activity Impairment + Classroom Impairment Questions: 
COVID-19 Infection


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of GS-5245 for the Treatment of COVID-19 in Participants With 
High-Risk for Disease Progression
Short Title: Study of GS-5245 in Participants With COVID-19 Who Have a High Risk of 
Developing Serious or Severe Illness
IND Number: This is a non-IND study.
EudraCT Number: 2022-002741-18
ClinicalTrials.gov Identifier: NCT05603143
Study Centers Planned:
Approximately 300 centers globally
Objectives and Endpoints: 
Primary Objective(s)
Primary Endpoint(s) 
•
To evaluate the efficacy of GS-5245 in reducing 
the rate of COVID-19–related hospitalization or 
all-cause death
•
Proportion of COVID-19–related hospitalization 
or all-cause death by Day 29
Secondary Objective(s)
Secondary Endpoint(s)
•
To evaluate the safety and tolerability of 
GS-5245 administered in nonhospitalized 
participants with COVID-19
•
Incidence of treatment-emergent adverse events 
(AEs) and laboratory abnormalities 
•
Incidence of serious AEs (SAEs) and AEs 
leading to study drug discontinuation
•
To evaluate the efficacy of GS-5245 in reducing 
all-cause hospitalization
•
Proportion of participants with all-cause 
hospitalization by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
COVID-19–related medically attended visits 
(MAVs) or all-cause death
•
Proportion of participants with COVID-19–
related MAVs or all-cause death by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
COVID-19–related MAVs
•
Proportion of participants with COVID-19–
related MAVs by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
all-cause death
•
Proportion of participants with all-cause death by 
Day 29


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•
To evaluate the efficacy of GS-5245 in reducing 
the duration and severity of COVID-19 
symptoms
•
Time to COVID-19 symptom alleviation by 
Day 15 
•
To evaluate the antiviral activity of GS-5245 on 
SARS-CoV-2 nasal swab viral load at Day 5
•
Change from baseline (Day 1) in SARS-CoV-2 
nasal swab viral load at Day 5
•
To evaluate the plasma pharmacokinetic(s) (PK) 
of GS-441524 (metabolite of GS-5245)
•
Plasma concentrations and PK parameters 
AUCtau, Ctau, and Cmax of GS-441524, as 
available
Study Design: This Phase 3 study will be a randomized, double-blind, placebo-controlled 
study comparing the safety and efficacy of oral GS-5245 with placebo in nonhospitalized 
participants with COVID-19 who are at high risk of progression to hospitalization.
After screening procedures, eligible participants may be randomized in a 1:1 ratio to receive 
GS-5245 or placebo.
Randomization will be stratified by duration of symptoms at enrollment (≤ 3 days versus 
> 3 days), and vaccination status (ever versus never).
Number of Participants Planned:
Approximately 2300 participants will be randomized into this study. Up to 3150 participants 
may be enrolled depending on the sample size re-estimation result. 
Target Population: Nonhospitalized participants with COVID-19 with at least 1 risk factor (if 
unvaccinated) and at least 2 risk factors (if vaccinated at any point) for disease progression. 
Duration of Intervention: Participants will receive oral GS-5245 or placebo for 5 days.
Diagnosis and Main Eligibility Criteria:
Participants must meet all the following inclusion criteria to be eligible for participation in this 
study:
1) Aged ≥ 18 years at screening.
2) Willing and able to provide written informed consent, or with a legal representative who 
can provide informed consent (where locally and nationally approved).
3) SARS-CoV-2 infection confirmed by PCR or an approved alternative assay (eg, Rapid 
Antigen Test) ≤ 5 days before randomization. Serologic tests will not be accepted.
4) Initial onset of COVID-19 signs/symptoms ≤ 5 days before randomization with ≥ 1 of the 
following targeted signs/symptoms present at randomization:
a) Stuffy or runny nose. 


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b) Sore throat. 
c) Shortness of breath (difficulty breathing).
d) Cough.
e) Low energy or tiredness. 
f)
Muscle or body aches. 
g) Headache.
h) Chills or shivering. 
i)
Feeling hot or feverish.
j)
Nausea.
k) Vomiting.
l)
Diarrhea.
5) Not currently hospitalized or requiring hospitalization.
6) Presence of ≥ 1 risk factor (if unvaccinated) or ≥ 2 risk factors (if vaccinated at any point) 
for progression to severe disease. Risk factors are the following:
a) Aged ≥ 50 years.
b) Current or recent (≤ 6 months prior to randomization) cancer (other than localized skin 
cancer).
c) Have human immunodeficiency virus infection.
d) Prior splenectomy.
e) Prior solid organ, stem cell, or bone marrow transplant.
f)
Have systemic rheumatologic or dermatologic disorders.
g) Use of systemic immunosuppressive agents, eg, high-dose corticosteroids (ie, ≥ 20 mg 
of prednisone or equivalent per day administered for ≥ 2 weeks), alkylating agents, 
antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic 
agents classified as severely immunosuppressive, tumor necrosis factor blockers, other 
biologic agents that are immunosuppressive or immunomodulatory.
h) Have cerebrovascular disease.


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i)
Have cardiovascular disease, including heart failure, coronary artery disease, 
cardiomyopathies, and hypertension.
j)
Have chronic kidney disease (provided participant does not meet exclusion criterion 7).
k) Have chronic lung disease (interstitial lung disease, pulmonary embolism, pulmonary 
hypertension, bronchiectasis, or chronic obstructive pulmonary disease).
l)
Have chronic liver disease.
m) Have cystic fibrosis.
n) Have diabetes mellitus, type 1 and/or type 2.
o) Have neurodevelopmental and/or neurodegenerative conditions.
p) Have a body mass index ≥ 25 kg/m2.
q) Have sickle cell disease.
r)
Have primary immunodeficiencies.
s) Have compensated cirrhosis.
t)
Have asthma.
u) Have ≥ 20 pack-year smoking history and currently smoking or have quit within the 
past 15 years.
Exclusion criteria for participation include:
1) Anticipated access to and use of authorized or approved COVID-19 therapies during the 
current COVID-19 illness < 5 days after randomization (therapies include 
nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir [RDV, Veklury®], 
monoclonal antibodies).
2) Received any approved, authorized, or investigational direct-acting antiviral drug against 
SARS-CoV-2 for the treatment of COVID-19 < 28 days or < 5 half-lives, whichever is 
longer, before randomization.
3) Anticipated need for hospitalization < 48 hours after randomization.
4) New oxygen requirement < 24 hours before randomization.
5) Known influenza or any other suspected or confirmed concurrent active systemic infection 
other than COVID-19 that may interfere with the evaluation of response to the study drug.


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6) Decompensated cirrhosis (Child-Pugh class B or class C) or acute liver injury/failure.
7) Undergoing dialysis, or known history of moderate or severe renal impairment, or known 
CLcr < 60 mL/min (as calculated by Cockroft-Gault) or eGFR < 60 mL/min/1.73m2 within 
the last 6 months. Potential participants meeting the laboratory criterion may be enrolled if 
test results available before dosing show that renal function no longer meets this criterion. 
8) Known history of any of the following abnormal laboratory results (< 6 months before 
randomization) unless confirmed as resolved to not meet criteria at screening.
a) Alanine aminotransferase (ALT) ≥ 5  upper limit of normal (ULN).
b) Bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s syndrome).
9) Positive urine pregnancy test at screening.
10) Breastfeeding (nursing).
11) Unwilling to use protocol-mandated birth control.
12) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
13) Requirement for ongoing therapy with or prior use of any prohibited medications.
14) Received an approved, authorized, or investigational COVID-19 vaccine (including 
booster dose) < 120 days before randomization. 
15) Any inability to take study drug or comply with study procedures that, in the opinion of 
the investigator, would make the participant unsuitable for the study. 
Study Procedures/Frequency:
•
Screening: within 48 hours of the baseline visit (screening visit can be the same as day as 
the baseline visit).
•
Study treatment period: Day 1 (baseline) to Day 5.
•
Posttreatment follow-up: Up to 29 days (+ 5 days) after the first dose of study drug 
(in-person or virtual).
The schedule of study procedures is presented in Table 1.
Test Product, Dose, and Mode of Administration: 
GS-5245 350 mg (1  350 mg tablet) administered orally twice daily without regard to food 
with approximately 240 mL of water for 5 days.


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Reference Therapy, Dose, and Mode of Administration: 
Placebo administered orally twice daily without regard to food with approximately 240 mL of 
water for 5 days.
Statistical Methods:
A total of 2300 participants provides > 90% power to detect a ratio of 0.25 (GS-5245 to 
placebo in the primary endpoint [proportion of COVID-19–related hospitalization or all-cause 
death by Day 29], which is equal to a hazard ratio of 0.25) using a 2-sided significance level of 
0.05 assuming the event rate is 2% in the placebo group.
The primary endpoint will be analyzed using a Cox proportional hazards model with the 
stratification factors (duration of symptoms and vaccination status) as covariates. The hazard 
ratio and 95% CI will be provided.
A gatekeeping approach will be used for testing the key secondary endpoints. The endpoints 
will be tested in the following sequential order:
•
Proportion of participants with all-cause hospitalization by Day 29.
•
Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29.
•
Proportion of participants with COVID-19–related MAVs by Day 29.
•
Proportion of participants with all-cause death by Day 29.
An unblinded interim analysis of efficacy and futility is planned after 50% of planned 
participants complete the Day 29 assessment or prematurely discontinue from the study, or 
50% of expected primary endpoint events occur, whichever comes first. If the interim is 
triggered by 50% of enrollment, an additional unblinded interim analysis may be conducted 
after 50% of expected events have occurred. The unblinded interim analysis at 50% of 
expected events will include a sample size re-estimation.


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STUDY SCHEMA
Figure 1.
Study Schema
COVID-19 = coronavirus disease 2019; D = Day
a
Access determined at the site level by the principal investigator and participant.
b
Effective COVID-19 antiviral therapies such as nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, 
monoclonal antibodies, or any other locally authorized/approved direct-acting therapy against SARS-CoV-2.
Participants who have no access to or cannot take errective COVID-19 antiviral therapies' 
Exclude pruticipants who have access to and can take effective COVID-19 antiviral therapiesb 
Unvaccinated + 
I 1isk factor 
Vaccinated + 
2 risk factors 
Initial symptoms within :S 5 days of enrollment 
D • 
0 
I 
2 
3 
4 
5 
15 
End of Study • 
29 
Screening within 
48 hours p1ior to 
the scheduled 
fast dose 
(Screening and 
Day I visits may 
occur on the 
Study Period (Study Days) 
................................................................ 
srune day) 
Stratification factors include: 
Treatment 
Period: 
Days 1 to 5 
I. Duration of symptoms at emollment (:S 3 days vs > 3 days) 
2. Vaccination status (ever vs never) 
o In-person 
1 :1 Randomization 
GS-5245 350 mg x 5 days (twice daily) 
Placebo x 5 days (twice dally) 
... In-person or viin1al 


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STUDY PROCEDURES TABLE
Table 1.
Study Procedures Table
Study Visit
Screeninga
Baseline/
Day 1a, b
Day 3b
Day 5b
Day 10
Day 15b
Day 29
Early 
Discontinuation 
Visitb
Visit Window
± 1 dayc
± 2 days
+ 5 days
Visit Type
In Persond
In Persond 
or Virtuale
In 
Persond
In Persond or Virtuale
In Persond
Written informed consent 
X
Medical historyf 
X
Document SARS-CoV-2 infection
X
Complete physical examinationg
X
X
X
X
Symptom-directed physical examination
X
X
Height and weight
X
Vital signsh 
X
X
X
X
X
X
X
X
Screening ALT, bilirubin, serum creatinine, 
and CLcr/eGFRi 
X
Chemistry, coagulation, and hematology 
panelsj
X
X
X
X
X
Urine or serum pregnancy testsk
X
X
X
X
Mid-turbinate nasal swabl
X
X
X
X
X
X
SARS-CoV-2 serology
X
MAV information/oxygen supplementation 
requiremento
X
X
X
X
X
X
X
CCI
CCI


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Study Visit
Screeninga
Baseline/
Day 1a, b
Day 3b
Day 5b
Day 10
Day 15b
Day 29
Early 
Discontinuation 
Visitb
Visit Window
± 1 dayc
± 2 days
+ 5 days
Visit Type
In Persond
In Persond 
or Virtuale
In 
Persond
In Persond or Virtuale
In Persond
COVID-19 Symptom Questionnairep
X
X
X
X
X
X
X
PROMIS-29
X
X
X
X
WPAI + CIQ: COVID19
X
X
X
X
Study drug dispensation
X
Study drug dosing (GS-5245 or placebo)
X
X
X
Study drug bottle returnq
X
X
X
X
X
Adverse events and concomitant medications
X
X
X
X
X
X
X
X
ALT = alanine aminotransferase; CLcr = creatinine clearance; COVID-19 = coronavirus disease 2019; ED = early discontinuation; eGFR = estimated glomerular filtration rate; 
MAV = medically attended visit; PCR = polymerase chain reaction; PK = pharmacokinetic(s); PROMIS-29 = Patient-Reported Outcomes Measurement Information System-29; 
RT-qPCR = reverse transcriptase-quantitative polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WPAI + CIQ:COVID19 = Work 
Productivity and Activity Impairment + Classroom Impairment Questions: COVID-19 Infection
a
Screening window is within 48 hours of the Day 1 visit. Day 1 visit may occur on the same day as screening. If the Day 1 and screening visits are the same day, do not repeat 
physical exam and vital signs.
b
Laboratory tests for safety will be performed on Days 1 and 5, on Days 3 and 15 when an in-person visit is conducted, and at early discontinuation.
c
Day 3 and Day 5 visits should be conducted on separate calendar days. 
d
In-person is defined as a visit at a medical facility or elsewhere by a health care provider (where permitted).
e
Virtual visit is defined as an interaction with a health care professional using telephone or online-based interaction (eg, telehealth, webcast, video conferencing).
f
Medical history will include the date of first COVID-19 symptoms, overall COVID-19 symptoms, all COVID-19 vaccinations prior to screening, exposure source, 
demographics, baseline characteristics, allergies, and all other medical history.
g
A complete physical examination must include source documentation of general appearance and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, 
mouth, and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; and neurological. For participants with 
compensated cirrhosis, a complete physical exam must also include a clinical assessment of ascites (absent, slight, or moderate) and a clinical assessment of hepatic 
encephalopathy (Absent, Grade I, Grade II, Grade III, or Grade IV), as described in Section 6.3.2.1. Urogenital and reproductive examination should only be completed if 
clinically indicated.
h
Vital signs include heart rate, respiratory rate, temperature, oxygen saturation, and blood pressure. Vital signs are collected at in-person visits only.
i
Screening: Serum ALT, bilirubin, serum creatinine, and CLcr/eGFR assessments at screening (prior to dosing) are not required unless deemed necessary by the investigator to 
confirm eligibility, using a local laboratory. See Appendix 11.4 for country-specific requirements.
j
All required baseline laboratory assessments should be collected prior to first study drug dose. 


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k 
At screening, a mine pregnancy test will be performed at the local laboratory for participants assigned female at birth and of childbea1ing potential. On Day 1, Day 15, and 
ED visits, these pa1ticipants will have a serum pregnancy test performed via the central laboratory for in-person visits or a urine pregnancy test for virtual visits. At screening, 
a follicle-stimulating ho1mone test is required to confirm the postmenopausal state in participants younger than 54 years, who have stopped menstmating for at least 
I 
r 
12 months but do not have documentation of ovarian hormonal faihu·e, as described in Appendix 11.3 
A mid-ttubinate nasal swab will be collected at in-person visits and used for SARS-Co V-2 RT-qPCR, potential multiplex viral PCR, potential infectious viral titer assessment, 
and otential resistance testino. The nasal swab must be collected b clinic/stud 
ersonnel in erson. For viitual visits on Da s 3, 10, or 15 no sam !es will be collected. 
o 
Me 1ca y at.ten e v1S1t rn ormation rnc u es any rnteractions w1 
1ea t 1 care pro ess1ona s o er t an stu y sta or es1gnees rnc u rng hospitalization; in-person 
emergency, m·gent, or primary care visits; or any other in-person visit attended by the participant and a health care professional. The nattu·e and cause of the visit should be 
identified. Medically attended visit information and oxygen supplementation information should be collected through Day 29. 
p 
The COVID-19 symptom questionnaire should be completed daily (at approxiniately the same time each day) from predose (prior to first dose on Day 1) through Day 15, and 
on Day 29. If a pa1ticipant discontinues from the study early, the pa1ticipant should complete this questionnaii·e during the early discontinuation visit. 
q 
Study dmg bottle should be returned by the pa1ticipant on Day 5, if the participant has already completed both doses of study dmg. If the participant has study dmg at the end 
of the Day 5 visit, the participant may return the study dmg bottle on Day 10. If the Day 10 visit is viitual, dmg accountability should be pe1fon11ed virtually and the 
pa1ticipant will be instmcted on returning the study dmg bottle. 
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1.
INTRODUCTION
1.1.
Background
Remdesivir (RDV; Veklury®) is approved for the treatment of COVID-19 in hospitalized and 
nonhospitalized patients in the United States (US), the European Union (EU), Japan, and other 
countries in pediatric and adult patients {VEKLURY 2022a, Veklury 2022b}. The broader utility 
of RDV for the nonhospitalized treatment of early infection with SARS-CoV-2 is limited due to 
the intravenous (IV) route of administration; therefore, availability of more convenient oral 
treatment options is crucial for early therapy. Molnupiravir (LagevrioTM) and 
nirmatrelvir/ritonavir (PaxlovidTM) are the only 2 oral medications authorized for emergency use 
for the treatment of COVID-19 in the US. In the EU, nirmatrelvir/ritonavir is the only oral 
medication authorized for the treatment of COVID-19 in adults who do not require supplemental 
oxygen and who are at increased risk of progression to severe disease (Conditional approval). 
Molnupiravir is not authorized in the EU but the Committee for Medicinal Products for Human 
Use has issued advice on its use under Article 5(3) for the treatment of confirmed COVID-19 in 
adults who do not require supplemental oxygen and who are at increased risk of progression to 
severe COVID-19 in the EU. Molnupiravir demonstrated limited efficacy in the MOVe-OUT 
study {Jayk Bernal 2022}. Nirmatrelvir/ritonavir demonstrated efficacy in nonhospitalized 
patients with COVID-19, but significant drug-drug interactions (DDIs) limit use particularly in 
participants aged 65 years and older or immunocompromised patients (Pfizer’s EPIC-HR 
[“Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients”] [Study C4671005]) 
{Hammond 2022}. Furthermore, the pill burden of the recommended dosage of 
nirmatrelvir/ritonavir (a total of 30 tablets over 5 days), may be challenging from an adherence 
standpoint.
GS-5245 is a mono-5’-isobutyryl ester prodrug of GS-441524. Following oral administration, 
GS-5245 is extensively hydrolyzed presystemically to the parent nucleoside GS-441524, which 
can then enter cells where it is subsequently anabolized to the same active triphosphate 
metabolite (GS-443902) as RDV. GS-5245 has been developed with the intent to deliver 
consistent and high systemic exposures to GS-441524 following oral administration. At targeted 
therapeutic exposures with GS-5245, GS-441524 exposures are anticipated to be approximately 
14-fold higher as compared to exposures with RDV.
Availability of a highly effective oral treatment with a high barrier to resistance, similar to that of 
RDV, with minimal DDIs and with fewer tablets to take (ie, the dose of GS-5245 selected for 
Phase 3 is one 350 mg tablet twice daily) has the potential to address a critical public health need 
in the ongoing COVID-19 pandemic.
GS-5245 represents a promising oral option for the treatment of COVID-19 in nonhospitalized 
patients who are at increased risk of progressing to severe COVID-19, that is anticipated to fulfill 
an unmet medical need.


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1.2.
Background on Study Interventions
1.2.1.
GS-5245
1.2.1.1.
General Information
GS-5245 is a mono-5’-isobutyryl ester prodrug of GS-441524, and following oral administration, 
is extensively hydrolyzed presystemically to yield the parent nucleoside of RDV, GS-441524. 
The prodrug GS-5245 was designed to specifically increase the oral bioavailability of 
GS-441524.
For further information on GS-5245, refer to the current investigator’s brochure (IB) for 
GS-5245, including information on the following:
•
Toxicology
•
Nonclinical pharmacology
•
Nonclinical pharmacokinetics (PK)
Additional relevant nonclinical toxicology and clinical data are provided in Section 1.2.1.1.1, 
Section 1.2.1.1.3, and Section 1.2.1.1.3.
1.2.1.1.1.
Toxicology
1.2.1.1.1.1.
Fertility Study
The objectives of the fertility study (Study TX-611-2011) were to determine the potential 
adverse effects/disturbances in the reproductive process resulting from oral administration of 
GS-5245 to male and female Wistar Han rats from premating to conception and from conception 
to implantation. These included identification of deficits in estrous cycling, tubal transport, 
implantation, development of the preimplantation stages of the embryo in the female, and 
functional reproductive effects (alterations in libido and epididymal sperm maturation) in the 
male. Four groups (25 main study and 6 toxicokinetic [TK] phases/groups) of male rats were 
administered GS-5245 by oral gavage doses once daily at 0 (vehicle control), 125, 250, or 
500 mg/kg/day. Males were dosed for 14 days prior to mating and continuing through one day 
prior to euthanasia. Three groups (25 main and 6 TK/groups) of female rats were dosed at 0, 125, 
or 250 mg/kg/day. An additional 25 females were not dosed but used for breeding purposes only 
for the 500 mg/kg/day males. Females in the main study were dosed for 14 days prior to mating 
and continuing through Gestation Day 7. 
There were no GS-5245–related effects on male survival, clinical and macroscopic observations, 
body weights, body weight gains, food consumption, and organ weights at ≤ 250 mg/kg/day. 
Male reproductive performance (mating, fertility, and pregnancy indices and precoital intervals) 
and spermatogenic parameters were unaffected by GS-5245 administration at ≤ 500 mg/kg/day. 
There were no GS-5245–related effects on female survival or clinical observations at 
125 mg/kg/day or on premating and gestation body weights, body weight gains, food 


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consumption, estrous cycle length, reproductive performance, macroscopic findings, or organ 
weights at ≤ 250 mg/kg/day. Intrauterine survival was also not affected by GS-5245 
administration at any dose level.
Based on the lack of effects on reproductive performance and spermatogenic parameters, a dose 
level of 500 mg/kg/day (the highest dose level tested in males) was considered to be the no 
observed adverse effect level (NOAEL) for male reproductive toxicity. Based on the lack of 
effects on female reproductive performance, estrous cyclicity, and intrauterine survival, the 
NOAEL for female reproductive toxicity and embryonic toxicity was considered to be 
250 mg/kg/day (the highest dose level tested in females).
Based on mortality, clinical observations, body weight losses, and lower body weight gains and 
food consumption at 500 mg/kg/day in males, a dose level of 250 mg/kg/day was considered to 
be the NOAEL for male systemic toxicity. Based on mortality, clinical observations, body 
weight losses, and lower body weight gains and food consumption at 250 mg/kg/day in females, 
a dose level of 125 mg/kg/day was considered to be the NOAEL for female systemic toxicity. 
At the NOAELs for male and female reproductive toxicity, systemic GS-441524 exposures were 
approximately 5.7- and 6.7-fold higher than projected therapeutic exposure with oral 350 mg 
twice daily GS-5245 administration.
The results and conclusions of the fertility study support the planned population in the Phase 3 
study. 
1.2.1.1.1.2.
Phototoxicity
Results of a 3T3 neutral red uptake (NRU) test with GS-441524 using mouse fibroblasts showed 
that GS-441524 was not cytotoxic and did not display an half-maximal inhibitory concentration 
(IC50) with or without ultraviolet radiation exposure, up to the highest soluble concentration 
tested (100 μg/mL) (Study TX-611-2026). Administration of GS-5245 is not considered to 
exhibit a photosafety risk.
1.2.1.1.2.
Nonclinical Pharmacokinetics: Rat Absorption, Distribution, Metabolism, and 
Excretion Study
A single dose [14C]GS-5245 radiolabeled study in rats following oral administration 
(Study AD-611-2021) showed rapid absorption, broad distribution to most tissues, and complete 
first-pass metabolism (Study AD-611-2022). No prodrug itself was detected in plasma, urine, 
bile, or feces. The plasma metabolite GS-441524 accounted for 98% of total plasma radioactivity 
exposure. Means of 33.1% and 51.7% of the administered radioactivity were excreted in urine 
and feces, respectively, by 168 hours. Renal excretion was the major route of elimination of 
GS-441524 from the systemic circulation. Fecal excretion of GS-5245 as GS-441524 metabolite 
was the major route of elimination of unabsorbed drug and is concordant with moderate oral 
bioavailability in rats (Study AD-611-2009).


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1.2.1.1.3.
Clinical Studies of GS-5245
1.2.1.1.3.1.
Study GS-US-611-6248
Study GS-US-611-6248 is an ongoing Phase 1 study in healthy volunteers to evaluate the safety, 
tolerability, and PK of GS-5245. This randomized, blinded, placebo-controlled study is 
evaluating single and multiple doses with staggered dose escalation and adaptive GS-5245 dose 
selection. The study will also evaluate the impact of food on bioavailability.
As of 02 May 2022, 48 participants have been administered GS-5245 at single doses of 100 mg 
(Cohort 1), 300 mg (Cohort 2), 900 mg (Cohort 3) and 1600 mg (Cohort 4) and multiple doses 
for 5 days at doses of 500 mg twice daily (Cohort 5) and 900 mg once daily (Cohort 6). Each 
cohort enrolled 8 participants who were randomized in a 3:1 ratio to receive oral GS-5245 or 
placebo. Preliminary PK and blinded safety data are available for all participants dosed in these 
6 cohorts. 
Additionally, preliminary topline PK data are available from 22 participants (11 in each cohort) 
administered GS-5245 at a single dose of 500 mg under fasted (Cohort 8) and fed (Cohort 9) 
conditions. The formulation of GS-5245 evaluated in these cohorts is the same as that for 
administration in the current Phase 3 study. Administration in the fasted state was defined as at 
least 10 hours of overnight fasting. Administration in the fed state was defined as within 
5 minutes of completion of a high-fat/high-calorie meal (800 to 1000 kcal, 50% fat). 
Additionally, participants in both cohorts were restricted from food (4 hours after dose) and 
water consumption (1 hour before and 2 hours after dose) except for 240 mL water given at the 
time of dosing. Topline safety data from Cohorts 8 and 9 are not yet available.
Disposition and Baseline Characteristics
Overall, for Cohorts 1 to 6, most participants were male (56.3%) and not Hispanic or Latino 
(87.5%). Approximately even proportions were White (45.8%) or Black or African American 
(41.7%). The median age was 31 years. Demographics were generally balanced between the 
groups.
Participant characteristics data for Cohorts 8 and 9 are not yet available.
Safety Results
Overall, for Cohorts 1 to 6, administration of GS-5245 or placebo was generally safe and well 
tolerated. 
Treatment-emergent adverse events (AEs) were reported for 10 of 48 (20.8%) participants. Most 
AEs were Grade 1. There was 1 Grade 2 AE (vertigo not attributed to study drug), and no 
Grade 3 or higher AEs. There were no serious AEs (SAEs), AEs leading to premature 
discontinuation of study drug or deaths. The only AEs reported in more than 1 participants were 
headache (3 of 48 participants [6.3%]), and contact dermatitis (2 of 48 participants [4.2%]). The 
only AEs attributed to study drug was Grade 1 headache, which was reported for 2 of 8 (25%) of 
participants in Cohort 5 (500 mg twice daily for 5 days).


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Overall, 25 of 48 participants (52.1%) had graded laboratory abnormalities. For each laboratory 
parameter, most abnormalities were reported for 1 or fewer participants in each cohort. The most 
frequently reported graded laboratory abnormality was decreased creatinine clearance (CLcr) 
which was reported for 13 of 48 participants (27.1%) overall and for 6 of 8 participants (75%) in 
Cohort 4 (1600 mg single dose). Creatinine clearance decreases were generally transient and 
returned to baseline levels. There was only 1 Grade 3 or higher laboratory abnormality: 
1 participant in Cohort 2 whose lipase was within normal limits on Days 2 and 5 (300 mg single 
dose) experienced a lipase elevation at Day 3.
There were no clinically relevant changes in vital signs, electrocardiograms (ECGs), or 
ophthalmologic examinations.
The safety profiles for Cohorts 8 and 9 are not yet available. In these cohorts, no SAEs, deaths, 
pregnancies, or study drug–related discontinuations were reported.
Pharmacokinetic Results
Plasma:
Overall, GS-5245 PK was characterized by fast absorption, linear PK, and similar terminal 
phases across 100 mg to 900 mg single doses tested. Less than dose-proportional increases in PK 
exposures were observed between 900 mg to 1600 mg (Table 2). Plasma exposures were 
exclusive to the GS-441524 metabolite; no detectable levels of GS-5245 prodrug were observed 
in the plasma at the 100 mg to 900 mg doses and transient exposure was observed at the 1600 mg 
dose. Multiple-dose PK was consistent with what was expected based on single-dose PK. 
Accumulation of GS-441524 after 5 days of dosing was consistent with plasma t1/2 
(approximately 35% and 13% after twice daily and once daily dosing, respectively) (Table 3).
Administration of GS-5245 with a high-fat meal had no effect on the overall plasma exposures of 
GS-441524; both Cmax and AUCinf were within the predefined no-effect bounds (0.60-1.67 for 
Cmax and 0.70-1.43 for AUCinf). The geometric least squares mean ratio (90% CI) of fed versus 
fasted for GS-441524 Cmax and AUCinf were 0.94 (0.73-1.22) and 1.13 (0.99-1.29), respectively. 
A high-fat meal slowed the rate of GS-5245 absorption, increasing GS-441524 Tmax from 0.75 to 
3.0 hours; this increase in Tmax is consistent with the anticipated delay in gastric emptying 
following a meal. The PK in Cohort 8 was consistent with data from previous cohorts, which 
received GS-5245 in fasted state. 
Urine:
GS-441524 metabolite renal excretion rate (CLr) was 150 to 180 mL/min, which is above the 
typical glomerular filtration rate (120 mL/min) and consistent with historical data with IV RDV. 
No GS-5245 prodrug was detected in urine. The majority of the dose excreted in urine as 
GS-441524 was recovered over the first 6 to 12 hours after dosing with small incremental 
increases over the subsequent intervals (up to 96 hours). Approximately 40% to 45% of GS-5245 
dose was recovered as GS-441524 in urine over first 24 hours postdose.


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Peripheral Blood Mononuclear Cells (PBMCs):
Robust intracellular activation of GS-441524 to active triphosphate metabolite (GS-443902) was 
observed. Dose-proportional increases in the intracellular concentrations of GS-443902 were 
observed in PBMCs. Substantial accumulation of intracellular GS-443902 levels was observed 
after repeat dosing for 5 days (6-fold for twice daily and 3-fold for once daily; AUC0-24h), which 
was consistent with the long half-life of this metabolite (Table 4).
Table 2.
GS-US-611-6248: Plasma Pharmacokinetic Parameters of GS-441524 
in Single Ascending Dose Cohorts 1 Through 4
PK Parametera
GS-5245 100 mg 
(N = 6)
GS-5245 300 mg 
(N = 6)
GS-5245 900 mg 
(N = 6)
GS-5245 1600 mg 
(N = 6)
GS-441524
Cmax (ng/mL)
570 (30.5)
1830 (32.6)
5980 (45.1)
7060 (24.7)
Tmax (h)
0.75 (0.56, 0.75)
0.75 (0.56, 1.5)
0.75 (0.75, 0.75)
1.50 (0.75, 1.88)
t1/2 (h)
6.3 (6.0, 6.7)
6.1 (5.0, 6.9)
6.5 (6.3, 6.9)
12.5 (7.1, 19.2)
AUCinf (h•ng/mL)
3820 (35.0)
10,900 (23.1)
37,200 (34.9)
48,100 (18.8)
%CV = percentage coefficient of variation; PK = pharmacokinetic(s); Q1 = first quartile; Q3 = third quartile
a
Data presented as mean (%CV), except for Tmax and t1/2 [median (Q1, Q3)].
Table 3.
GS-US-611-6248: Plasma Pharmacokinetic Parameters of GS-441524 
in Multiple Ascending Dose Cohorts 5 and 6
PK Parametera
Multiple Dose
Day 1
(GS-5245 500 mg 
BID) 
(N = 6)
Multiple Dose 
Day 5
(GS-5245 500 mg 
BID)
(N = 6)
Multiple Dose 
Day 1
(GS-5245 900 mg 
QD)
(N = 6)
Multiple Dose 
Day 5
(GS-5245 900 mg 
QD)
(N = 6)
GS-441524
Cmax (ng/mL)
3820 (32.7)
4620 (18.2)
6230 (14.5)
5180 (19.6)
Tmax (h)
0.75 (0.69-1.5)
0.75 (0.50-1.5)
0.75 (0.75-1.88)
1.5 (0.75-3.0)
C24 (ng/mL)
—
533 (17.0)
—
158 (29.5)
t1/2 (h)
—
—
—
10.3 (9.1, 19.0)
AUC0-24h (h•ng/mL)b
~31,800b
~43,000b
32,000 (11.5)
35,500 (12.3)
%CV = percentage coefficient of variation; BID = twice daily; PK = pharmacokinetic(s); Q1 = first quartile; Q3 = third quartile; 
QD = once daily
a
Data are presented as mean (%CV), except for Tmax as median (Q1, Q3).
b
For BID dosing AUC0-24h = 2  AUC0-12h and does not account for the expected additional accumulation; Day 1 
AUC0-12h = 15,900 (18.4); Day 5 AUC0-12h = 21,500 (19.3).


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Table 4.
GS-US-611-6248: PBMC Pharmacokinetic Parameters of GS-443902 
in Multiple Ascending Dose Cohorts 5 and 6
PK Parametera
Multiple Dose 
Day 1
(GS-5245 500 mg 
BID)
(N = 6)
Multiple Dose
Day 5
(GS-5245 500 mg 
BID)
(N = 6)
Multiple Dose
Day 1
(GS-5245 900 mg 
QD)
(N = 6)
Multiple Dose 
Day 5
(GS-5245 900 mg 
QD)
(N = 6)
GS-443902
Cmax (μM)
8.67 (41.4)
46.8 (50.0)
7.15 (56.5)
27.5 (44.1)
Tmax (h)
9.0 (6.0, 12.0)
12.0 (4.5, 12.0)
24.0 (6.0, 24.0)
—
C24 (μM)
—
46.0 (33.4)
—
23.2 (65.6)
t1/2 (h)
—
—
—
34.8 (28.9, 44.3)c
AUC0-24h (h•μM)b
~132b
~852b
104 (45.7)
348 (6.0)
%CV = percentage coefficient of variation; BID = twice daily; PBMC = peripheral blood mononuclear cell; 
PK = pharmacokinetic(s); Q1 = first quartile; Q3 = third quartile; QD = once daily
a
Data are presented as mean (%CV), except for Tmax and t1/2 as median (Q1, Q3).
b
For BID dosing AUC0-24h = 2  AUC0-12h and does not account for the expected additional accumulation; Day 1 
AUC0-12h = 65.9 (39.8); Day 5 AUC0-12h = 426 (48.4).
c
n = 3.
Conclusion
Overall, GS-5245 at single doses of 100 mg to 1600 mg and multiple doses of 500 mg twice 
daily or 900 mg once daily has been generally safe and well tolerated. Transient Grade 2 CLcr 
changes were predominantly observed in participants who received 1600 mg or placebo (6 of 
8 participants [75%]). There were no AEs associated with the laboratory findings. The only 
treatment-related AE reported in more than 1 participant was Grade 1 headache (n = 2).
Oral administration of GS-5245 resulted in high plasma exposures of the GS-441524 metabolite, 
with no detectable levels of prodrug itself. GS-5245 exhibited linear PK and similar terminal 
phases across 100 mg to 900 mg single doses tested. Less than proportional increases in AUC 
and Cmax were observed between the 900 mg and 1600 mg single doses tested. Terminal plasma 
t1/2 of GS-441524 following oral administration of GS-5245 was 6 to 6.5 hours. Robust 
activation of GS-441524 to intracellular active triphosphate metabolite was observed and 
significant accumulation following twice daily dosing. Administration of GS-5245 with a 
high-fat meal decreased the rate but not the extent of GS-5245 absorption; thus, GS-5245 may be 
administered without regard to food. 
1.2.1.1.3.2.
Study GS-US-611-6409
Study GS-US-611-6409 is an ongoing Phase 1 study to evaluate transporter and cytochrome 
P450 enzyme (CYP)-mediated DDIs between GS-5245 and probe drugs. This is an open-label, 
multicenter, fixed- (Cohorts 1, 2, 3, 5, and 7) or randomized-sequence (Cohorts 4 and 6) 
crossover study in healthy participants. The following interactions are planned to be evaluated in 
each cohort:


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•
Cohorts 1 and 2: GS-5245 as a victim of strong P-glycoprotein (P-gp) inhibition using 
ritonavir and nirmatrelvir/ritonavir, respectively.
•
Cohort 3: GS-5245 perpetrator effect on a probe CYP3A substrate midazolam (MDZ).
•
Cohort 4: GS-5245 perpetrator effect on a probe P-gp substrate, dabigatran (DAB).
•
Cohort 5: GS-5245 perpetrator effect on a probe organic anion transporting polypeptide 
(OATP) 1B1/1B3 substrate, pitavastatin (PIT).
•
Cohort 6: GS-5245 perpetrator effect on a probe organic cation transporter (OCT) 1 substrate 
metformin (MET).
•
Cohort 7: GS-5245 as a victim of gastric acid suppression using famotidine (FAM).
As of February 22, 2023, preliminary PK results are available in Cohorts 1 (n = 15), 3 (n = 19), 
5 (n = 23), and 7 (n = 14). For Cohort 1, participants received a single dose of GS-5245 350 mg 
on Day 1, followed by ritonavir 100 mg twice daily on Days 4 to 8 with a single dose of 
GS-5245 350 mg coadministered on Day 6. For Cohort 3, participants received a single dose of 
MDZ 2.5 mg on Day 1 and a single dose of GS-5245 500 mg coadministered with a single dose 
of MDZ 2.5 mg on Day 3. For Cohort 5, participants received a single dose of PIT 2 mg and a 
single dose of GS-5245 500 mg coadministered with a single dose of PIT 2 mg on Day 4. For 
Cohort 7, participants received a single dose of GS-5245 350 mg on Day 1 and a single dose of 
FAM 40 mg followed by a single dose of GS-5245 350 mg 2 hours after FAM on Day 4. All 
doses were oral and administered under fasting conditions. Cohort 2 was not enrolled based on 
emerging results from Cohort 1.
The safety profiles for Cohorts 1, 3, 5, and 7 are not yet available. In these cohorts, no SAEs, 
deaths, pregnancies, or study drug–related discontinuations were reported.
Pharmacokinetic Results
GS-5245 as a Perpetrator 
Cohort 3: Midazolam was used as a sensitive CYP3A substrate. Coadministration of MDZ with 
GS-5245 did not result in changes to plasma exposures of MDZ or its metabolite, 
1-hydroxymidazolam (1-OH-MDZ), as the geometric mean ratio (GMR) and 90% CI for Cmax, 
AUClast, and AUCinf were mostly within the predefined no-effect bounds of 80.0% to 125% 
(Table 5). 


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Table 5.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of Midazolam 
in Cohort 3
PK Parametera
MDZ 2.5 mg
(Reference, N = 19)
MDZ 2.5 mg + GS-5245 
500 mg
(Test, N = 19)
%GMR (90% CI)
Test/Reference
MDZ
Cmax (ng/mL)
10.0 (39.6)
11.5 (39.3)
114 (105, 124)
AUClast (h•ng/mL)
29.3 (50.5)
32.4 (51.2)
109 (103, 115)
AUCinf (h•ng/mL)
30.7 (50.7)
33.5 (50.6)
108 (102, 114)
1-OH-MDZ
Cmax (ng/mL)
3.75 (47.4)
4.27 (33.8)
117 (104, 132)
AUClast (h•ng/mL)
9.59 (44.5)
10.4 (27)
112 (103, 122)
AUCinf (h•ng/mL)
10.0 (30.8)b
11.4 (25.9)c
116 (107, 126)
%CV = percentage coefficient of variation; CI = confidence interval; GMR = geometric mean ratio; MDZ = midazolam; 
PK = pharmacokinetic(s); 1-OH-MDZ = 1-hydroxymidazolam
a
Data are presented as mean (%CV), unless otherwise specified.
b
N = 13, terminal elimination slope was not reliably estimated for some profiles, ie, adjusted R2 < 0.8. 
c
N = 18, terminal elimination slope was not reliably estimated for some profiles, ie, adjusted R2 < 0.8. 
Cohort 5: Pitavastatin was used as a sensitive OATP1B1/1B3 substrate. Coadministration of PIT 
with GS-5245 did not result in clinically significant changes to plasma exposures of PIT, as the 
GMR for Cmax, AUClast, and AUCinf were increased by 28% to 31% (Table 6). 
Table 6.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of Pitavastatin 
in Cohort 5
PK Parametera
PIT 2.0 mg
(Reference, N = 23)
PIT 2.0 mg + GS-5245 
500 mg
(Test, N = 20)
%GMR (90% CI)
Test/Reference
PIT
Cmax (ng/mL)
24.7 (43.1)
31.1 (61.1)
130 (112, 151)
AUClast (h•ng/mL)
56.5 (47.7)
77.90 (68.1)b
131 (121, 142)
AUCinf (h•ng/mL)
61.70 (45.5)
83.11 (66.2)b
128 (118, 138)
%CV = percentage coefficient of variation; CI = confidence interval; GMR = geometric mean ratio; PIT = pitavastatin; 
PK = pharmacokinetic(s)
a
Data are presented as mean (%CV), unless otherwise specified.
b
N = 18, terminal elimination slope was not reliably estimated for some profiles, ie, adjusted R2 < 0.8. 
GS-5245 as a Victim 
Cohort 1: Ritonavir was used as a strong P-gp inhibitor. Coadministration of GS-5245 with 
ritonavir did not result in changes to plasma exposures of GS-441524, as the GMR and 90% CI 
for Cmax, AUClast, and AUCinf were within the predefined no-effect bounds of 70.0% to 143% 
(Table 7).


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Table 7.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of GS-441524 
in Cohort 1
PK Parametera
GS-5245 350 mg
(Reference, N = 15)
RTV 100 mg BID
+ GS-5245 350 mg
(Test, N = 15)
%GMR (90% CI)
Test/Reference
GS-441524
Cmax (ng/mL)
2,700 (52.2)
2,700 (36.3)
104 (93.3, 117)
AUClast (h•ng/mL)
13,700 (27.5)
15,700 (20.6)
116 (108, 124)
AUCinf (h•ng/mL)
14,000 (26.8)
15,800 (20.4)
114 (106, 122)
%CV = percentage coefficient of variation; BID = twice daily; CI = confidence interval; GMR = geometric mean ratio; 
PK = pharmacokinetic(s); RTV = ritonavir
a
Data are presented as mean (%CV), unless otherwise specified.
Cohort 7: Famotidine was used as a representative acid-reducing agent (ARA). The overall effect 
of increased gastric pH by FAM on the absorption of GS-5245 was small. There was a 
32.5% decrease in the Cmax of GS-441524 with FAM, while the GMR and 90% CI for AUClast 
and AUCinf of GS-441524 were within the predefined no-effect bounds of 70.0% to 143% 
(Table 8).
Table 8.
GS-US-611-6409: Plasma Pharmacokinetic Parameters of GS-441524 
in Cohort 7
PK Parametera
GS-5245 350 mg
(Reference, N = 14)
GS-5245 350 mg + FAM 
40 mg
(Test, N = 13)b
%GMR (90% CI)
Test/Reference
GS-441524
Cmax (ng/mL)
2670 (31.6)
1800 (29.5)
67.5 (55.3, 82.3)
AUClast (h•ng/mL)
13,900 (19.6)
10,500 (18.8)
76.6 (71.4, 82.3)
AUCinf (h•ng/mL)
14,000 (19.4)
10,700 (17.9)
77.0 (71.9, 82.5)
%CV = percentage coefficient of variation; CI = confidence interval; FAM = famotidine; GMR = geometric mean ratio
a
Data are presented as mean (%CV), unless otherwise specified.
b
Data were not provided for 1 participant on Day 4.
Conclusion
GS-5245 as a perpetrator: GS-5245 is not an inhibitor of CYP3A (as observed with MDZ) or a 
clinically relevant inhibitor of OATP1B1/1B3 (as observed with PIT).
GS-5245 as a victim: There was no effect of P-gp inhibition (as observed with coadministration 
of GS-5245 with ritonavir) on plasma exposures of GS-441524. There was no clinically 
significant effect of increased gastric pH (as observed with FAM) on the plasma exposures of 
GS-441524; thus, GS-5245 may be coadministered with ARAs including antacids, other 
histamine H2-receptor antagonists, as well as proton-pump inhibitors.


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1.3.
Rationale for This Study
COVID-19 is a cause of an ongoing global pandemic with IV RDV being the first antiviral 
treatment approved by regulatory agencies in the US {VEKLURY 2022a, Veklury 2022b}, 
Europe {VEKLURY 2022a, Veklury 2022b} and multiple countries. More convenient options 
are needed for early intervention in the nonhospitalized COVID-19 population.
The oral bioavailability of RDV is low based on nonclinical studies (< 1% in cynomolgus 
monkey) and unlikely to generate adequate human systemic exposure of RDV to drive antiviral 
activity against SARS-CoV-2 in the lung {Mackman 2021}. GS-5245 is an ester prodrug of the 
parent nucleoside of RDV, GS-441524. Following oral administration, GS-5245 is projected to 
deliver high systemic levels of GS-441524 and adequate formation of the active nucleoside 
triphosphate metabolite, GS-443902, in tissues where SARS-CoV-2 replicates. Administration of 
oral GS-5245 therefore represents a promising approach for the treatment of COVID-19.
This Phase 3 superiority study will evaluate GS-5245 compared with placebo in participants who 
are at high risk for disease progression but who:
•
Cannot take existing therapies that are authorized or approved (ie, nirmatrelvir/ritonavir, 
molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies, or any other locally authorized or 
approved direct-acting therapy against SARS-CoV-2) because of medical contraindications 
or clinical concerns from the investigator. 
•
Continue to lack access to existing therapies that are authorized or approved after exhausting 
all locally available means in attempts to make these therapies accessible for participants.
Participants who do not have medical or clinical contraindications to authorized or approved 
therapies, and also have concurrent access to and ability to easily receive nirmatrelvir/ritonavir, 
molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies, or any other locally authorized or 
approved direct-acting therapy against SARS-CoV-2, are excluded from enrollment and should 
be treated with these agents outside this clinical study.
1.4.
Rationale for Dose Selection of GS-5245
The proposed dose for evaluation in this Phase 3 study is GS-5245 350 mg twice daily for 
5 days. This dose was selected based on the totality of available clinical and nonclinical data and 
with careful consideration of the overall risk-benefit profile.
GS-5245 safety and PK were evaluated in a Phase 1 single and multiple ascending dose study 
(GS-US-611-6248) in healthy participants. Single GS-5245 doses up to 1600 mg and multiple 
doses of GS-5245 500 mg twice daily and GS-5245 900 mg once daily for 5 days were generally 
safe and well tolerated (most AEs were Grade 1 in severity). A graded laboratory abnormality of 
decreased CLcr was observed across all cohorts, although there was a disproportionately higher 
number of participants with decreased CLcr at the highest dose evaluated (single GS-5245 
1600 mg dose).


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Following oral administration of GS-5245, the GS-441524 metabolite was the only circulating 
species. The plasma half-life of this metabolite was approximately 6 hours, supporting twice 
daily dosing. The twice daily dosing regimen also provided higher daily exposure (AUC0-24h), 
higher Ctau concentrations, and lower Cmax as compared with once daily dosing 
(Section 1.2.1.1.2).
GS-5245 builds on the already proven mechanism of action of RDV that is inhibition of 
SARS-CoV-2 RNA polymerase by the active triphosphate metabolite, GS-443902. The major 
metabolic pathways leading to formation of the GS-443902 metabolite are different between 
RDV and GS-5245. For GS-5245, the major metabolic pathway is through phosphorylation of 
the GS-441524 metabolite by cellular kinases, a pathway that is believed to play a minor role in 
activation of RDV to GS-443902 metabolite. In order to overcome the less efficient conversion 
to GS-443902, the levels of GS-441524 need to be approximately 14-fold higher, as compared 
with what is observed after RDV, in order to result in the similar levels of intracellular active 
metabolite. Robust intracellular formation of active metabolite was observed in the 
GS-US-611-6248 clinical study in PBMCs (eg, GS-5245 500 mg administered twice daily 
achieved GS-443902 levels comparable with IV RDV on Day 1 and exceeded those on later days 
by approximately 4-fold). The intracellular formation of GS-443902 was dose-proportional and 
significant accumulation was observed following twice daily dosing (approximately 6-fold 
accumulation by Day 5).
GS-5245 showed therapeutic efficacy in multiple SARS-CoV-2 animal models (ie, mouse, ferret 
and African green monkeys [AGMs]). Administration of GS-5245 to SARS-CoV-2-infected 
mice (10 mg/kg twice daily; AUC0-24h = 10,500 h•ng/mL), ferrets (20 mg/kg once daily; 
AUC0-24h = 28,500 h•ng/mL) and AGM (60 mg/kg once daily; AUC0-24h = 25,700 h•ng/mL) for 
5 days resulted in a significant reduction of clinical signs of respiratory disease, infectious virus 
titers in lungs, and genomic RNA compared with vehicle-treated animals. Similarly, in the AGM 
model, IV delivery of parent nucleoside (20 mg/kg once daily; AUC0-24h = 42,800 h•ng/mL) and 
oral administration of GS-621763, a tri-isobutyryl ester tool prodrug of GS-441524 (60 mg/kg 
once daily; AUC0-24h = 18,200 h•ng/mL); (120 mg/kg once daily; AUC0-24h = 36,400 h•ng/mL) 
significantly reduced SARS-CoV-2 levels in the lower airways, as early as 1 to 2 days after 
infusion {Cox 2021, Pitts 2022}.
GS-5245 350 mg twice daily dose was selected for evaluation in this Phase 3 study for the 
treatment of COVID-19 in participants at high risk for disease progression; this dosing regimen 
should provide systemic exposures of GS-441524 (predicted AUC0-24h = 30,100 h•ng/mL) 
associated with efficacy in the SARS-CoV-2 animal models. Moreover, this dosing regimen 
allows for GS-441524 concentrations over the dosing interval to be predominantly maintained 
above the effective concentration (EC50) needed for SARS-CoV-2 viral inhibition in normal 
human bronchial epithelia cells (EC50 = 713 ng/mL). This dosing regimen also provides a 
substantial exposure (Cmax) margin relative to the 1600 mg dose (approximately 2- to 3-fold) 
where potential drug-related effects on CLcr were observed. Additionally, plasma exposures of 
GS-441524 in participants with mild renal impairment are expected to be within the range of 
those observed in the GS-5245 500 mg twice daily cohort in Study GS-US-611-6248. This is 
supported by the RDV renal impairment study (GS-US-540-9015), where mild renal impairment 


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resulted in approximately 19% increase in AUCinf and approximately 6.7% increase in Cmax of 
this metabolite.
1.4.1.
Participants with Compensated Cirrhosis
Hepatic metabolism and/or excretion is expected to be minimal (< 20%) in the elimination of 
GS-5245 or the plasma metabolite GS-441524, and thus, hepatic impairment is unlikely to alter 
the PK sufficiently to warrant dose adjustment of GS-5245. In the first-in-human study 
(GS-US-611-6248), GS-5245 was shown to be extensively hydrolyzed to GS-441524 metabolite 
presystemically with no detectable concentrations of the prodrug itself in plasma. Most of the 
absorbed dose (assuming 40% to 60% absorption) was excreted in urine over 24 hours postdose 
as GS-441524 metabolite (see Section 1.2.1.1.3.1). 
The proposed biotransformation and elimination pathways of GS-5245 and GS-441524 are also 
supported by nonclinical data, including the radiolabeled absorption, distribution, metabolism, 
and excretion study in rats (Study AD-611-2021; Study AD-611-2022). Renal excretion was the 
major route of elimination of GS-441524 from the systemic circulation in these studies. 
Additional data from portal vein-cannulated dog and cynomolgus monkey (Study AD-611-2016; 
AD-611-2017) suggest GS-5245 metabolism occurs primarily in the gut. Only transient and low 
levels of intact GS-5245 were observed in the portal vein. This is consistent with the in vitro 
intestinal instability of GS-5245 (Study AD-611-2024). 
Together, clinical and nonclinical data indicate minimal liver involvement in metabolism of 
GS-5245 following oral administration and support the use of the full clinical dose in participants 
with compensated cirrhosis in this Phase 3 study. 
1.5.
Risk/Benefit Assessment for the Study
Potential risks of a participant’s study involvement include unknown AEs, general risks 
associated with laboratory blood draws, and the associated pain and discomfort of phlebotomy.
Strategies to mitigate these risks include close monitoring of participants’ clinical statuses, 
laboratory values, and AEs. Parameters for discontinuation of the study drug due to AEs will be 
clearly defined and closely followed.
Participants in this study will receive either GS-5245 or placebo. Conducting a fully powered 
Phase 3 safety and efficacy study allows for the most rapid assessment of the potential of 
GS-5245 to provide a treatment option for participants with COVID-19. Participant safety will 
be further protected by the oversight of the data monitoring committee (DMC) that will evaluate 
safety data when the first 200 participants reach Day 29 or prematurely discontinue from the 
study and when 50% of planned participants complete the Day 29 assessment or prematurely 
discontinue from the study, or 50% of expected primary endpoint events occur, whichever 
happens earlier.


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Participants who are willing and able to take an authorized or approved therapy for COVID-19 
will be excluded from the study. Before approving the study, institutional review boards 
(IRBs)/institutional ethics committees (IECs) will evaluate whether in accordance with local 
authorizations, approvals, treatment guidelines, and availability, there are potentially eligible 
participants who cannot or will not be able to access alternative care.
An infectious disease pandemic may pose additional risks to study drug availability, the study 
visit schedule, and adherence to protocol-specified safety monitoring or laboratory assessments. 
Refer to Appendix 11.2 for further details on the risks and risk mitigation strategy.
Considering the above, the benefit -risk balance for this study is considered positive.
1.6.
Compliance
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.


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2.
OBJECTIVES AND ENDPOINTS
Primary Objective(s)
Primary Endpoint(s) 
•
To evaluate the efficacy of GS-5245 in reducing 
the rate of COVID-19–related hospitalization or 
all-cause death
•
Proportion of COVID-19–related hospitalization 
or all-cause death by Day 29
Secondary Objective(s)
Secondary Endpoint(s)
•
To evaluate the safety and tolerability of GS-5245 
administered in nonhospitalized participants with 
COVID-19
•
Incidence of treatment-emergent AEs and 
laboratory abnormalities
•
Incidence of SAEs and AEs leading to study drug 
discontinuation
•
To evaluate the efficacy of GS-5245 in reducing 
all-cause hospitalization
•
Proportion of participants with all-cause 
hospitalization by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
COVID-19–related medically attended visits 
(MAVs) or all-cause death
•
Proportion of participants with COVID-19–
related MAVs or all-cause death by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
COVID-19–related MAVs
•
Proportion of participants with COVID-19–
related MAVs by Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
all-cause death
•
Proportion of participants with all-cause death by 
Day 29
•
To evaluate the efficacy of GS-5245 in reducing 
the duration and severity of COVID-19 symptoms 
•
Time to COVID-19 symptom alleviation by 
Day 15
•
To evaluate the antiviral activity of GS-5245 on 
SARS-CoV-2 nasal swab viral load at Day 5
•
Change from baseline (Day 1) in SARS-CoV-2 
nasal swab viral load at Day 5
•
To evaluate the plasma PK of GS-441524 
(metabolite of GS-5245)
•
Plasma concentrations and PK parameters 
AUCtau, Ctau, and Cmax of GS-441524, as 
available
CCI
CCI


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CCI


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3.
STUDY DESIGN
3.1.
Study Design Overview
This Phase 3 study will be a randomized, double-blind, placebo-controlled study comparing the 
safety and efficacy of oral GS-5245 with placebo in nonhospitalized participants with COVID-19 
who are at high risk of progression to hospitalization.
After screening procedures, eligible participants may be randomized in a 1:1 ratio to receive 
treatment with GS-5245 or placebo.
Randomization will be stratified by duration of symptoms at enrollment (≤ 3 days versus 
> 3 days) and vaccination status (ever versus never). 
An overview of the study design is shown in Figure 1.
3.2.
Duration of Intervention
Duration of dosing is 5 days.
3.3.
Protocol-Specific Discontinuation Criteria
3.3.1.
Criteria for Early Discontinuation for the Individual Participants
3.3.1.1.
Criteria for Early Discontinuation for the Individual Participants From Study 
Intervention
Study drug will be discontinued in the following instances:
•
An SAE suspected to be related to study drug.
•
Any ≥ Grade 3 clinically significant AE suspected to be related to study drug.
•
An AE, or worsening of clinical condition requiring clinical intervention, that would, in the 
judgment of the investigator, affect assessments of clinical status to a significant degree.
•
Any ≥ Grade 3 clinically significant laboratory abnormality (if confirmed by repeat testing) 
suspected to be related to study drug. 
Except if baseline or on-treatment CLcr < 50 mL/min or eGFR < 50 mL/min/1.73m2, then 
study drug is to be discontinued without confirmation by repeat testing and irrespective of 
relatedness.
•
Unacceptable toxicity, as defined in Section 7.7, or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study-specific procedures or is considered 
not to be in the participant’s best interest.
•
Baseline or on-treatment alanine aminotransferase (ALT) ≥ 5  ULN.


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•
Baseline or on-treatment bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s 
syndrome).
•
Participant request to discontinue for any reason.
•
Participant noncompliance.
•
Pregnancy (refer to Appendix 11.3).
•
Discontinuation of the study by sponsor.
If a participant discontinues study drug, every attempt should be made to keep the participant in 
the study and continue to perform the required study-related follow-up and procedures.
3.3.1.2.
Criteria for Early Discontinuation for the Individual Participant From the Study
The participant will be discontinued from the study regardless of whether treatment is ongoing in 
the following instances:
•
Withdrawal of consent.
•
Death.
3.3.2.
Criteria for Early Discontinuation of the Study
The study will be discontinued in the following instances:
•
Discontinuation of the study at the request of Gilead Sciences (Gilead) or a regulatory 
agency, IRB, or IEC.
3.3.3.
Loss to Follow-up
Should the participant fail to attend a scheduled protocol-specific visit, sites will need to make at 
least 3 attempts by a combination of telephone, email, or mail to contact the participant. Sites 
must document all attempts to contact the participant. If a participant does not respond within 
5 days after the third contact, the participant will be considered lost to follow-up and no 
additional contact will be required.
3.4.
Definitions for Time of Primary Endpoint and End of Study
3.4.1.
Primary Endpoint
The date for the last participant visit for the primary endpoint is the date of the last visit to 
perform assessments for the primary analysis.


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3.4.2.
End of Study
The end of this study will be the last participant’s last observation (or visit).
3.5.
Source Data
The source data for this study will be obtained from original records (eg, clinic notes, hospital 
records, participant charts), central laboratory, local laboratory, and specialty laboratory (for PK 
data), participant-reported outcomes, and interactive response technology (IRT).


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
Approximately 2300 participants will be randomized into the study.
4.1.1.
Participant Replacement
Participants who discontinue before the end of the study will not be replaced.
4.2.
Inclusion Criteria
Participants must meet all the following inclusion criteria to be eligible for participation in this 
study:
1) Aged ≥ 18 years at screening.
2) Willing and able to provide written informed consent, or with a legal representative who can 
provide informed consent (where locally and nationally approved).
3) SARS-CoV-2 infection confirmed by PCR or an approved alternative assay (eg, Rapid 
Antigen Test) ≤ 5 days before randomization. Serologic tests will not be accepted.
4) Initial onset of COVID-19 signs/symptoms ≤ 5 days before randomization with ≥ 1 of the 
following targeted signs/symptoms present at randomization.
a) Stuffy or runny nose. 
b) Sore throat. 
c) Shortness of breath (difficulty breathing).
d) Cough.
e) Low energy or tiredness. 
f)
Muscle or body aches. 
g) Headache.
h) Chills or shivering. 
i)
Feeling hot or feverish.
j)
Nausea.
k) Vomiting.


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l)
Diarrhea.
5) Not currently hospitalized or requiring hospitalization.
6) Presence of ≥ 1 risk factor (if unvaccinated) or ≥ 2 risk factors (if vaccinated at any point) for 
progression to severe disease. Risk factors are the following:
a) Aged ≥ 50 years.
b) Current or recent (≤ 6 months prior to randomization) cancer (other than localized skin 
cancer).
c) Have human immunodeficiency virus infection.
d) Prior splenectomy.
e) Prior solid organ, stem cell, or bone marrow transplant.
f)
Have systemic rheumatologic or dermatologic disorders.
g) Use of systemic immunosuppressive agents, eg, high-dose corticosteroids (ie, ≥ 20 mg of 
prednisone or equivalent per day administered for ≥ 2 weeks), alkylating agents, 
antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic 
agents classified as severely immunosuppressive, tumor necrosis factor blockers, other 
biologic agents that are immunosuppressive or immunomodulatory.
h) Have cerebrovascular disease.
i)
Have cardiovascular disease, including heart failure, coronary artery disease, 
cardiomyopathies, and hypertension.
j)
Have chronic kidney disease (provided participant does not meet exclusion criterion 7).
k) Have chronic lung disease (interstitial lung disease, pulmonary embolism, pulmonary 
hypertension, bronchiectasis, or chronic obstructive pulmonary disease) 
l)
Have chronic liver disease.
m) Have cystic fibrosis.
n) Have diabetes mellitus, type 1 and/or type 2.
o) Have neurodevelopmental and/or neurodegenerative conditions.
p) Have a body mass index ≥ 25 kg/m2.
q) Have sickle cell disease. 


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r)
Have primary immunodeficiencies.
s) Have compensated cirrhosis. 
t)
Have asthma.
u) Have ≥ 20 pack-year smoking history and currently smoking or have quit within the past 
15 years.
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1) Anticipated access to and use of authorized or approved COVID-19 therapies during the 
current COVID-19 illness < 5 days after randomization (therapies include 
nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies).
2) Received any approved, authorized, or investigational direct-acting antiviral drug against 
SARS-CoV-2 for the treatment of COVID-19 < 28 days or < 5 half-lives, whichever is 
longer, before randomization.
3) Anticipated need for hospitalization < 48 hours after randomization.
4) New oxygen requirement < 24 hours before randomization.
5) Known influenza or any other suspected or confirmed concurrent active systemic infection 
other than COVID-19 that may interfere with the evaluation of response to the study drug.
6) Decompensated cirrhosis (Child-Pugh class B or class C) or acute liver injury/failure. 
7) Undergoing dialysis, or known history of moderate or severe renal impairment, or known 
CLcr < 60 mL/min (as calculated by Cockroft-Gault) or eGFR < 60 mL/min/1.73m2 within 
the last 6 months. Potential participants meeting the laboratory criterion may be enrolled if 
test results available before dosing show that renal function no longer meets this criterion. 
See Appendix 11.4 for country-specific requirements.
8) Known history of any of the following abnormal laboratory results (< 6 months before 
randomization) unless confirmed as resolved to not meet criteria at screening. See 
Appendix 11.4 for country-specific requirements regarding these laboratory exclusions.
a) ALT ≥ 5  ULN.
b) Bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s syndrome). 
9) Positive urine pregnancy test at screening.


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10) Breastfeeding (nursing).
11) Unwilling to use protocol-mandated birth control.
12) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
13) Requirement for ongoing therapy with or prior use of any prohibited medications. Prohibited 
medications are identified in Section 5.4.1.
14) Received an approved, authorized, or investigational COVID-19 vaccine (including booster 
dose) < 120 days before randomization.
15) Any inability to take study drug or comply with study procedures that, in the opinion of the 
investigator, would make the participant unsuitable for the study.


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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Randomization, Blinding, and Treatment Code Access
5.1.1.
Randomization
Participants who meet randomization eligibility criteria will be randomized in a 1:1 ratio to 
GS-5245 or placebo starting on Day 1 and assigned a participant number. Randomization will be 
stratified by duration of symptoms at enrollment (≤ 3 days versus > 3 days) and vaccination 
status (ever versus never).
5.1.2.
Blinding
The study is a double-blinded study where participants, personnel directly involved in the 
conduct of study, and sponsor will not know the treatment participants received.
During the study, participants and all personnel directly involved in the conduct of the study will 
be blinded to treatment assignment. Specified personnel may be unblinded based on their study 
role. Study drug will be dispensed by the study pharmacist, or designee, in a blinded fashion to 
the participants. The Pharmacokinetics File Administrator, or designee, in Bioanalytical 
Operations and/or Clinical Data Management who facilitates the data transfer of 
pharmacokinetic files between Gilead and vendors will remain unblinded. Individuals in Clinical 
Virology and Biomarker and Bioanalytical Operations performing sample selection for resistance 
analysis may be unblinded. Individuals in Clinical Packaging and Labeling or Clinical Supply 
Management who have an Unblinded Inventory Manager role in an IRT for purposes of study 
drug inventory management will remain unblinded. Individuals in Gilead Patient Safety who are 
responsible for safety signal detection, investigational new drug safety reporting, and/or 
expedited reporting of suspected unexpected serious adverse reactions may be unblinded to 
individual case data and/or group-level summaries. Regulatory Quality and Compliance 
personnel in Research and Development may also be unblinded for purposes of supporting 
Quality Assurance activities and/or regulatory agency inspections. Biostatisticians and 
programmers employed by contract research organizations may be unblinded for dataset creation 
and analyses (eg, outputs for DMC review, PK merge with clinical data).
5.1.3.
Planned Interim Internal Unblinding
Additionally, if the DMC recommends early study discontinuation due to efficacy/futility after 
reviewing the unblinded interim analysis results, a Gilead internal unblinded team independent 
of the blinded study team may be assembled, to assess the safety, any available PK, and/or 
efficacy of GS-5245 for planning and development of this compound. This group will consist of 
at least 1 representative from Clinical Development, Biostatistics, and Patient Safety, and may 
include other personnel as necessary. The Gilead medical monitor, other Clinical Development, 
Biostatistics, or Patient Safety personnel directly interacting with the study sites or data 
processing or analysis will not be participating in the internal monitoring committee and will not 
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The membership, conduct, and meeting schedule of the internal unblinded team will be 
documented as specified in Gilead procedural documents.
5.1.4.
Procedures for Breaking the Blind on Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the participant, the investigator may obtain the participant’s treatment assignment directly 
from the IRT for that participant. Gilead recommends but does not require that the investigator 
contact the Gilead medical monitor before breaking the blind. Treatment assignment should 
remain blinded unless that knowledge is necessary to determine participant emergency medical 
care. The rationale for unblinding must be clearly explained in source documentation along with 
the date on which the treatment assignment was obtained. The investigator is requested to 
contact the Gilead medical monitor promptly in any case of treatment unblinding.
Blinding of study drug is critical to the integrity of this clinical study. Therefore, if a 
participant’s treatment assignment is disclosed to the investigator, the participant will have study 
drug discontinued. All participants will be followed until study completion unless consent to do 
so is specifically withdrawn by the participant.
5.2.
Description and Handling
5.2.1.
Formulation
The GS-5245 350-mg strength tablets are oval shaped, debossed with “GSI” on one side and 
“5245” on the other side, and film-coated light yellow. In addition to the active ingredient, each 
film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, 
crospovidone, magnesium stearate, macrogol polyvinyl alcohol graft copolymer, talc, titanium 
dioxide, glyceryl mono and dicaprylocaprate (glyceryl monocaprylocaprate type I), polyvinyl 
alcohol, and yellow iron oxide.
Placebo tablets are identical in size, shape, color, and appearance to the corresponding active 
strength GS-5245 tablets. The placebo tablets contain commonly used excipients, including 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
macrogol polyvinyl alcohol graft copolymer, talc, titanium dioxide, glyceryl mono and 
dicaprylocaprate (glyceryl monocaprylocaprate type I), polyvinyl alcohol, and yellow iron oxide.
5.2.2.
Packaging and Labeling
The GS-5245 350 mg tablets and corresponding placebo tablets are packaged in white, 
high-density polyethylene bottles. Each bottle also contains polyester packing material and is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.
Study drugs to be distributed to participating centers shall be labeled to meet applicable 
requirements of the US Food and Drug Administration (FDA), the EU Guideline to Good 
Manufacturing Practice - Annex 13 (Investigational Medicinal Products), the Japan-GCP 
(Ministerial Ordinance on Good Clinical Practice for Drugs), as applicable, and/or other local 
regulations, as applicable.


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5.2.3.
Storage and Handling
GS-5245 and placebo tablets should be stored below 30 °C (86 °F). Storage conditions are 
specified on the label. Until dispensed to the participants, all bottles of study drugs should be 
stored in a securely locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drugs should not be stored in a container 
other than the container in which they were supplied. Keep the bottle tightly closed to protect 
from moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration
Participants will receive study drug with dosing frequency, as follows:
•
GS-5245 350 mg (1  350 mg tablet) or placebo administered orally twice daily without 
regard to food for 5 days.
Study drug will be administered with approximately 240 mL of water.
5.4.
Prior and Concomitant Medications
5.4.1.
Prior and Concomitant Medications That Are Prohibited 
There are no restrictions on concomitant medications based on the potential for PK DDI with 
GS-5245. Medications in Table 9 are prohibited while participants are taking study drug.
For all participants, medical care, including hospitalization, if required, is not 
restricted. Additionally, medications used for supportive and symptomatic treatment of 
COVID-19 are allowed and there are no restrictions other than those indicated in Table 9. 
Permissible medications may include anti-inflammatories (eg, ibuprofen, naproxen), COVID-19 
specific immunomodulator therapies (eg, dexamethasone, tocilizumab, baricitinib, anakinra), 
antipyretics (eg, paracetamol/acetaminophen), bronchodilators and inhaled corticosteroids (eg, 
albuterol, fluticasone), decongestants (eg, phenylephrine, pseudoephedrine) and any other locally 
prescribed or over-the-counter treatments for COVID-19 symptoms. 
In instances where a prohibited medication is initiated before discussion with the Gilead medical 
monitor, the investigator must notify Gilead as soon as the investigator is aware of the use of the 
prohibited medication. In such instances, study drug must be discontinued, but the participant 
should continue in the study (See Section 6.4).


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Table 9.
Prior and Concomitant Medications That Are Prohibited 
COVID-19 = coronavirus disease 2019; IV = intravenous; RDV = remdesivir; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2
a
Concomitantly with GS-5245.
5.5.
Accountability for Study Drug(s)
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug bottles. This includes acknowledgment of receipt of each shipment of study drug (quantity 
and condition). All used and unused study drug bottles dispensed to participants must be returned 
to the site.
Each investigational site must keep accountability records that capture:
•
The date received, quantity, and condition of study drug bottles.
•
The date, participant number, and the quantity of study drug bottles.
•
The date, quantity of used, unused study drug bottles returned, and number of tablets within 
returned bottles along with the initials of the person recording the information.
5.5.1.
Study Drug Return or Disposal
Gilead recommends that used and unused study drugs, which includes bottles, be destroyed at the 
site. If the site has an appropriate standard operating procedure for drug destruction as 
determined by Gilead, the site may destroy used (empty or partially empty) and unused study 
drug bottles in accordance with that site’s approved procedural documents. A copy of the site’s 
approved procedural document will be obtained for the electronic trial master file. If the study 
drug is destroyed at the site, the investigator must maintain accurate records for all study drugs 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the study drugs. Upon study completion, copies 
of the study drug accountability records must be filed at the site. Another copy will be provided 
to Gilead.
If the site does not have an appropriate standard operating procedure for study drug destruction, 
used and unused study drugs are to be sent to the designated disposal facility for destruction. The 
study monitor will provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
Medication Class
Prohibited Medicationsa 
COVID-19 medications
Nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies 
against COVID-19, or any other locally authorized/approved direct-acting therapy 
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The study procedures to be conducted for each paiticipant screened or enrolled in the study are 
presented in tabular fonn in Table 1 and described in the sections below. 
The investigator must doclllllent any deviation from the protocol procedures and notify Gilead or 
the contract reseai·ch organization. 
6.1. 
Informed Consent 
Written info1m ed consent must be obtained from each paiticipant before initiation of any 
screening procedure. After a paiticipant has provided info1med consent, the investigator and 
other study personnel will dete1mine if the paiticipant is eligible for paiticipation in the study 
(Section 4.2). 
-
I 
6.2. 
Screening, Participant Enrollment, and Treatment Assignment 
Paiticipants will be screened within 48 hours before enrollment in the study. Each paiticipant 
will be assigned a unique screening nlllllber using an IRT. Pa1ticipants meeting all of the 
inclusion criteria and none of the exclusion criteria will return to the clinic within 48 hours for 
randoinization into the study. 
Enny into screening does not gt1ai·antee enrollment into the study. Gilead, at its sole discretion, 
may suspend screening and/or enrollment at any site or study wide at any time. 
It is the responsibility of the investigator to ensure that pa1ticipants are eligible to paiticipate in 
the study prior to enrollment and continue to remain eligible throughout the study. 
Once written infonned consent has been obtained, all screening and adinission tests and 
assessments have been assessed (including recording the dates of COVID-19 vaccinations), and 
study eligibility has been confnmed, paiticipants will be randoinized to receive GS-5245 or 
placebo on Day 1. Whenever possible, Day 1 dosing should occur on the same day as 
randoinization. 
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This Phase 3 superiority study will evaluate GS-5245 compared with placebo in participants who 
do not have access to or cannot take existing therapies that are authorized or approved (ie, 
nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies, or any other 
locally authorized/approved direct-acting therapy against SARS-CoV-2).
Participants who have access to and intend to take aforementioned existing therapies are 
excluded from enrollment and must be treated with these agents outside this clinical study.
Participants will receive GS-5245 or placebo as described in Section 5.3.
6.3.
Instructions for Study Procedures
An in-person visit is defined as a visit at a medical facility or elsewhere by a health care provider 
(where permitted).
6.3.1.
Adverse Events
From the time informed consent is obtained through the first administration of study drug, record 
all SAEs, as well as any AEs related to protocol-required procedures, on the AE electronic case 
report form (eCRF). All other untoward medical occurrences observed during the screening 
period, including exacerbation or changes in medical history, are to be considered medical 
history. After study drug administration, report all AEs and SAEs. See Section 7 for additional 
details.
6.3.2.
Safety Assessments
Safety will be evaluated throughout the study. Refer to Table 1 for a schedule of assessments.
6.3.2.1.
Physical Examination
Physical examinations conducted throughout the study during in-person visits will be a complete 
physical examination or a symptom-driven physical examination, as outlined in Table 1. 
For participants with compensated cirrhosis, when a complete physical exam is conducted, the 
exam should also include:
•
Clinical assessment of ascites (absent, slight, or moderate). 
•
Clinical assessment of hepatic encephalopathy, as follows: 
Absent: no clinical manifestations of hepatic encephalopathy.
Grade I: changes in behavior, mild confusion, slurred speech, disordered sleep.
Grade II: lethargy, moderate confusion.
Grade III: marked confusion (stupor), incoherent speech, sleeping but arousable.
Grade IV: coma, unresponsive to pain. 


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6.3.2.2.
Medical History
Review medical history, including the date of first COVID-19 symptoms, overall COVID-19 
symptoms, exposure source, vaccination history, demographics, baseline characteristics, 
allergies, and all other medical history.
6.3.2.3.
Vital Signs
Vital sign measurements include heart rate, respiratory rate, temperature, oxygen saturation, and 
blood pressure. Refer to Table 1 for vital signs collection time points.
6.3.2.4.
Body Mass Index
Height and weight will be collected at screening for calculation of body mass index for inclusion 
criteria.
6.3.2.5.
Clinical Laboratory Assessments
Blood sample collection for the following laboratory analyses (Table 10) will be performed at 
the specified time points, where visits are conducted in person (Table 1). If screening laboratory 
analyses are deemed necessary by the investigator prior to randomization, these analyses should 
be performed using a local laboratory for expedited results. If a ≥ Grade 3 clinically significant 
laboratory abnormality needs to be repeated for confirmation, a local laboratory may be used if 
urgent results are needed for participant safety. However, a concurrent second set of blood 
samples should be drawn and sent to the central laboratory for proper documentation and data 
integrity. All other laboratory analyses performed on blood samples after screening should be 
collected and sent to the central laboratory. See Appendix 11.4 for country-specific 
requirements. 
•
Chemistry 
eGFR according to Cockcroft-Gault equation for CLcr {Cockcroft 1976}. Weight at 
screening will be used for all CLcr calculations.
Men:
(140 – age in years)  (weight in kg)  CLcr (mL/min)
72  (serum creatinine in mg/dL)
Women:
(140 – age in years)  (weight in kg)  0.85  CLcr (mL/min)
72  (serum creatinine in mg/dL)
•
Hematology
•
Coagulation


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Table 10. 
Laboratory Analytes 
Safety Laboratory Measurements 
Chemistry 
Other Laborato1-y 
(Serum or Plasma) 
Hematology 
Coagulation 
Measurements 
alkaline phosphatase, 
hemoglobin, hematocrit, 
prothrombin time, partial 
serum and wine 
AST, ALT, total bilimbin, 
red blood cell count, 
thromboplastin time, 
pregnancy tests 
total protein, albumin, 
platelet count, white blood 
intemational no1malized 
and sernm 
lactate dehydrogenase, 
cell count with differential 
ratio 
follicle-stimulating 
creatine phosphokinase, 
( absolute and percentage) 
honnone in 
bicarbonate, blood mea 
including 
amenon-hoeic 
nitrogen, calcium, 
neutrophils, monocytes, 
participants < 54 years 
chloride, creatinine, 
eosinophils, basophils, 
of age 
glucose, lipase, 
lymphocytes 
magnesium, phosphorus, 
phannacokinetics 
potassium, sodium, uric 
acid, creatinine clearance 
anti-SARS-Co V-2 
antibodies 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SARS-CoV-2 = severe acute respiratory syndrome 
coronavims 2 
Refer to Table 1 for collection time points. 
6.3.2.6. 
Concomitant Medications 
Review of concomitant medications and protocol restrictions will occur at the times shown in 
Table 1. See Section 5.4 for more infonnation about concomitant medications. 
6.3.2.7. 
Medically Attended Visits 
Review of MA V info1mation will occur at the times shown in Table 1. Medically attended visits 
are any interaction with health care professionals other than study staff or designees including 
hospitalization; in-person emergency, urgent, or primaiy care visits; or any other in-person visit 
attended by the pa1ticipant and a health cai·e profession. 
6.3.2.8. 
Pregnancy Tests 
Urine and/or sernm pregnancy tests will be perfo1med for paiticipants assigned female at biith 
and of childbearing potential at the times shown in Table 1. At screening, a follicle-stimulating 
ho1mone test is requii·ed to confom the postmenopausal state in paiticipants younger than 
54 years, who have stopped menstrnating for at least 12 months but do not have documentation 
of ovarian ho1m onal failure, as described in Appendix 11.3. 
6.3.3. 
Pharmacokinetics 
Sparse PK assessments will be conducted in all 
Table 1. 
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SARS-CoV-2 Serology 
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Blood samples will be collected to assess anti-SARS-CoV-2 antibodies at the time point 
specified in Table 1. Any remaining specimens from blood samples collected dming the study 
will be stored and retained for possible future biomarker-related testing. These stored samples 
may be used by Gilead or its research partners for retesting anti-SARS-Co V-2 antibodies, for 
testing to learn more about how the study drng has worked, or for clinical laborato1y testing to 
provide additional safety data. At the conclusion of this study, these samples may be retained in 
storage by Gilead for a period of up to 15 years. 
Samples collected for biomarker assessments will be destroyed no later than 15 years after the 
end of the study or per country requirements (Section 9.1.4). 
Clinical Virology 
Virology Testing 
6.3.5. 
6.3.5.1. 
6.3.5.1.1. 
Virology Samples to Address the Study Objectives 
Mid-turbinate nasal swab samples will be used to assess SARS-CoV-2 viral load by reverse 
tr·anscriptase-quantitative polymerase chain reaction (RT-qPCR). Once viral load testing is 
complete, the remnant samples may be used to evaluate res irato1 viral coinfection, 
SARS-CoV-2 infectious viral titer 
6.3.5.1.2. 
Virology Sample Storage 
Any remaining specimens from nasal swab samples collected dming the study will be stored and 
retained for possible future virology-related testing. These stored samples may be used by Gilead 
or its research partners for viral genotyping/phenotyping assays or their development, for 
retesting the amount of vims present in the sample, or for testing to learn more about how the 
study drng has worked or clinical laborato1y testing to provide additional safety data. At the 
conclusion of this study, these samples may be retained in storage by Gilead for a period up to 
15 years or per country requirements. 
6.3.6. 
Patient-Reported Outcomes 
Patient-reported outcomes, if available, will be required at the time points shown in Table 1. 
6.3.6.1. 
COVID-19 Symptom Questionnaire 
The COVID-19 symptom questionnaire, if available, to be completed daily at approximately the 
same time each day, was adapted from published FDA guidance on Assessing COVID-19-
Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials ofDrngs and 
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Biological Products for COVID-19 Prevention or Treatment Guidance for Industry {U. S. 
Department of Health & Human Services (DHHS) 2020}. It aims to capture the most clinically 
relevant symptoms of COVID-19 using an easily interpretable verbal response scale. 
6.3.6.2.
Work Productivity and Activity Impairment Questionnaire + Classroom 
Impairment Questions: COVID-19 Infection 
The WPAI + CIQ: COVID-19 Infection Specific questionnaire, if available, is a questionnaire to 
measure impairments in both paid work and unpaid work, as well as educational impact. It 
measures absenteeism and presenteeism, as well as the impairments in unpaid activity because of 
health problems during the past 7 days. It has been validated to quantify work or education 
impairments for numerous diseases {Reilly 1993}.
6.3.6.3.
Patient-Reported Outcomes Measurement Information System-29 
Up to 30% of people infected with SARS-CoV-2 have at least 1 symptom persisting longer than 
4 weeks {Azzolini 2022}. PROMIS-29, if available, is a set of person-centered measures 
assessing physical, mental, and social health {HealthMeasures 2022}. The tool has been used to 
determine the prevalence and characteristics of impairment after recovery from acute COVID-19 
{Romano 2022}.
6.4.
Assessments for Early Discontinuation From the Study
If a participant discontinues study dosing (for example, as a result of an AE), every attempt 
should be made to keep the participant in the study and continue to perform the required 
study-related follow-up and procedures (see Section 3.3.1.1, Criteria for Early Discontinuation 
for the Individual Participant). If this is not possible or acceptable to the participant or 
investigator, the participant may be withdrawn from the study.
6.5.
Assessments for End of Study
A participant who completes or discontinues from the study early will have an end of study visit 
(either Day 29 visit or early discontinuation, as applicable) for assessments and procedures 
specified in Table 1.
6.6.
Poststudy Care
The long-term care of the participant will remain the responsibility of their primary treating 
physician. There is no provision for poststudy availability.
6.7.
Sample Storage
The stored biological samples may be used by Gilead or its research partner for additional testing 
to provide supplemental data to answer questions that relate to the main study. At the end of this 
study, these samples may be retained in storage by Gilead for a period up to 15 years or per 
country requirements.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events and Serious Adverse Events
7.1.1.
Adverse Events
An AE is any untoward medical occurrence in a clinical study participant administered a study 
drug that does not necessarily have a causal relationship with the treatment. An AE can therefore 
be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the 
use of a study drug, whether or not the AE is considered related to the study drug. Adverse 
events may also include pretreatment or posttreatment complications that occur as a result of 
protocol-specified procedures or special situations (Section 7.1.3).
An AE does not include the following:
•
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, or transfusion. 
The condition that led to the procedure may be an AE and must be reported.
•
Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen.
•
Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions).
•
Overdose without clinical sequelae (Section 7.1.3).
•
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the informed consent form is signed and not related to a protocol-associated procedure 
is not an AE but rather considered to be preexisting and should be documented as medical 
history.
Preexisting events that increase in severity or change in nature after study drug initiation or 
during or as a consequence of participation in the clinical study will also be considered AEs.
7.1.2.
Serious Adverse Events
An SAE is defined as an event that, at any dose, results in the following:
•
Death.
•
A life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the participant was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe).
•
In-patient hospitalization or prolongation of existing hospitalization.


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•
Persistent or significant disability/incapacity.
•
A congenital anomaly/birth defect.
•
A medically important event or reaction: Such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse.
7.1.3.
Study Drugs and Gilead Concomitant Medications Special Situation Reports
Special situation reports (SSRs) include all reports of medication error, abuse, misuse, overdose, 
occupational exposure, drug interactions, exposure via breastfeeding, unexpected benefit, 
transmission of infectious agents via the product, counterfeit of falsified medicine, and 
pregnancy regardless of an associated AE.
Medication error is any unintentional error in the prescribing, dispensing, preparation for 
administration or administration of a study drug while the medication is in the control of a health 
care professional, participant, or consumer. Medication errors may be classified as a medication 
error without an AE, which includes situations of missed dose, medication error with an AE, 
intercepted medication error, or potential medication error.
Abuse is defined as persistent or sporadic intentional excessive use of a study drug by a 
participant.
Misuse is defined as any intentional and inappropriate use of a study drug that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a study 
drug given per administration or cumulatively that is above the maximum recommended dose as 
per protocol or in the product labeling (as it applies to the daily dose of the participant in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the participant has taken the excess dose(s). Overdose cannot be established 
when the participant cannot account for the discrepancy, except in cases in which the 
investigator has reason to suspect that the participant has taken the additional dose(s).
Occupational exposure is defined as exposure to a study drug as a result of one’s professional or 
nonprofessional occupation.
Drug interaction is defined as any drug/drug, drug/food, or drug/alcohol, or drug/device 
interaction.


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Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial.
Transmission of infectious agents is defined as any suspected transmission of an infected agent 
through a Gilead study drug.
Counterfeit or falsified medicine is defined as any study drug with a false representation of (a) its 
identity, (b) its source, or (c) its history.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship for each 
study drug using clinical judgment and the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, preexisting condition, underlying disease, 
intercurrent illness, concomitant medication).
•
Yes: There is reasonable possibility that the AE may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:
•
No: Evidence exists that the AE has an etiology other than the study procedure.
•
Yes: The AE occurred as a result of protocol procedures (eg, venipuncture).
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events Toxicity Grading Scale, Version 2.1 (corrected, 
July 2017) available at https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
(Section 8.6.3). For each episode, the highest grade attained should be reported as defined in the 
grading scale.


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7.3.
Investigator Reporting Requirements and Instructions
7.3.1.
Requirements for Collection Before Study Drug Initiation
After informed consent, but before initiation of study drug, the following types of events must be 
reported on the applicable eCRFs: all SAEs and any AEs that are related to protocol-required 
procedures.
7.3.2.
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug and report the AEs on the eCRFs as instructed.
All AEs and clinically significant laboratory abnormalities should be followed until resolution or 
until the AE is stable, if possible. Gilead may request that certain AEs be followed beyond the 
protocol-defined follow-up period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the participant first consents to 
participate in the study (ie, signing the informed consent form [ICF]) and throughout the duration 
of the study, including the posttreatment follow-up visit, must be reported on the applicable 
eCRFs and to Gilead Patient Safety as instructed below in this section. This also includes any 
SAEs resulting from protocol-associated procedures performed after the ICF is signed.
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if the investigator learns of any SAEs that occur after the protocol-defined follow-up 
period has concluded and the event is deemed relevant to the use of study drug, the investigator 
should promptly document and report the event to Gilead Patient Safety.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situation Reports
All study drug SSRs that occur from study drug initiation and throughout the duration of the 
study, including the posttreatment follow-up visit, must be reported to Gilead Patient Safety 
(Section 7.4.2). Adverse events and SAEs resulting from SSRs must be reported in accordance 
with the AE and SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Medications Reports
7.3.5.1.
Gilead Concomitant Medications Special Situation Report
Special situation reports involving a Gilead concomitant medication (not considered study drug), 
that occur after the participant first consents to participate in the study (ie, signing of the ICF) 
and throughout the duration of the study, including the posttreatment follow-up visit, must be 
reported to Gilead Patient Safety utilizing the paper SSR (Section 7.4.2.2).


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7.3.5.2.
Non-Gilead Concomitant Medications Report
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, for special situations that result in AEs because of a non-Gilead 
concomitant medication, the AE should be reported on the AE eCRF.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
All clinical sequelae in relation to these SSRs will be reported as AEs or SAEs at the same time 
using the AE eCRF and/or the SAE eCRF. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.
7.4.
Reporting Process for Serious Adverse Events and Special Situation Reports
7.4.1.
Serious Adverse Event Reporting Process
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be transmitted by email or fax when requested and applicable. 
Transmission of such documents should occur without personal participant identification, 
maintaining the traceability of a document to the participant identifiers.
Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the SAE narrative section of the Safety Report 
Form eCRF.
7.4.1.1.
Electronic Serious Adverse Event Reporting Process
Site personnel will record all SAE data on the applicable eCRFs and from there transmit the SAE 
information to Gilead Patient Safety within 24 hours of the investigator’s knowledge of the event 
from the time of the ICF signature throughout the duration of the study, including the 
protocol-required posttreatment follow-up period.
If for any reason it is not possible to record and transmit the SAE information electronically, 
record the SAE on the paper SAE reporting form and transmit within 24 hours to:
Gilead Patient Safety:
Email: Safety_FC@gilead.com
or
Fax: 1-650-522-5477


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If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SAE reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to Gilead Patient Safety.
7.4.2.
Special Situation Reporting Process
7.4.2.1.
Electronic Special Situations Reporting Process for Study Drug
Site personnel will record all SSR data on the applicable eCRFs and from there transmit the SSR 
information within 24 hours of the investigator’s knowledge to Gilead Patient Safety from study 
drug initiation throughout the duration of the study, including the protocol-required 
posttreatment follow-up period.
If for any reason it is not possible to record and transmit the SSR information electronically, 
record the SSR on the paper special situations reporting form and transmit within 24 hours to:
Gilead Patient Safety 
Email: Safety_FC@gilead.com 
or
Fax: 1-650-522-5477 
If an SSR has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. If the database is not locked, any SSR reported via paper must be 
transcribed as soon as possible on the applicable eCRFs and transmitted to Gilead Patient Safety.
See Section7.4.2.2 for instructions on reporting special situations with Gilead concomitant 
medications.
7.4.2.2.
Reporting Process for Gilead Concomitant Medications
Special situations that involve Gilead concomitant medications that are not considered study 
drug must be reported within 24 hours of the investigator’s knowledge of the event to Gilead 
Patient Safety utilizing the paper SSR form and transmitted to:
Gilead Patient Safety:
Email: Safety_FC@gilead.com
or
Fax: 1-650-522-5477
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the SSR form; however, special situations that result in AEs because of a non-Gilead 
concomitant medication, must be reported on the AE eCRF.


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7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies identified at any time from the start of the study to 
30 days after last study dose in participants and/or pregnancies in partners resulting from 
exposure to sperm from a participant in the study period in which contraceptive measures are 
needed. Pregnancies should be reported to Gilead Patient Safety within 24 hours of becoming 
aware of the pregnancy using the pregnancy report form. Contact details for transmitting the 
pregnancy report form are as follows:
Gilead Patient Safety:
Email: Safety_FC@gilead.com
or
Fax: 1-650-522-5477 
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion because of complications or other medical reasons) must be reported within 
24 hours as an SAE, as described in Section7.4.1. The underlying medical reason for this 
procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.4.1. Furthermore, any SAE occurring as an adverse pregnancy outcome after the study 
must be reported to the Gilead Patient Safety. However, if a pregnancy-related SAE occurs in a 
partner, it should not be captured in the eCRF, but reported via the paper pregnancy outcome 
report form.
The participant should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome of the pregnancy/partner pregnancy should be reported to Gilead 
Patient Safety using the pregnancy outcome report form. If the end of the pregnancy/partner 
pregnancy occurs after the study has been completed, the outcome should be reported directly to:
Gilead Patient Safety:
Email: Safety_FC@gilead.com
or
Fax: 1-650-522-5477
Refer to Appendix 11.3 for Pregnancy Precautions, Definition for Childbearing Potential, and 
Contraceptive Requirements.


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7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, which may be in the form of line listings, 
serious adverse drug reactions, or suspected unexpected serious adverse reactions. In accordance 
with the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of applicable 
suspected unexpected serious adverse reactions as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant suspected unexpected 
serious adverse reaction reports associated with any study drug. The investigator should notify 
the IRB/IEC of suspected unexpected serious adverse reaction reports as soon as is practical, 
where this is required by local regulatory agencies, and in accordance with the local institutional 
policy.
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, x-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.1 (corrected, July 2017). For AEs associated 
with laboratory abnormalities, the event should be graded on the basis of the clinical severity in 
the context of the underlying conditions; this may or may not be in agreement with the grading 
of the laboratory abnormality.
The DAIDS scale is available at:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf


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7.7.
Toxicity Management
7.7.1.
GS-5245
All clinical and clinically significant laboratory toxicities will be managed according to the 
guidelines described below.
The Gilead medical monitor should be consulted prior to study drug discontinuation when 
medically feasible. Before discontinuation of study drug for AEs or laboratory abnormalities, an 
assessment of the participant’s medical situation should be made by the investigator.
For Grade 3 and Grade 4 clinically significant laboratory abnormalities that need to be confirmed 
by repeat testing, a local laboratory may be used if urgent results are needed for participant 
safety. However, a concurrent second set of blood samples should be drawn and sent to the 
central laboratory for proper documentation and data integrity.
7.7.1.1.
Laboratory Events Meeting Discontinuation Criteria
Laboratory events meeting discontinuation criteria are discussed in Section 3.3.1.1.
7.7.1.2.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.7.1.3.
Grade 3 Laboratory Abnormality or Clinical Event
For a Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.
For a Grade 3 clinically significant laboratory abnormality or clinical event confirmed by repeat 
testing, that is considered to be related to study drug, the participant will be discontinued from 
study drug. The participant should be managed according to local practice.
Additionally, participants who have a CLcr < 50 mL/min (by Cockcroft-Gault equation) will be 
discontinued from study drug whether considered related to the study drug or not (refer to 
Section 3.3.1.1).
Recurrence of laboratory abnormalities considered unrelated to study drug may not require 
permanent discontinuation but requires discussion with the Gilead medical monitor.
7.7.1.4.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinically significant laboratory abnormality or clinical event confirmed by repeat 
testing, that is considered to be related to study drug, the participant will be discontinued from 
study drug. The participant should be managed according to local practice. The participant 
should be followed as clinically indicated until the laboratory abnormality returns to baseline or 
is otherwise explained, whichever occurs first. A clinically significant Grade 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
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Study drug may be continued without dose interruption for a clinically nonsignificant Grade 4 
laboratory abnormality (eg, Grade 4 creatine kinase elevation after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to study drug.
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor, and the appropriate course of action will be discussed and decided. 
Whether or not considered treatment-related, all participants experiencing AEs must be 
monitored periodically until symptoms subside, any abnormal laboratory values have resolved or 
returned to baseline levels or they are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the Gilead medical monitor.


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8.
STATISTICAL CONSIDERATIONS
Details of the statistical methods will be provided in the statistical analysis plan, including any 
deviations from the original statistical analyses planned.
8.1.
Analysis Objectives and Endpoints
Objectives and endpoints are listed in Section 2.
8.2.
Planned Analyses
8.2.1.
Interim Analysis
Before the final analysis, interim analyses will be conducted, and the analyses may be submitted 
to regulatory agencies to seek guidance for the overall clinical development program.
8.2.1.1.
Data Monitoring Committee Analysis
The first DMC meeting will be based on data collected after the first 200 participants have 
reached Day 29 or prematurely discontinued from the study and will include safety data.
The second DMC meeting will be based on data collected after 50% of planned participants 
complete the Day 29 assessment or prematurely discontinue from the study, or 50% of expected 
primary endpoint events occur, whichever happens earlier. The DMC meeting will include 
review of safety and formal evaluation of futility and efficacy. The DMC may provide 
recommendation on stopping enrollment to the study if the prespecified boundaries for efficacy 
(outlined in Section 8.7) or futility are crossed. If the second DMC meeting is triggered by 
50% planned enrollment, a third DMC meeting may be conducted after 50% of expected primary 
endpoint events as appropriate. If the second DMC meeting is triggered by 50% of expected 
primary endpoint events, a third DMC meeting is not planned. An interim analysis 
communication plan will be created.
Further details are provided in the DMC charter.
8.2.2.
Final Analysis
The unblinded final analysis will be performed after all participants have completed the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized. Unless efficacy or futility boundaries are crossed at the interim 
analysis, the analysis of the primary endpoint of COVID-19–related hospitalization or all-cause 
death by Day 29 and key α-controlled secondary endpoints will be conducted at the time of the 
final analysis. The overall type I error rate will be controlled at the two-sided 0.05 significance 
level using the Lan-DeMets approach with O’Brien-Fleming type spending function.


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8.3.1. 
8.3.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
Final 
Amendment 1 
The prima1y analysis set for efficacy analyses is defined as the Full Analysis Set (FAS), which 
will include all paiiicipants who (1) ai·e randomized into the study and (2) have received at least 
1 dose of study diug. Paiiicipants will be grouped according to the treatment to which they were 
randomized. 
8.3.1.2. 
Safety 
The prima1y analysis set for safety analyses is defined as the Safety Analysis Set, which will 
include all pa1iicipants who (1) are randomized into the study and (2) have received at least 
1 dose of study diug. Paiiicipants will be grouped according to the treatment which they 
received. 
All data collected during treatment plus 30 days will be included in the safety sUllllnai·ies. 
8.3.1.3. 
Virology 
The Virology Analysis Set will include all pa1iicipants who (1) are randomized into the study, 
(2) have received at least 1 dose of study diug, and (3) have positive SARS-CoV-2 viral load at 
baseline. Paiiicipants will be grouped according to the treatment they received. 
8.3.1.4. 
Phaimacokinetics 
The PK Analysis Set will include all randomized paiiicipants who received at least 1 dose of 
GS-5245 and had at least 1 nonmissing PK concentration datum repo1ied by the PK laborato1y 
for each respective analyte. 
-
8.3.2. 
Data Handling Conventions 
Natural logai·ithm transfo1mation for PK pai·ameters will be applied for PK analysis. 
For sUllllnaiy statistics, PK concentration values below the limit of quantitation will be treated as 
zero at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points. 
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Laboratory data that are continuous in nature but are less than the LLOQ or above the upper limit 
of quantitation, will be imputed to the value of the lower or upper limit plus or minus 
1 significant digit, respectively (eg, if the result of a continuous laboratory test is < 20, a value of 
19 will be assigned).
Missing data can have an impact upon the interpretation of the study data. In general, values for 
missing data will not be imputed. However, a missing pretreatment laboratory result would be 
treated as normal (ie, no toxicity grade) for the laboratory abnormality summary.
All available data for participants that do not complete the study will be included in data listings.
8.4.
Demographic and Baseline Characteristics Analysis
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, randomization stratification group, age. 
For categorical demographic and baseline characteristics, a Cochran-Mantel-Haenszel test will 
be used to compare treatment groups. For continuous demographic and baseline characteristics, a 
Wilcoxon rank sum test will be used to compare treatment groups.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary endpoint is the proportion of COVID-19–related hospitalization or all-cause death 
by Day 29. COVID-19–related hospitalization is defined as ≥ 24 hours of acute care for a reason 
related to COVID-19, in a hospital or similar acute care facility, including emergency rooms or 
temporary facilities instituted to address medical needs of those with COVID-19. This includes 
specialized acute medical care units within an assisted living facility or nursing home. This does 
not include hospitalization for the purposes of public health and/or clinical study execution. The 
date and duration of hospital admission, and primary reason for hospitalization (including if the 
hospitalization is related to COVID-19) will be recorded.
The primary endpoint will be analyzed using a Cox proportional hazards model with the 
stratification factors (duration of symptoms and vaccination status) as covariates. The hazard 
ratio and 95% CI will be provided. Handling of intercurrent events is defined in Section 8.5.3.
The number and percentage of participants with COVID-19–related hospitalization or all-cause 
death by Day 29, and reasons for missing data will be summarized.
The FAS will be used for the primary efficacy endpoint analysis.
Sensitivity analyses may be conducted using the following alternative approaches for the primary 
endpoint.


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•
Missing hospitalization status will be imputed using multiple imputation assuming missing at 
random.
•
A participant with missing hospitalization status will be imputed as the participant was 
hospitalized.
8.5.2.
Secondary Analyses
The secondary endpoints of COVID-19–related MAVs or all-cause death by Day 29 and 
all-cause death will be analyzed similarly as in the primary analysis. The secondary endpoints of 
all-cause hospitalization by Day 29 and COVID-19–related MAVs will be analyzed using a 
competing risk analysis approach, with death as the competing risk. 
Medically attended visits are defined as any interactions with health care professionals other than 
study staff or designees including hospitalization; in-person emergency, urgent, or primary care 
visits; or any other in-person visit attended by the participant and a health care professional. The 
nature and cause of the visit should be identified. 
All-cause hospitalization is defined as ≥ 24 hours of acute care, in a hospital or similar acute care 
facility, including emergency rooms or temporary facilities instituted to address medical needs of 
those with COVID-19. This includes specialized acute medical care units within an assisted 
living facility or nursing home. This does not include hospitalization for the purposes of public 
health and/or clinical study execution. The date and duration of hospital admission, and primary 
reason for hospitalization (including if the hospitalization is related to COVID-19) will be 
recorded.
A gatekeeping approach will be used for testing the key secondary endpoints. The endpoints will 
be tested in the following sequential order:
•
Proportion of participants with all-cause hospitalization by Day 29.
•
Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29.
•
Proportion of participants with COVID-19–related MAVs by Day 29.
Change from baseline in SARS-CoV-2 nasal swab viral load to Day 5 will be summarized by 
treatment groups and compared between treatment groups using a mixed-effects model repeated 
measures (MMRM) approach.
The Kaplan-Meier product limit method will be used to estimate, and log-rank test will be used 
to compare treatment groups for the time to symptom alleviation of targeted COVID-19 
symptoms.
Handling of intercurrent events for key secondary efficacy endpoints is defined in Section 8.5.3.


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8.5.3.
Intercurrent Events
Handling of intercurrent events for the primary endpoint and secondary efficacy endpoints 
relevant to hospitalization/death and symptom duration are shown in Table 11.
Table 11.
Handling of Intercurrent Events
Endpoint
Intercurrent event
Strategy
Description
Discontinue randomized 
treatment prior to endpoint (due 
to AE, lack of efficacy, 
investigator's discretion, 
noncompliance with study drug, 
protocol violation, participant 
decision, lost to follow-up)
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Proportion of COVID-19–related 
hospitalization or all-cause death 
by Day 29
Proportion of participants with 
all-cause hospitalization by Day 
29
Proportion of participants with 
COVID-19–related MAVs or 
all-cause death by Day 29
Proportion of participants with 
COVID-19–related MAVs by 
Day 29
Proportion of participants with 
all-cause death by Day 29
Use of rescue medication
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Hospitalization for the treatment 
of COVID-19 or all-cause death
Composite 
policy
Hospitalization for the 
treatment of COVID-19 
or all-cause death means 
never achieve symptom 
alleviation (censored at 
Day 14)
Discontinue randomized 
treatment prior to symptom 
alleviation (due to AE, lack of 
efficacy, investigator's 
discretion, noncompliance with 
study drug, protocol violation, 
participant decision, lost to 
follow-up)
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Time to COVID-19 symptom 
alleviation by Day 15
Use of rescue medication
Composite 
policy
Use of rescue 
medication means never 
achieve symptom 
alleviation (censor at 
Day 14)
AE = adverse event; COVID-19 = coronavirus disease 2019; MAV = medically attended visit


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8.6.
Safety Analysis
All safety data collected on or after the randomization date through 30 days after the date of the 
last dose of study drug will be summarized by treatment group (according to the study drug 
received). Data for the pretreatment period and after the date of last dose of study drug plus 
30 days will be included in data listings.
8.6.1.
Extent of Exposure
A participant’s extent of exposure to study drug data will be generated from the study drug 
administration data. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory AEs will be coded using the current version of the Medical Dictionary 
for Regulatory Activities. System organ class, high-level group term, high-level term, preferred 
term, and lower-level term will be attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
AE will be defined as any AE that begins on or after the date of first dose of study drug up to the 
date of last dose of study drug plus 30 days.
Summaries (number and percentage of participants) of treatment-emergent AEs (by system 
organ class, and preferred term) will be provided by treatment group.
8.6.3.
Laboratory Evaluations
Selected laboratory test data (using conventional units) will be summarized using only observed 
data. Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 (corrected, July 2017).
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline up to the date of last dose of study drug 
plus 30 days will be summarized by treatment group. If baseline data are missing, then any 
graded abnormality (ie, at least a Grade 1) will be considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug or after the participant has 
been discontinued from treatment for at least 30 days will be included in a data listing.
8.7.
Adjustments for Multiplicity
The overall two-sided type I error rate of 0.05 for the primary and key α-controlled secondary 
endpoints will be controlled using the Lan-DeMets approach with O’Brien-Fleming type 
spending function accompanying a gatekeeping testing strategy (ie, the primary efficacy 
endpoint will be tested first, and the key α-controlled secondary endpoints will be tested only if 
the primary efficacy endpoint is met).


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The O’Brien-Fleming approach will be used for decision making. The information fraction and 
the actual stopping boundaries will depend on the exact timing of the interim analysis. Example 
decision boundaries are shown in Table 12. 
Table 12. 
Boundaries for Interim and Final Analysis 
DMC Scenario Example 
Interim Efficacy 
Boundary (One-Sided 
P Value) 
Interim Futility 
Boundary (One-Sided 
P Value) 
Final 
Two-Sided P 
Value 
Second DMC occurs at 50% of 
primary endpoint events 
(0.5 information fraction) 
≤ 0.0015 
> 0.5055 
≤ 0.0490 
Second DMC occurs at 50% of 
enrollment (0.35 information 
fraction) and the third DMC at 
50% of primary endpoint events 
(0.5 information fraction) 
2nd DMC: ≤ 0.0002 
 
3rd DMC: ≤ 0.0015 
2nd DMC: > 0.8342 
 
3rd DMC: > 0.5128 
≤ 0.0490 
DMC = data monitoring committee 
8.8. 
Pharmacokinetic Analysis 
Plasma concentrations and pharmacokinetic parameters for GS-5245 metabolite, GS-441524, 
will be listed and summarized using descriptive statistics by treatment. Exposure-safety and 
efficacy may be conducted as needed, if sufficient data are available. 
8.9. 
Sample Size 
A total of 2300 participants provides > 90% power to detect a ratio of 0.25 (GS-5245 to placebo) 
in the primary endpoint (proportion of COVID-19–related hospitalization or all-cause death by 
Day 29), which is equal to a hazard ratio of 0.25 using a 2-sided significance level of 0.05 
assuming the placebo event rate is 2% in the placebo group. The estimate of 2% in the placebo 
group is based on the placebo event rate for COVID-19 in the EPIC-SR study {Pfizer Inc 2022} 
and vaccine efficacy data from the Centers for Disease Control and Prevention Morbidity and 
Mortality Weekly Report {Ferdinands 2022, Thompson 2022}. 
The sample size may be increased based on the unblinded sample size re-estimation. The sample 
size calculation was performed using software EAST (Version 6.5, module for log-rank test 
given accrual duration and study duration and 1 or 2 interim analyses using the Lan-DeMets 
approach with O’Brien-Fleming type spending function, with sample size re-estimation). 
8.9.1. 
Sample Size Re-estimation 
A sample size re-estimation is planned at the interim analysis when approximately 50% of 
expected primary endpoint events occur, due to the uncertainty in hospitalization or death rate in 
the placebo arm. All possible interim results will be partitioned into 3 zones–Favorable, 
Promising, and Unfavorable–depending on the size of observed conditional power (CP) under 
the current trend at the interim. If the CP falls into the Favorable zone, the study will continue 


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with the originally planned sample size of 2300 patients. If the CP falls into the Promising zone, 
the total sample size may be increased. If the CP falls into the Unfavorable zone but the interim 
result has not met the futility boundary, the study will also continue with the originally planned 
sample size of 2300 patients. 
The DMC will review the unblinded data at the interim analysis and communicate the decision 
on sample size to the study team. The overall type I error is controlled at 0.05 using the method 
proposed by Cui-Hung-Wang approach {Cui 2019, Muller 2004}. Further details will be 
included in the DMC charter and an adaptation plan. 
8.10. 
Data Monitoring Committee 
A multidisciplinary DMC consisting of non-Gilead personnel will review the progress of the 
study, perform interim review of safety data after the first 200 participants have reached Day 29 
or prematurely discontinued from the study, and provide recommendation to Gilead whether the 
nature, frequency, and severity of AEs associated with study drug warrant the early 
discontinuation of the study in the best interests of the participant, whether the study should 
continue as planned, or whether the study should continue with modifications. The DMC may 
also provide recommendations as needed regarding study design. The DMC will have 2 or 3 
formal (unblinded data review) meetings. The first formal meeting will review safety data after 
the first 200 participants complete the Day 29 assessment or prematurely discontinue from the 
study. The second formal meeting will review safety, efficacy, and futility data after 50% of 
participants complete the Day 29 assessment or prematurely discontinue from the study or 50% 
of expected primary endpoint events have occurred, whichever happens earlier. If the second 
DMC meeting is triggered by 50% of planned participants completing the Day 29 visit or 
prematurely discontinuing, a third DMC meeting may be conducted after 50% of expected 
primary endpoint events, as appropriate. The DMC may make a recommendation of stopping 
enrollment to the study if the prespecified efficacy or futility stopping criteria are met. 
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct, and meeting schedule. 
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study discontinuation, Gilead retains final decision-making authority on all aspects 
of the study. If the DMC recommends stopping the study for lack of efficacy, a Gilead Oversight 
Committee will be unblinded to confirm the DMC recommendation. 


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with ICH E6(R2) 
addendum to its guideline for GCP and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide prompt and accurate documentation of their 
financial interest or arrangements with the sponsor or proprietary interests in the study drug. This 
documentation must be provided before the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last participant completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or Gilead as appropriate according to local regulations) will submit this 
protocol, ICF, and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study participant activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC for any modifications made to the protocol or any accompanying material to be 
provided to the participant after initial IRB/IEC approval, with the exception of those necessary 
to reduce immediate risk to study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study before undertaking any study-related procedures. The investigator 
must use the most current IRB/IEC approved ICF for documenting written informed consent. 
Each ICF will be appropriately signed and dated by the participant or the participant’s legally 
authorized representative, the person conducting the consent discussion, and an impartial witness 
(if required by IRB/IEC or local requirements).


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The ICF will inform participants about planned sample retention. In addition to the 
study-specific ICF to be signed by each participant participating in the study, participants will be 
required to document additional consent to provide additional samples in accordance with 
applicable regulations. The results of the tests performed on the samples will not be given to the 
participant or the investigator. The stored biological samples will be destroyed no later than 
15 years after the end of study or per country requirements, but participants may at any time 
request that their stored samples be destroyed.
9.1.5.
Confidentiality
The investigator must ensure that participants anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to Gilead, IRB/IEC, or the laboratory. Laboratory specimens 
must be labeled in such a way as to protect participant identity while allowing the results to be 
recorded to the proper participant. Refer to specific laboratory instructions or in accordance with 
local regulations. Note: The investigator must keep a screening log with details for all 
participants screened and enrolled in the study, in accordance with the site procedures and 
regulations. Participant data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, eCRFs, study drug information, and any other study information, remains the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the investigational site to any third party or otherwise 
into the public domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and 
(2) participant clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRFs, IRB/IEC, and 
governmental approval with correspondence, the ICF(s), drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each participant:
•
Participant identification.


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•
Documentation that participant meets eligibility criteria (ie, medical history, physical 
examination, and confirmation of diagnosis [to support inclusion and exclusion criteria]).
•
Documentation of the reason(s) a consented participant is not enrolled.
•
Participation in study (including study number).
•
Study discussed and date of informed consent.
•
Dates of all visits.
•
Documentation that protocol-specific procedures were performed.
•
Results of efficacy parameters, as required by the protocol.
•
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return.
•
Record of all AEs and other safety parameters (start and end date; causality and severity) and 
documentation that adequate medical care has been provided for any AE.
•
Concomitant medication (start and end date; dose if relevant; dose changes).
•
Date of study completion and reason for early discontinuation if it occurs.
All clinical study documents must be retained by the investigator for at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (ie, the US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the investigational site for any 
or all of the documents, special arrangements must be made between the investigator and Gilead 
to store these records securely away from the site so that they can be returned sealed to the 
investigator in case of an inspection. When source documents are required for the continued care 
of the participant, appropriate copies should be made for storage away from the site.


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9.1.7.
Electronic Case Report Forms
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the electronic data capture (EDC) system unless otherwise 
directed. The eCRF casebook will only capture the data required per the protocol schedule of 
events and procedures, unless collected by a non-EDC vendor system (eg, central laboratory). 
The Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility are available. Data entry should be performed in accordance with the eCRF 
Completion Guidelines provided by the sponsor. Subsequent to data entry, a study monitor may 
perform source data verification. System-generated or manual queries will be issued in the EDC 
system as data discrepancies are identified by the study monitor or Gilead personnel who 
routinely review the data for completeness, correctness, and consistency. The site investigator, 
site coordinator, or other designee is responsible for responding to the queries in a timely 
manner, within the system, either by confirming the data as correct or updating the original entry, 
and providing the reason for the update (eg, data entry error). Original entries as well as any 
changes to data fields will be stored in the audit trail of the system. Regular oversight by the 
principal investigator of the data entered into the EDC system is expected to occur on an ongoing 
basis throughout the study to ensure quality and completeness. At a minimum, before any 
interim, final, or other time points (as instructed by Gilead), the investigator will apply his/her 
electronic signature to confirm that the forms have been reviewed and that the entries accurately 
reflect the information in the source documents. At the conclusion of the study, Gilead will 
provide the site investigator with a read-only archive copy of the data entered. This archive must 
be stored in accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigator Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, to IRB/IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Gilead. The investigator must submit all protocol modifications to the 
IRB/IEC in accordance with local requirements and receive documented IRB/IEC approval 
before modifications can be implemented.


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9.2.2.
Study Reports and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) when 
applicable and in accordance with local regulatory requirements. Gilead will ensure that the 
report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (E3). Note that an abbreviated report may be prepared in certain cases. For studies 
with sites in countries following the EU Regulation No. 536/2014, a CSR will be submitted 
within 1 year (6 months for pediatric studies, in accordance with Regulation [EC] 
No. 1901/2006) after the global end of study (as defined in Section 3.4.2)
Investigators in this study may communicate, orally present, or publish study data in scientific 
journals or other scholarly media in accordance with the Gilead clinical trial agreement.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study personnel may be asked to provide services performed under this 
protocol (eg, attendance at investigator meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to federal and state agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal 
and/or travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation and any participant records in order to verify the adherence 
to the protocol and the accuracy of the data recorded in the eCRF. The study monitor is 
responsible for routine review of the eCRF form at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them. The investigator agrees to cooperate with the study monitor to ensure that 
any problems detected through any type of monitoring (central, off-site, or on-site monitoring) 
are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the Gilead study monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Gilead reserves the right to terminate the study at any time, and the investigator has the right to 
terminate the study at his or her site. Should this be necessary, both parties will arrange 
discontinuation procedures and notify the participants, appropriate regulatory authority(ies) and 
IRB/IEC. In terminating the study, Gilead and the investigator will ensure that adequate 
consideration is given to the protection of the participants’ interests.


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10.
REFERENCES
Azzolini E, Levi R, Sarti R, Pozzi C, Mollura M, Mantovani A, et al. Association Between 
BNT162b2 Vaccination and Long COVID After Infections Not Requiring 
Hospitalization in Health Care Workers. JAMA 2022;328 (7):676-8.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Cox RM, Wolf JD, Lieber CM, Sourimant J, Lin MJ, Babusis D, et al. Oral prodrug of 
remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets. 
Nature communications 2021;12 (1):6415.
Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 
2019;17 (3):181-92.
Ferdinands JM, Rao S, Dixon BE, Mitchell PK, DeSilva MB, Irving SA, et al. Waning 2-Dose 
and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated 
Emergency Department and Urgent Care Encounters and Hospitalizations Among 
Adults During Periods of Delta and Omicron Variant Predominance - VISION 
Network, 10 States, August 2021-January 2022. MMWR. Morbidity and 
mortality weekly report 2022;71 (7):255-63.
Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, et al. Oral 
Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 
2022;386 (15):1397-408.
HealthMeasures, National Institutes of Health (NIH). Intro to PROMIS®. Available at: 
https://www.healthmeasures.net/explore-measurement-systems/promis/intro-to-
promis. Accessed: 22 August 2022. Last Updated: 05 August.  2022:
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, 
et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N 
Engl J Med 2022;386 (6):509-20.
Mackman RL, Hui HC, Perron M, Murakami E, Palmiotti C, Lee G, et al. Prodrugs of a 1'-CN-4-
Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir 
(GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in 
the African Green Monkey Model of RSV. J Med Chem 2021;64 (8):5001-17.
Muller HH, Schafer H. A general statistical principle for changing a design any time during the 
course of a trial. Stat Med 2004;23 (16):2497-508.
Pfizer Inc. Pfizer Reports Additional Data on PAXLOVID™Supporting Upcoming New Drug 
Application Submission to U.S. FDA [Press Release].  2022:


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Pitts J, Babusis D, Vermillion MS, Subramanian R, Barrett K, Lye D, et al. Intravenous delivery 
of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 
infection. Antiviral Res 2022;203:105329.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics 1993;4 (5):353-65.
Romano C, Fehnel S, Stoddard J, Sadoff J, Lewis S, McNulty P, et al. Development of a novel 
patient-reported outcome measure to assess signs and symptoms of COVID-19. J 
Patient Rep Outcomes 2022;6 (1):85.
Thompson MG, Natarajan K, Irving SA, Rowley EA, Griggs EP, Gaglani M, et al. Effectiveness 
of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency 
Department and Urgent Care Encounters and Hospitalizations Among Adults 
During Periods of Delta and Omicron Variant Predominance - VISION Network, 
10 States, August 2021-January 2022. MMWR. Morbidity and mortality weekly 
report 2022;71 (4):139-45.
U. S. Department of Health & Human Services (DHHS), Food and Drug Administration (FDA), 
Center for Drug Evaluation amd Research (CDER), Center for Biologic 
Evaluation and Research (CBER). 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.  September, 2020.
VEKLURY, Gilead Sciences Inc. VEKLURY® (remdesivir) for injection, for intravenous use. 
VEKLURY® (remdesivir) injection, for intravenous use. U.S. Prescribing 
Information. Foster City, CA. Revised: June.  2022a:
Veklury, Gilead Sciences Ireland UC. Veklury 100 mg powder for concentrate for solution for 
infusion. Summary of Product Characteristics. County Cork, Ireland. Revised 
April.  2022b:


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11.
APPENDICES


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11.1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
STUDY ACKNOWLEDGMENT
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of GS-5245 for the Treatment of COVID-19 in Participants With High-Risk for Disease 
Progression
GS-US-611-6273, Amendment 1 Protocol, 29 March 2023
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Director, Clinical Development
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD


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11.2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study.
These risks can be summarized as follows:
1) Study drug supplies to participants and sites:
a) Participants may be unable to return to the site for a number of visits to get the study 
drug, or the site may be unable to accept any participant visits. Without study drugs, the 
participant would not be able to continue receiving the study drug as planned per 
protocol.
Mitigation plan: Study drug supplies may be provided to the participant from the site 
without a clinic visit, once it is confirmed that the participant may safely continue on 
study drug as determined by the principal investigator. A remote study visit, via phone or 
video conferencing, must be performed before remote study drug resupply. At the earliest 
opportunity, the site will schedule in-person participant visits and return to the protocol’s 
regular schedule of assessments. A qualified courier may be utilized to ship the study 
drug from sites to study participants if permitted by the local ethics 
committee/institutional review board/regulatory authority as applicable and with 
sponsor's approval.
b) Shipments of study drug could be delayed because of transportation issues. Without study 
drug, the participant would not be able to continue receiving the study drug as planned 
per protocol.
Mitigation plan: The site’s study drug inventory should be closely monitored. Site staff 
should notify the sponsor or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. The sponsor will continue to monitor 
inventory at the study drug depot and investigational sites. Manual shipments will be 
triggered as necessary.
2) Participant safety monitoring and follow-up:
a) Participants may be unable or unwilling to come to the investigational site for their 
scheduled study visits as required per protocol.
Mitigation plan: For participants who may be unable or unwilling to visit the 
investigational site for their scheduled study visits as required per protocol, the principal 
investigator or qualified delegate will conduct a remote study visit, via phone or video 
conferencing, to assess the participant within the target visit window date whenever 
possible. During the remote study visit, the following information at minimum will be 
reviewed:


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i)
Confirm if participant has experienced any AEs/SAEs/special situations (including 
pregnancy) and follow up on any unresolved AEs/SAEs.
ii) Review the current list of concomitant medications and document any new 
concomitant medications.
iii) If applicable, confirm electronic diary questionnaires and participant-reported 
outcomes have been completed and transmitted.
iv) If applicable, confirm the participant’s study drug supply is sufficient to last until the 
next planned visit date. If study drug resupply is needed, it will be provided as 
described above in (1).
v) If applicable, remind the participant to maintain current dosing and to keep all 
dispensed study drug kits for return at the next on-site visit.
b) Participants may be unable or unwilling to travel to the site for planned assessments (eg, 
safety blood draws); hence samples may not be sent for central laboratory analyses.
Mitigation plan: Local laboratories or other vendors may be utilized as appropriate to 
monitor participant safety until the participant can return to the site for their regular 
follow-up per protocol. Any changes in the party conducting laboratory assessments for 
the study because of the pandemic will be documented accordingly. Pregnancy testing 
may be performed using a home urine pregnancy test if local laboratory pregnancy 
testing is not feasible.
c) Participants may be unable or unwilling to attend the study visit to sign an updated 
informed consent form version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with the local ethics committee/institutional review board and national laws 
and regulations. Remote consent will be allowed if has been approved by the local ethics 
committee/institutional review board. The consent process will be documented and 
confirmed by normal consent procedure at the earliest opportunity.
3) Protocol and monitoring compliance:
a) Protocol deviations may occur in case scheduled visits cannot be conducted as planned 
per protocol.
Mitigation plan: If it is not possible to complete a required procedure, an unscheduled 
visit should be conducted as soon as possible when conditions allow. The situation should 
be recorded and explained as a protocol deviation. Any missed participant visits or 
deviation to the protocol because of the pandemic must be reported in the eCRF and 
described in the clinical study report (CSR). Any remote study visits that are conducted 
in lieu of clinic visits because of the pandemic will be documented as a protocol 
deviation related to the pandemic.


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Gilead Sciences, Inc. 
Amendment 1
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b) Study monitors may be unable to carry out source data review or source data verification, 
or study drug accountability or assess protocol and Good Clinical Practice compliance. 
This may lead to delays in source data verification, an increase in protocol deviations, or 
underreporting of AEs.
Mitigation plan: The study monitor is to remain in close communication with the site to 
ensure data entry and query resolution. Remote source data verification may be arranged 
if allowed by local regulation and the Study Monitoring Plan. The study monitor is to 
reference the Study Monitoring Plan for guidance on how to conduct an off-site 
monitoring visit. The study staff is to save and document all relevant communication in 
the study files. The status of sites that cannot accept monitoring visits and/or participants 
on site, must be tracked centrally and updated on a regular basis.
4) Missing data and data integrity:
There may be an increased amount of missing data because of participants missing 
visits/assessments. This could have an impact on the analysis and the interpretation of 
clinical study data.
Mitigation plan: Implications of a pandemic on methodological aspects for the study will be 
thoroughly assessed and documented, and relevant actions will be taken as appropriate (eg, 
modification of the statistical analysis plan) and in compliance with regulatory authorities’ 
guidance. Overall, the CSR will describe the impact of the pandemic on the interpretability of 
study data.
Risks will be assessed continuously, and temporary measures will be implemented to mitigate 
these risks as part of a mitigation plan, as described above. These measures will be 
communicated to the relevant stakeholders as appropriate and are intended to provide alternate 
methods that will ensure the evaluation and assessment of the safety of participants who are 
enrolled in this study.
Since these potential risks are considered mitigated with the implementation of these measures, 
the expected benefit-risk assessment of GS-5245 in study participants remains unchanged.


GS-5245
Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 82
29 March 2023
11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and 
Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a participant assigned female at birth is considered of childbearing 
potential following the initiation of puberty (Tanner stage 2, Tanner staging only required if the 
participant is believed to be prepubescent) until becoming postmenopausal, or unless the 
participant is permanently sterile or has medically documented ovarian failure. Permanent 
sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a 
participant assigned female at birth of any age.
Participants assigned female at birth are considered to be in a postmenopausal state when they 
are at least 54 years of age with cessation of previously occurring menses for at least 12 months 
without an alternative cause. In addition, participants assigned female at birth younger than 
54 years with amenorrhea of at least 12 months also may be considered postmenopausal if their 
follicle-stimulating hormone level is in the postmenopausal range and they are not using 
hormonal contraception or hormonal replacement therapy.
b. Definition of Fertility in a Participant Assigned Male at Birth
For the purposes of this study, a participant assigned male at birth is considered fertile after the 
initiation of puberty unless the participant is permanently sterile by bilateral orchidectomy or 
with medical documentation.
2) Contraception Requirements for Participants Assigned Female at Birth and of 
Childbearing Potential
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-5245 is contraindicated in pregnancy as a malformative effect is noted in early pregnancy 
based on nonclinical data. An increased rate of adverse fetal effects, including postimplantation 
loss and fetal visceral malformations related to the development of the heart, blood vessels, and 
liver, were noted in rabbits administered GS-5245 250 mg/kg/day. Data from clinical 
pharmacokinetic interaction studies of GS-5245 have demonstrated that there is no reduction in 
the clinical efficacy of hormonal contraception. Refer to the latest version of the investigator’s 
brochure for additional information.
b. Contraception Requirements for Participants Assigned Female at Birth and of 
Childbearing Potential
The inclusion of participants assigned female at birth and of childbearing potential requires the 
use of highly effective contraceptive measures with a failure rate of less than 1% per year. They 
must have a negative pregnancy test at the screening visit before randomization. A pregnancy 
test will also be performed at the Day 15 visit. 


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Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 83
29 March 2023
Duration of required contraception for participants assigned female at birth and of childbearing 
potential in this clinical study should start from the screening visit until 14 days after the last 
study dose. 
Participants assigned female at birth and of childbearing potential must agree to 1 of the 
following contraceptive methods:
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle. 
Or
Consistent and correct use of 1 of the following methods of birth control listed below: 
•
Hormonal or nonhormonal intrauterine device (IUD). 
•
Subdermal contraceptive implant.
•
Bilateral tubal occlusion (upon medical assessment of surgical success).
•
Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success).
Or 
Participants assigned female at birth and of childbearing potential who wish to use a hormonally 
based method must use it in conjunction with a barrier method, preferably a male condom. 
Hormonal methods are restricted to those associated with the inhibition of ovulation. Hormonally 
based contraceptives and barrier methods permitted for use in this protocol are as follows:
•
Hormonal methods (each method must be used with a barrier method, preferably male 
condom)
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Transdermal contraceptive patch
Contraceptive vaginal ring
•
Barrier methods (each method must be used with a hormonal method)
Male condom (with or without spermicide)
Female condom (with or without spermicide)


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Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 84
29 March 2023
Diaphragm with spermicide
Cervical cap with spermicide
Sponge with spermicide
Inclusion of methods of contraception in this list of permitted methods does not imply that the 
method is approved in any country or region. Methods should only be used if locally approved. 
Participants assigned female at birth and of childbearing potential must also refrain from egg 
donation and in vitro fertilization during treatment and until the end of contraception 
requirement.
The above requirements apply only as specified, and not to sexual encounters in which 
pregnancy is not a possible outcome. 
3)
Contraception Requirements for Participants Assigned Male at Birth
It is theoretically possible that a relevant systemic concentration of study drug may be achieved 
in a partner assigned female at birth from exposure to the participant’s seminal fluid and pose a 
potential risk to an embryo/fetus. A participant assigned male at birth with a partner assigned 
female at birth and of childbearing potential must use highly effective contraceptive measures 
with a failure rate of less than 1% per year through at least 14 days after last dose of study drug. 
Please refer to the contraceptive requirements listed above for female participants.
Participants assigned male at birth must also refrain from sperm donation or cryopreservation of 
germ cells during treatment and until the end of contraception requirement.
The above requirements apply only as specified, and not to sexual encounters in which 
pregnancy is not a possible outcome. 
4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5)
Procedures to Be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from start of the study to 30 days after the last 
study drug dose. Study drug must be discontinued immediately, and medical monitor should be 
notified. 
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study to 30 days after the last study drug dose must also report the 
information to the investigator. Instructions for reporting pregnancy, partner pregnancy, and 
pregnancy outcome are outlined in Section 7.4.2.3. 


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Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 85
29 March 2023
11.4.
Country-Specific Requirements
11.4.1.
Additional Country-Specific Requirements for South Africa
A summary of changes specific to sites in South Africa is provided below. These changes are not 
reflected in the body of the protocol but should be considered a part of the protocol requirements 
for South Africa.
Country-specific Requirements
Protocol Sections
As per a request for Supplementary Information on 11 November 2022 from South 
Africa, study procedures were updated to clarify that the screening serum creatinine, 
creatinine clearance (CLcr)/estimated glomerular filtration rate (eGFR), alanine 
aminotransferase (ALT), bilirubin, and aspartate aminotransferase (AST) assessments 
are mandatory to detect laboratory abnormalities prior to the first study drug dose.
Section 6.3.2.5, and 
Table 1 footnote i
Study Visit
Screeninga
Baseline/
Day 1a,b
Day 3b
Day 5b
Day 10
Day 15b
Day 29
Early 
Discontinuation 
Visitb
Study 
Window
± 1 dayc
± 2 days
+ 5 days
Visit Type
In Persond
In Persond 
or Virtuale
In Persond
In Persond or Virtuale
In Persond
Screening 
ALT, AST, 
bilirubin, 
serum 
creatinine, 
and CLcr 
/eGFRi
X
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CLcr = creatinine clearance; eGFR = estimated glomerular 
filtration rate


GS-5245
Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 86
29 March 2023
11.4.2.
Additional Country-Specific Requirements for the United Kingdom
A summary of changes specific to sites in the United Kingdom (UK) is provided below. These 
changes are not reflected in the body of the protocol but should be considered a part of the 
protocol requirements for the UK.
Country-specific Requirements
Protocol Sections
Screening serum creatinine, CLcr/eGFR, ALT, AST, and bilirubin assessments are 
mandatory to detect laboratory abnormalities prior to dosing of study drug to ensure that 
kidney and liver function are not exclusionary prior to administering the first dose of 
study drug. 
Study procedures Table 1, footnote i has been updated.
Section 6.3.2.5 and 
Table 1 footnote i
Exclusion Criteria 7 and for any/all reference to historical eGFR or CLcr laboratory 
values, will have the word “known” removed in all such instances. The phrase “within 
the last 6 months” has been removed as this is not applicable for the UK. Exclusion 
Criteria 7 now reads as “Undergoing dialysis, or history of moderate or severe renal 
impairment, or CLcr < 60 mL/min (as calculated by Cockroft-Gault) or eGFR 
< 60 mL/min/1.73m2. Potential participants meeting the laboratory criterion may be 
enrolled if test results available before dosing show that renal function no longer meets 
this criterion.”
Section 4.3
Exclusion Criteria 8 and any/all reference to ALT or bilirubin, will have the word 
“known,” and “history”, “< 6 months before randomization”, and “unless confirmed as 
resolved to not meet criteria at screening” removed in all such instances and specific 
range of ULN amended. Exclusion Criteria 8 now reads as: “Any of the following 
abnormal laboratory results at screening: 
a. ALT ≥ 5 × ULN. 
b. Bilirubin > ULN.”
Section 4.3


GS-5245 
Protocol GS-US-611-6273 
Gilead Sciences, Inc. 
11.5. 
Amendment History 
Final 
Amendment 1 
High-level summaries of the histo1y of this study's amendments are provided in tabular f01m in 
the subsections below (from most recent amendment to oldest), with changes listed in each table 
in order of impo1iance. Minor changes such as the con ection of typographic en ors, grammar, or 
fo1m atting are not detailed. 
A separate tracked change (red-lined) document comparing the original protocol to this 
amendment will be made available upon the publication of this protocol. 
11.5.1. 
Amendment 1 (29 March 2023) 
Rationale fo1· Key Changes Included in Amendment 1 
Addition/modification of risk factors and targeted signs/symptoms of COVID-19 
to inclusion criteria to align with Center for Disease Control and Prevention. 
Overall clarifications and updates to inclusion/exclusion criteria resulting from 
queries received from sites and/or regulatory agencies. 
Additional relevant nonclinical toxicology, phannacology, and PK language 
included based on Phase I chug-drug interactions and radiolabeled ADME. 
Consequently, restrictions on coachninistration of acid-reducing agents were 
removed, ho1monal contraceptive measures amended, and phototoxicity results 
demonstrating that GS-5245 is not considered a photosafety risk have been 
incorporated. 
Text updated regarding the clinical studies of GS-5245 to include latest available 
data including food effect data from Study GS-US-611-6248. Consequently, 
restrictions on administration of GS-5245 around food intake were removed. 
Language updated regarding participants with compensated cin·hosis. 
Prior and concomitant medications that are prohibited was expanded to include 
ensitrelvir. 
Updates to seconda1y 
omissions (PK) and re 
coinfections). 
objectives and endpoints to capture 
analyses (PROs, viral titer, and 
Study chug discontinuation criteria clarifications and updated language (with 
coITesponding inclusion criteria and toxicity management) for exclusion of 
participants with prior or cuITent elevated bilirnbin level. 
Addition/clarification of efficacy analysis to include handling of intercuffent 
events. 
Addition of definitions for medically attended visits and COVID-19-related 
hospitalization. 
Minor changes to include clarifications or coITect omissions/e1rnrs. 
CONFIDENTIAL 
Page 87 
Affected Sections 
Synopsis and Section 4.2 
Synopsis, Sections 4.2 and 
4.3 
Sections 1.2. l. l. l, 
1.2.1. l. l.l, 1.2.1. l. l.2, 
1.2.1.1.2, 5.4. 1, and 
Appendix 11.3 
Synopsis, Sections 
1.2.1.l.3.l, 1.2.1.1.3.2, and 
5.3 
Sections 1.4.1 and 6.3.2.1 
Section 5.4.1 
Sections 6.3.6, 6.3.6.1, 
6.3.6.2, and 6.3.6.3 
Synopsis, Section 2 
Synopsis, Table I, Sections 
3.3.1.1, 4.3, 7.7.1.3, and 
7.7.1.4 
Sections 8.5.1, 8.5.2, and 
8.5.3 
Section 8.5 
Throughout, as needed 
29 March 2023 


GS-5245
Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 88
29 March 2023
11.5.2.
Amendment 0.2 (20 January 2023)
Rationale for Key Changes Included in Amendment 0.2
Affected Sections
Cohort numbers are corrected to include 1600 mg dose in the information 
presented for Phase 1 Study GS-US-611-6248 in healthy volunteers to evaluate 
the safety, tolerability, and PK of GS-5245.
Sections 1.2.1.2.1 and 1.4
Screening serum creatinine, CLcr/eGFR, ALT, AST, and bilirubin assessments are 
mandatory to detect laboratory abnormalities prior to dosing of drug to ensure that 
kidney and liver function are not exclusionary prior to administering the first dose 
of study drug. 
Study procedures Table 1, footnote h was updated.
Section 6.3.2.4 and Table 1 
footnote h
Exclusion Criteria 7 and for any/all reference to historical eGFR or CLcr 
laboratory values, will have the word “known” removed in all such instances. The 
phrase “within the last 6 months” has been removed as this is not applicable for 
the UK.
Section 4.3
Exclusion Criteria 8 and any/all reference to ALT or bilirubin, will have the word 
“known,” and “history” ” and “< 6 months before randomization” removed in all 
such instances as this is not applicable for the UK.
Section 4.3
Exclusion Criteria 8b, the phrase “bilirubin ≥ 5  ULN” has been changed to 
“bilirubin > ULN.” This has been changed at the request of the Medicine and 
Healthcare Products Regulatory Agency.
Section 7.4.3
In Exclusion Criterion 13 after the requirement for ongoing therapy with or prior 
use of any prohibited medications, reference added “Prohibited medications are 
identified in Section 5.4.1.”
Section 4.3
For instances of study drug administration “participants should take measures to 
minimize exposure to ultraviolet (UV) light for the duration of the study and for 
1 week after the last dose of study drug. Possible examples of UV protection 
measures include using sunscreen with broad spectrum sun protection factor of 
30 or above, wearing hats and long-sleeved clothing with UV protection factor of 
50 or above, and avoiding UV exposure between the hours of 10am and 4pm.” 
This has been added at the request of the Medicines and Healthcare Products 
Regulatory Agency as there is no currently available data on the phototoxicity of 
study drug.
Section 5.3
Minor changes to correct typographic errors.
Throughout, as needed


GS-5245
Protocol GS-US-611-6273
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 89
29 March 2023
11.5.3.
Amendment 0.1 (05 December 2022)
Rationale for Key Changes Included in Amendment 0.1
Affected Sections
As per a request for Supplementary Information (RSI) on 11 November 2022 
from South Africa, study procedures were updated to clarify that the screening 
blood tests are mandatory to detect laboratory abnormalities prior to the first study 
drug dose for sites in South Africa due to the high risk of disease progression in 
the intended population group.
Section 6.3.2.4, and Table 1 
footnote h
Changes introduced in Administrative Amendment 1 dated 22 August 2022 are 
integrated in this amendment but are not summarized here as the changes were 
administrative in nature. However, these changes will be reflected in the red-lined 
document comparing the original protocol to this amendment.
Section 7.4.2.2 (old 
section #), Section 7.3.5.1, 
Section 7.4.2.1, and 
Appendix 11.3
Minor changes to correct typographic errors.
Throughout, as needed
11.5.4.
Administrative Amendment 0.0.1 (22 August 2022)
Rationale for Key Changes Included in Amendment 0.0.1
Affected Sections
As defined in Section 7.4.2.1, this study will use an Electronic Special Situations 
Reporting Process for Study Drug.
Deleted old Section 7.4.2.2 as it previously specified a Paper Special Situation 
Reporting Process for Study Drug which was not intended to be used in this 
section. This section was included in error.
Section 7.4.2.2 (old section)
Fixed broken link so it now links to newly numbered Section 7.4.2.2 (Reporting 
Process for Gilead Concomitant Medications)
Section 7.3.5.1
Fixed broken link so it now links to newly numbered Section 7.4.2.2 (Reporting 
Process for Gilead Concomitant Medications)
Section 7.4.2.1
Updated section link so it now links to newly numbered Section 7.4.2.3 
(Pregnancy Reporting Process)
Appendix 11.3


Prot GS-US-611-6273 amd-1
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 30-Mar-2023
16:34:06
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of GS-5245 for the 
Treatment of COVID-19 in Participants With High-Risk for 
Disease Progression
Name of Test Drug:
Obeldesivir (ODV, GS-5245)
Study Number:
GS-US-611-6273
Protocol Version (Date):
Amendment 1 (29 March 2023)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
22 January 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
PPD
(rJ GILEAU 
-


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Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................6
1.1.
Study Objectives........................................................................................................................................6
1.2.
Study Design .............................................................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
TYPE OF PLANNED ANALYSIS........................................................................................................................9
2.1.
Interim Analyses........................................................................................................................................9
2.1.1.
DMC Analysis.........................................................................................................................9
2.2.
Final Analysis............................................................................................................................................9
2.3.
Changes from Protocol-Specified Analyses..............................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Randomized Analysis Set................................................................................................10
3.1.2.
Full Analysis Set....................................................................................................................10
3.1.3.
Full Analysis Positive Set......................................................................................................10
3.1.4.
Virology Analysis Set............................................................................................................10
3.1.5.
Safety Analysis Set................................................................................................................11
3.1.6.
Pharmacokinetic Analysis Set ...............................................................................................11
3.1.7.
Pharmacokinetic Substudy Analysis Set ...............................................................................11
3.2.
Subject Grouping.....................................................................................................................................11
3.3.
Strata and Covariates...............................................................................................................................11
3.4.
Examination of Subject Subgroups .........................................................................................................12
3.5.
Multiple Comparisons .............................................................................................................................12
3.6.
Missing Data and Outliers.......................................................................................................................13
3.6.1.
Missing Data..........................................................................................................................13
3.6.2.
Outliers ..................................................................................................................................13
3.7.
Data Handling Conventions and Transformations ..................................................................................13
3.8.
Analysis Visit Windows..........................................................................................................................15
3.8.1.
Definition of Study Day ........................................................................................................15
3.8.2.
Analysis Visit Windows........................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................18
4.
SUBJECT DISPOSITION ...................................................................................................................................20
4.1.
Subject Enrollment and Disposition........................................................................................................20
4.2.
Extent of Study Drug Exposure...............................................................................................................21
4.2.1.
Duration of Exposure to Study Drug.....................................................................................21
4.2.2.
Total Number of Tablets Administered.................................................................................21
4.3.
Protocol Deviations .................................................................................................................................22
4.4.
Assessment of COVID-19 Impact...........................................................................................................22
5.
BASELINE CHARACTERISTICS .....................................................................................................................23
5.1.
Demographics and Baseline Characteristics ...........................................................................................23


GS-5245 
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Statistical Analysis Plan - Final Analysis 
Version 1.0 
5.2. 
Other Baseline Characteristics ................................................................................................................ 23 
5.3. 
Medical Histoiy ....................................................................................................................................... 24 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 25 
6.1. 
Pri1nruy Efficacy Endpoint ...................................................................................................................... 25 
6.1. 1. 
Definition of the Prima1y Efficacy Endpoint ........................................................................ 25 
6.1.2. 
Statistical Hypothesis for the Primruy Efficacy Endpoint ..................................................... 25 
6.1.3. 
Primruy Analysis of the Prima1y Efficacy Endpoint.. ........................................................... 25 
6.2. 
Secondruy Endpoints ............................................................................................................................... 26 
6.2.1. 
Anal sis of Secondru Efficac End oints ........................................................................... 29 
6.4. 
IntercwTent Events .................................................................................................................................. 31 
6.5. 
Changes From Protocol-Specified Efficacy Analyses ........................................................................... .32 
7. 
SAFETY ANALYSES ......................................................................................................................................... 34 
7.1. 
Adverse Events and Deaths ..................................................................................................................... 34 
7.1. 1. 
Adverse Event Dictiona1y ..................................................................................................... 34 
7.1.2. 
Adverse Event Severity ......................................................................................................... 34 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 34 
7.1.4. 
Serious Adverse Events ......................................................................................................... 34 
7.1.5. 
Treatinent-Emergent Adverse Events .................................................................................... 34 
7.1.6. 
Swnmaries of Adverse Events and Deaths ............................................................................ 35 
7.1.7. 
Additional Analysis of Adverse Events ............................................................................... .36 
7.2. 
Laborato1y Evaluations ........................................................................................................................... 37 
7.2.1. 
Swnmaries ofNwneric Labora.t01y Results .......................................................................... 37 
7.2.2. 
Graded Labora.to1y Values .................................................................................................... 38 
7.2.3. 
Liver-Related Laborato1y Evaluations .................................................................................. 39 
7.3. 
Body Weight and Vital Signs .................................................................................................................. 39 
7 .4. 
Prior and Concoinitant Medications ....................................................................................................... .40 
7.4.1. 
Prior Medications ................................................................................................................. .40 
7.4.2. 
Conco1nitant Medications ..................................................................................................... .40 
7. 5. 
Other Safety Measures ........................................................................................................................... .41 
7 .6. 
Changes From Protocol-Specified Safety Analyses ............................................................................... .41 
8. 
PHARMA CO KINETIC ANALYSES ................................................................................................................. .42 
8.1. 
PK Sample Collection ............................................................................................................................ .42 
8.2. 
PK Analyses Related to Intensive PK Srunpling .................................................................................... .42 
8.3. 
PK Analyses Related to Sparse PK Srunpling ........................................................................................ .43 
8.4. 
Changes From Protocol-Specified PK Analyses .................................................................................... .43 
9. 
REFERENCES ..................................................................................................................................................... 44 
10. SOFTWARE ........................................................................................................................................................ .45 
11. SAP REVISION .................................................................................................................................................. .46 
12. APPENDICES ..................................................................................................................................................... .47 
CONFIDENTIAL 
Page3 
22 Janua1y 2024 


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Statistical Analysis Plan – Final Analysis
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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Vital Signs..................................................................................16
Table 3-2.
Analysis Visit Windows for SARS-CoV-2 Mid-turbinate Nasal Swab..................................17
Table 3-3.
Analysis Visit Windows for Hematology, Chemistry, and Coagulation Laboratory 
Tests.........................................................................................................................................17
Table 3-4.
Analysis Visit Windows for Urine or Serum Pregnancy Tests ...............................................17
Table 3-5.
Analysis Visit Windows for the SIC Questionnaire................................................................18
Table 6-1.
Handling of Intercurrent Events ..............................................................................................31
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ............................................................................................................................7


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Version 1.0
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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CoV
coronavirus
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
DAIDS
Division of AIDS
DMC
data monitoring committee
eGFR
estimated glomerular filtration rate
FAS
Full Analysis Set
FAPS
Full Analysis Positive Set
HLT
high-level term
ID
identification
IXRS
interactive voice or web response system
LLOQ
lower limit of quantification
LLT
lowest-level term
LOD
limit of detection
LOQ
limit of quantitation
MAVs
medically attended visits
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model repeated measures
PK
pharmacokinetic(s)
PT
preferred term
Q1, Q3
first quartile, third quartile
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SD
standard deviation
SIC
Symptoms of Infection with Coronavirus-19
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WHO
World Health Organization


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INTRODUCTION 
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This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study repo1t (CSR) 
for Study GS-US-611-6273. This SAP is based on the study protocol Amendment 1 dated 
29 March 2023 and the electronic case repo1t f01m (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
1.1. 
Study Objectives 
The primaiy objective of this study is as follows: 
• 
To evaluate the efficacy of GS-5245 in reducing the rate of COVID-19-related 
hospitalization or all-cause death 
The secondaiy objectives of this study ai·e as follows: 
• 
To evaluate the safety and tolerability of GS-5245 administered in nonhospitalized 
paiticipants with COVID-19 
• 
To evaluate the efficacy of GS-5245 in reducing all-cause hospitalization 
• 
To evaluate the efficacy of GS-5245 in reducing COVID-19- related medically attended 
visits (MA Vs) or all-cause death 
• 
To evaluate the efficacy of GS-5245 in reducing COVID-19- related MA Vs 
• 
To evaluate the efficacy of GS-5245 in reducing all-cause death 
• 
To evaluate the efficacy of GS-5245 in reducing the duration and severity of COVID-19 
symptoms 
• 
To evaluate the antiviral activity of GS-5245 on SARS-Co V-2 nasal swab viral load at Day 5 
• 
To evaluate the plasma phaimacokinetics (PK) of GS-441524 (metabolite of GS-5245) 
I 
I 
I 
I 
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I 
1.2. 
Study Design 
Version 1.0 
This Phase 3 study is a randomized, double-blind, placebo-controlled study comparing the safety 
and efficacy of oral GS-5245 with placebo in nonhospitalized pa1ticipants with COVID-19 who 
are at high risk of progression to hospitalization. 
Randomization will be stratified by duration of symptoms at emollment 
(~ 3 days versus > 3 days) and vaccination status (ever versus never). 
An overview of the study design is shown in Figure 1. 
Figure 1. 
Study Schema 
Participants who have no access lo 01· cannol take effective COVID-19 antivh11l therapies' 
Exclude par1icipa111s who have access 10 and can lake effec1ive COVIL>- 19 antiviral lbernpies• 
Unvaccinated + I risk factor 
Vaccinated + 2 1isk factors 
Initial symptoms within $ 5 days of enrollment 
D 
Screening wirhin 
~8 hours p1ior to 
I 2 3 4 
5 
JO 
15 
=~::::: 
··i··· i·i··············••:••···
· 
Day I v1s1ts may 
occuronrhe 
Study Period (Study Days) 
same day) 
Treatment 
Sb·atification factors include: 
Oays 1 to 5 
2. Vaccination status (ever vs never) 
Visit 
In-person 
Peiiod: 
l. Duration of symptoms at enrollment ($ 3 days vs > 3 days) 8 
End of Study 
t 
29 
1: 1 Randomization 
GS-5245 350 mg x 5 days (m1c.e daily) 
Placebo x 5 days (twice daily) 
• 
In-person or vimtal 
COVID-19 = coronavims disease 2019; D = Day 
a 
Access determined at the site level by the principal investigator and participant. 
b 
Effective COVID-19 antivirnl thernpies such as nitmatrelvir/ritonavir, molnupiravit·, ensitrelvit·, intravenous remdesivir, 
monoclonal antibodies, or any other locally authorized/approved dit·ect-acting therapy against SARS-CoV-2. 
Approximately 2300 paiticipants were planned to be randomized into the study. After screening 
procedures, eligible paiticipants ai·e randomized in a 1: 1 ratio to receive treatment with GS-5245 
or placebo. 
The schedule of study procedures is presented in Appendix 1. 
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1.3.
Sample Size and Power
A total sample size of approximately 2300 participants provides approximately 90% power to 
detect a ratio of 0.25 (GS-5245 to placebo) in the primary endpoint (proportion of 
COVID-19-related hospitalization or all-cause death by Day 29), which is equal to a hazard ratio 
of 0.25 using a 2-sided significance level of 0.05 assuming the placebo event rate is 2% in the 
placebo group. The estimate of 2% in the placebo group is based on the placebo event rate for 
COVID-19 in the EPIC-SR study {Pfizer Inc 2022} and vaccine efficacy data from the 
Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report {Ferdinands 
2022, Thompson 2022}.
The sample size calculation was performed using software East® (Version 6.5, module for 
log-rank test given accrual duration and study duration and 1 or 2 interim analyses using the 
Lan DeMets approach with O’Brien-Fleming type spending function, with sample size 
re-estimation).


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
2.1.1.
DMC Analysis
An external multidisciplinary Data Monitoring Committee (DMC) will review the progress of 
the study and perform interim reviews of the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will make 
recommendations to the sponsor if the nature, frequency, and severity of adverse effects 
associated with the study treatment warrant the early termination of the study, the continuation of 
the study, or the continuation of the study with modifications.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
The initial review was conducted after the first 200 participants completed the Day 29 
assessment or prematurely discontinued from the study.
A second DMC meeting to evaluate safety, futility, and efficacy was planned after 50% of the 
total planned participants had completed the Day 29 assessment or prematurely discontinued 
from the study, or 50% of expected primary endpoint events had occurred. However, the interim 
futility and efficacy analysis was not performed due to the stop of study enrollment prior to 
reaching the planned number of participants and events.
2.2.
Final Analysis
The unblinded final analysis will be performed after all participants have completed the study, 
outstanding data queries have been resolved or adjudicated as unresolvable, and the data have 
been cleaned and finalized.
2.3.
Changes from Protocol-Specified Analyses
The DMC meeting to formally evaluate futility and efficacy was not performed due to the stop of 
enrollment at close of business on 06 October 2023 after less than 50% of the participants were 
randomized. The reasons for stopping enrollment were due to lower-than-expected event rate for 
the primary endpoint.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-participant listings will be presented for all participants in the All Randomized Analysis Set 
and sorted by participant identification (ID) number, visit date, and time (if applicable). Data 
collected on log forms, such as adverse events (AEs), will be presented in chronological order 
within the participant. The treatment group to which participants were randomized will be used 
in the listings. Age, sex at birth, race, and ethnicity will be included in the listings, as space 
permits.
SARS-CoV-2 viral load will be used throughout the SAP for SARS-CoV-2 RT-qPCR viral load.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion will be 
summarized by treatment group and overall.
A listing of reasons for exclusion from analysis sets will be provided by participant.
3.1.1.
All Randomized Analysis Set
All Randomized Analysis Set includes all participants who were randomized in the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized participants who received at least 1 dose of 
study drug.
3.1.3.
Full Analysis Positive Set
The Full Analysis Positive Set (FAPS) includes all randomized participants who received at least 
1 dose of study drug and are SARS-CoV-2 positive at baseline as confirmed by 
Cepheid's Xpert Xpress CoV-2/Flu/RSV plus test or SARS-CoV-2 RT-qPCR test from central 
lab. This is the primary analysis set for efficacy analyses.
3.1.4.
Virology Analysis Set
The Virology Analysis Set includes all randomized participants who received at least 1 dose of 
study drug and had baseline SARS-CoV-2 viral load ≥ lower limit of quantification (LLOQ). 
Refer to Section 3.7 for the definition of LLOQ.


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3.1.5.
Safety Analysis Set
The Safety Analysis Set includes all participants who received at least 1 dose of study drug. This 
is the primary analysis set for safety analyses.
3.1.6.
Pharmacokinetic Analysis Set
The PK Analysis Set will include all randomized participants who received at least 1 dose of 
study drug and have at least 1 nonmissing concentration value reported by the PK laboratory. 
This is the primary analysis set for all PK analyses.
3.1.7.
Pharmacokinetic Substudy Analysis Set
The PK Substudy Analysis Set will include all randomized participants who received at least 
1 dose of study drug, participated in the PK substudy, and have at least 1 nonmissing postdose 
concentration. This is the primary analysis set for detailed PK analysis of intensive PK sampling.
3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Set, FAPS, or Virology Analysis Set, 
participants will be grouped according to the treatment to which they were randomized. For 
analyses based on the Safety Analysis Set, participants will be grouped according to the actual 
treatment received. The actual treatment received will differ from the randomized treatment only 
when their actual treatment differs from randomized treatment for the entire treatment duration.
For the PK Analysis Set and PK Substudy Analysis Set, participants will be grouped according 
to the actual treatment they received.
3.3.
Strata and Covariates
Participants will be randomly assigned to treatment groups via the interactive voice or web 
response system (IXRS) in a 1:1 ratio using a stratified randomization schedule. Stratification 
will be based on the following variables:
•
Duration of symptoms at enrollment: ≤ 3 days versus > 3 days
•
Vaccination status: ever versus never
If there are discrepancies in stratification factor values between the IXRS and the clinical 
database, the values recorded in the clinical database will be used for analyses. Additionally, 
stratification discrepancies will be reviewed and assessed. Based on the assessment of 
stratification discrepancies, a sensitivity analysis of the primary endpoint may be performed.
The primary efficacy endpoint will be evaluated using stratification factors as covariates or 
stratification variables for analyses, as specified in Section 6. If there is an imbalance in 
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be performed that include these baseline values in efficacy analysis models as covariates; these 
evaluations will be considered sensitivity analyses.
If 5 events or fewer across both treatment groups are observed within 1 or more stratum, the 
primary and key secondary endpoints will be evaluated in the same analyses without using the 
corresponding stratification factor(s).
3.4.
Examination of Subject Subgroups
Subgrouping of participants based on randomization stratification factors will be explored for 
subgroup analyses. In addition, select efficacy endpoint(s) may be examined using the following 
subgroups:
•
Baseline SARS-CoV-2 viral load: < 6 log10 copies/mL versus ≥ 6 log10 copies/mL
The safety endpoint(s) may be examined using the following subgroups:
•
Age: ≥ 18 – < 65 years, ≥ 65 – < 75 years, ≥ 75 – < 85 years, ≥ 85 years
•
Sex at birth: Male versus Female
•
Race: (a) Asian, (b) Black, (c) White, (d) Other
•
Region: Europe versus ex-Europe
•
BMI: < 25 kg/m2, ≥ 25 – < 30 kg/m2, ≥ 30 kg/m2
•
BMI: < 30 kg/m2 versus ≥ 30 kg/m2
•
Baseline estimated glomerular filtration rate (eGFR): Creatinine Clearance by 
Cockcroft-Gault: ≥ 90 mL/min, ≥ 60 – < 90 mL/min, ≥ 30 – < 60 mL/min, < 30 mL/min
Other subgroups may be considered based on imbalances between treatment groups observed in 
other baseline characteristics.
3.5.
Multiple Comparisons
The overall 2-sided type I error rate of 0.05 for the primary endpoint and key alpha-controlled 
secondary endpoints will be controlled using a gatekeeping testing strategy (ie, the primary 
efficacy endpoint will be tested first, and the key alpha-controlled secondary endpoints will be 
tested in a sequential manner only if the primary efficacy endpoint is met).


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A gatekeeping approach will be used for testing the key secondary endpoints. The endpoints will 
be tested in the following sequential order in the final analyses:
1. Proportion of participants with all-cause hospitalization by Day 29.
2. Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29.
3. Proportion of participants with COVID-19–related MAVs by Day 29.
4. Proportion of participants with all-cause death by Day 29.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
Participants with missing outcomes for the primary endpoint due to premature discontinuation 
from the study will be censored at the Last Study Date defined in Section 3.8.1.
For missing last dosing date of study drug, imputation rules are described in Section 4.2. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. Unless specified otherwise, all data will be included in the 
data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. 
If age at Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the randomization date will be used instead of the Day 1 visit date. For screen failures, the 
date the first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (eg, estimates of creatinine clearance, age at 
date of AE) will be based on age derived from date of birth and the date of the measurement or 
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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.
•
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper LOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the lower or upper LOQ, 
respectively).
SARS-CoV-2 viral load results that are below LLOQ but have a positive signal will be reported 
as “<2228cp/mL SARSCoV2 detected” and those that are below lower limit of detection (LOD) 
and negative will be reported as “No SARS-CoV2 detected”. The data will be imputed as 
follows:
•
A value of 1114 copies/mL (half of the LOQ 2228 copies/mL) will be used to calculate 
descriptive statistics if the datum is reported as “<2228cp/mL SARSCoV2 detected”.
•
A value of 746.5 copies/mL (half of the LOD 1493 copies/mL) will be used to calculate 
descriptive statistics if the datum is reported as “No SARS-CoV2 detected”.
SARS-CoV-2 infectious viral titer result will be imputed as follows:
•
A value of 100 PFU/mL (half of the LOQ 200 PFU/mL) will be used to calculate descriptive 
statistics if the datum is reported as “< 200 PFU/mL” and the corresponding qualitative result 
is “Positive”.
•
A value of 50 PFU/mL (1/4 of the LOQ 200 PFU/mL) will be used to calculate descriptive 
statistics if the datum is reported as “< 200 PFU/mL” and the corresponding qualitative result 
is “Negative”.
For baseline SARS-CoV-2 viral load, results of “No SARS-CoV2 detected”, “Inconclusive”, 
“<2228cp/mL SARSCoV2 detected” are considered as < LLOQ; numerical results are 
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Numerical result of SARS-CoV-2 viral load and SARS-CoV-2 infectious viral titer from samples 
collected with less than specified volume of test solution will not be included in viral load or 
infectious viral titer analyses. The positive or negative result of these samples will not be 
impacted.
Any SARS-CoV-2 viral load and infectious viral titer samples collected on or after the day when 
the participants are receiving additional COVID-19 treatments (see Appendix 3) will be excluded 
from the viral load or infectious viral titer analysis.
Base 10 logarithm transformation will be used for analyzing SARS-CoV-2 viral load and 
SARS-CoV-2 infectious viral titer.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
Natural logarithm transformation will be used for analyzing concentrations in intensive PK 
samples from the PK Substudy. Concentration values that are BLQ will be presented as “BLQ” 
in the concentration data listing. Values that are BLQ will be treated as 0 at predose time points, 
and one-half the value of the LOQ at postdose time points for summary purposes. Values that are 
0 or characters will be excluded from the calculation of geometric means.
The following conventions will be used for the presentation of summary and order statistics for 
PK concentrations:
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:
•
For assessment dates on or after the first dosing date: Assessment Date – First Dosing 
Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date


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Therefore, Study Day 1 is the day of first dose of study drug administration.
Last Dose Date is defined as the maximum, nonmissing, nonzero dose end date of treatment 
recorded on the Study Drug Administration eCRF form with “Study Drug Permanently 
Withdrawn” box checked for participants who prematurely discontinued or completed study drug 
according to the Study Drug Completion eCRF. Refer to Section 4.2 for missing date imputation, 
if necessary.
Last Study Date is the latest of the study drug start dates and end dates, the in-person or virtual 
visit dates, the vital sign collection dates, the questionnaire collection dates, the laboratory 
collection dates, and the death date (if applicable, for participants who died during the study, the 
death date will be the Last Study Date. For participants who died after completing the study or 
after prematurely discontinuing the study, the death date will not be considered for the 
Last Study Date).
Baseline value is defined as the last value obtained on or prior to the first dose date unless 
otherwise specified (see Section 3.8.3).
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for vital signs are provided in Table 3-1.
Table 3-1.
Analysis Visit Windows for Vital Signs
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
7
Day 10
10
8
12
Day 15
15
13
22
Day 29
29
23
34
*
If the nominal visit is a scheduled visit and the assessment is done on Day 4 (ie, Study Day = 4), assign to Day 3 or Day 5 
analysis window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on 
Day 4, assign to Day 3 analysis window.
The analysis windows for SARS-CoV-2 mid-turbinate nasal swab are provided in Table 3-2.


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Table 3-2.
Analysis Visit Windows for SARS-CoV-2 Mid-turbinate Nasal Swab
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
7
Day 10
10
8
12
Day 15
15
13
22
*
If the nominal visit is a scheduled visit and the assessment is done on Day 4 (ie, Study Day = 4), assign to Day 3 or Day 5 
analysis window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on 
Day 4, assign to Day 3 analysis window.
The analysis windows for hematology, chemistry, and coagulation laboratory tests are provided 
in Table 3-3.
Table 3-3.
Analysis Visit Windows for Hematology, Chemistry, and Coagulation 
Laboratory Tests
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
10
Day 15
15
11
22
*
If the nominal visit is a scheduled visit and the assessment is done on Day 4 (ie, Study Day = 4), assign to Day 3 or Day 5 
analysis window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on 
Day 4, assign to Day 3 analysis window.
The analysis windows for urine or serum pregnancy tests are provided in Table 3-4.
Table 3-4.
Analysis Visit Windows for Urine or Serum Pregnancy Tests
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 15
15
2
22
The Symptoms of Infection with Coronavirus-19 (SIC) questionnaire will be completed daily 
from predose at Day 1 to Day 15 visit, then at Day 29 visit. Windows are not assigned and 
results will be summarized for each applicable Study Day through Day 15. For the Day 29 
nominal visit, the analysis window is provided in Table 3-5.


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Table 3-5.
Analysis Visit Windows for the SIC Questionnaire
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 29
29
24
34
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline questionnaire data, the last nonmissing value on or prior to the first dosing date 
of study drug will be selected. If there are multiple records on or prior to the first dose date, 
the record prior to and closest to the first dose date and time will be used if available; 
otherwise the record after and closest to the first dose date and time will be used.
•
For baseline data other than questionnaire, the last nonmissing value on or prior to the first 
dosing date of study drug will be selected, unless specified differently. If there are multiple 
records on the same day, the baseline value will be selected as follows:
o
For continuous data:
▪
For SARS-CoV-2 viral load and SARS-CoV-2 infectious viral titer, if there is more 
than 1 record on the selected day, the latest value will be selected. If there are 
multiple records with the same time or no time recorded on the same day, the 
geometric mean value (copies/mL) will be taken.
▪
For other continuous data, the average of the measurements will be taken.
o
For categorical data:
▪
For SARS-CoV-2 positivity based on RT-qPCR, positivity based on infectious viral 
titer and Multiplex viral PCR, the worst severity (ie, a positive result, if available) 
will be selected.
▪
For other categorical data, the lowest severity will be selected.


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•
For postbaseline values:
o
The record closest to the nominal day for that visit will be selected.
o
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
o
If there is more than 1 record on the selected day, values will be selected for analysis as 
follows:
▪
For SARS-CoV-2 viral load and SARS-CoV-2 infectious viral titer, if there is more 
than 1 record on the selected day, the latest value will be selected. If there are 
multiple records with the same time or no time recorded on the same day, the 
geometric mean value (copies/mL) will be taken.
▪
For time to symptom alleviation, all records within the analysis visit window will be 
used.
▪
For questionnaire data to be summarized, if there is more than 1 record on the 
selected day, the latest value will be selected.
▪
For other parameters, if there is more than 1 record on the selected day, the average 
will be taken for continuous data and the worst severity will be taken for categorical 
data, unless otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
Key study dates (ie, first participant screened, first participant randomized, last participant 
randomized, last participant last visit for the primary endpoint, and last participant last visit for 
the CSR) will be provided.
A summary of participant enrollment will be provided by treatment group for each investigator 
within a country, and overall using the All Randomized Analysis Set. The summary will present 
the number and percentage of participants enrolled. For each column, the denominator for the 
percentage calculation will be the total number of participants analyzed for that column.
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of participants in the stratum will be the total number of enrolled participants. If there 
are discrepancies in the value used for stratification assignment between the IXRS and the 
clinical database, the value collected in the clinical database will be used for the summary. A 
listing of participants with discrepancies in the value used for stratification assignment between 
the IXRS and the clinical database at the time of data finalization will be provided, if applicable.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of participant disposition will be provided by treatment group and overall. This 
summary will present the number of participants screened, the number of participants who met 
all eligibility criteria but were not randomized with reasons these participants were not 
randomized, the number of participants randomized, and the number of participants in each of 
the categories listed below:
•
Safety Analysis Set
•
FAS
•
FAPS
•
Completed study drug
•
Did not complete study drug with reasons for premature discontinuation of study drug
•
Completed study
•
Did not complete the study with reasons for premature discontinuation of study


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For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 
the percentage calculation will be the number of participants in the Safety Analysis Set. 
In addition, a flowchart will be provided to depict the disposition.
A by-participant listing of reasons for premature study drug or study discontinuation will be 
provided by participant ID number in ascending order.
4.2.
Extent of Study Drug Exposure
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug and number of tablets taken will be summarized by 
treatment group for the Safety Analysis Set.
A by-participant listing of study drug administration and drug accountability will be provided 
separately by participant ID number (in ascending order).
Total duration of exposure (in days) to study drug will be defined as last dosing date minus first 
dosing date plus 1. If the last study drug dosing date is missing for a participant, the last dose 
date is imputed as the earliest date from the following:
•
Day 5 if the participant took 2 tablets on Day 1
•
Day 6 if the participant took 1 tablet on Day 1
•
Last study visit date
Study day for the imputed last dose day will not exceed Day 6.
4.2.2.
Total Number of Tablets Administered
The total number of tablets administered will be summarized using descriptive statistics.
The presumed total number of tablets administered to a participant will be determined by the 
data collected on the drug accountability CRF using the following formula:
Total Number of Tablets Administered =
No. of Tablets Dispensed ―
No. of Tablets Returned
The maximum tablets administered is 10 tablets.
For missing number of tablets returned, imputation rules are described in programming 
specifications.
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No formal statistical testing is planned.
A by-participant listing of study drug administration and drug accountability will be provided 
separately by participant ID number (in ascending order).
4.3.
Protocol Deviations 
Participants who did not meet the eligibility criteria for study entry but were enrolled in the 
study, will be summarized regardless of whether they were exempted by the sponsor or not. The 
summary will present the number and percentage of participants who did not meet at least 
1 eligibility criterion and the number of participants who did not meet specific criteria by 
treatment group based on the All Randomized Analysis Set. A by-participant listing will be 
provided for all randomized participants who did not meet at least 1 eligibility (inclusion or 
exclusion) criterion. The listing will present the eligibility criterion (or criteria if more than 
1 deviation) that participants did not meet and related comments, if collected.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations and 
the total number of important protocol deviations by deviation category (eg, eligibility criteria, 
informed consent) will be summarized by treatment group for the All Randomized Analysis Set. 
A by-participant listing will be provided for those participants with important protocol deviation.
4.4.
Assessment of COVID-19 Impact
The study is in nonhospitalized participants with COVID-19; thus, no additional assessment of 
COVID-19 impact will be included.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (eg, age, age group [≥ 18 – < 65, ≥ 65 – < 75, ≥ 75 – < 85, 
≥ 85 years], sex, race, and ethnicity) and baseline characteristics (eg, body weight, height, and 
body mass index [BMI]) will be summarized by treatment group and overall using descriptive 
statistics for continuous variables and using number and percentage of participants for 
categorical variables. The summary of demographic data and baseline characteristics will be 
provided for the Safety Analysis Set and FAPS.
For categorical data, the Cochran-Mantel-Haenszel (CMH) test (ie, general association statistic 
for nominal data and row mean scores for ordinal data) will be used to compare the 2 treatment 
groups. For continuous data, the 2-sided Wilcoxon rank sum test will be used to compare the 
2 treatment groups.
Similar summaries will be provided for the following subgroups corresponding to randomization 
strata: duration of symptoms at enrollment (≤ 3 days versus > 3 days); vaccination status 
(ever versus never)
A by-participant demographic listing, including the informed consent date, will be provided by 
participant ID number in ascending order.
5.2.
Other Baseline Characteristics
The following baseline disease characteristics will be summarized by treatment group and 
overall using descriptive statistics for continuous variables and using number and percentage of 
participants for categorical variables for the Safety Analysis Set and FAPS:
•
Randomization strata: duration of symptoms at enrollment (≤ 3 days versus > 3 days); 
vaccination status (ever versus never)
•
Duration of COVID-19 symptoms prior to first dose of study drug
•
Duration from first positive SARS-CoV-2 diagnostic test to first dose of study drug
•
Risk factors defined in the inclusion criteria
•
Total number of risk factors
•
Number of targeted COVID-19 symptoms at baseline measured via the SIC questionnaire
•
Summary for each COVID-19 targeted symptom at baseline, where an answer “No” to the 
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•
Baseline seropositivity: overall positive, ie, anti-spike antibody positive or anti-nucleocapsid 
antibody positive, versus overall negative, ie, both anti-spike antibody and anti-nucleocapsid 
antibody negative
•
Baseline respiratory viral coinfections: None; Yes subdivided into: Influenza A; Influenza B; 
respiratory syncytial virus (RSV)
•
Baseline SARS-CoV-2 viral load (as a continuous variable, and a categorical variable with 
< 6 log10 copies/mL versus ≥ 6 log10 copies/mL)
•
Baseline eGFR: Creatinine Clearance by Cockcroft-Gault: ≥ 90 mL/min, ≥ 60–< 90 mL/min, 
≥ 30 – < 60 mL/min, < 30 mL/min
For categorical data, the CMH test (ie, general association statistic for nominal data and row 
mean scores for ordinal data) will be used to compare the 2 treatment groups. For continuous 
data, the 2-sided Wilcoxon rank sum test will be used to compare the 2 treatment groups.
Similar summaries (except randomization strata) will be provided for the following subgroups 
corresponding to randomization strata: duration of symptoms at enrollment (≤ 3 days versus 
> 3 days); vaccination status (ever versus never).
A by-participant listing of other baseline characteristics will be provided by participant 
ID number in ascending order.
5.3.
Medical History
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed, or before the first dose of study drug and not related to a 
protocol-associated procedure is considered to be preexisting and should be documented as 
medical history. General medical history data will be collected at screening. It will be coded 
using the current version of Medical Dictionary for Regulatory Activities (MedDRA). A 
summary table will present the percentages of participants reporting each medical history 
preferred term, sorted first in alphabetical order by system organ class (SOC) and then by 
preferred term (PT) in descending order of total frequency within SOC. In addition, medical 
history will also be summarized by PT only, in descending order of total frequency.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary endpoint of the study is the proportion of COVID-19–related hospitalization or 
all-cause death by Day 29. The endpoint will be derived by combining the available all-cause 
death and COVID-19–related hospitalization reported by the site.
COVID-19–related hospitalization is defined as ≥ 24 hours of acute care for a reason related to 
COVID-19, in a hospital or similar acute care facility, including emergency rooms or temporary 
facilities instituted to address medical needs of those with COVID-19. This includes specialized 
acute medical care units within an assisted living facility or nursing home. This does not include 
hospitalization for the purposes of public health and/or clinical study execution. The date and 
duration of hospital admission, and primary reason for hospitalization (including if the 
hospitalization is related to COVID-19) will be recorded.
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
Null hypothesis: The hazard ratio of COVID-19–related hospitalization or all-cause death by 
Day 29 between the 2 treatment groups is equal to 1.
Alternative hypothesis: The hazard ratio of COVID-19–related hospitalization or all-cause 
death by Day 29 between the 2 treatment groups is not equal to 1.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The FAPS will be used for the primary efficacy endpoint analysis.
The hazard ratio of COVID-19–related hospitalization or all-cause death by Day 29 between the 
2 treatment groups will be estimated using a Cox proportional hazards model with the 
stratification factors (duration of symptoms and vaccination status) as covariates. The hazard 
ratio, p-value, 95% confidence interval (CI) for the hazard ratio from the Cox model, and 
proportion of COVID-19-related hospitalization or all-cause death at Day 29 from the 
Kaplan-Meier estimate will be provided. In addition, the p-value from stratified log rank test will 
be provided. If 5 events or fewer across both treatment groups are observed within 1 or more 
stratum, the primary endpoint will be evaluated in the same analysis described above without 
using the corresponding stratification factor(s) as covariates.
If a participant prematurely discontinues from the study prior to Day 29 and prior to 
COVID-19-related hospitalization and is alive by Day 29, or the hospitalization status is missing, 
the participant is censored at the Last Study Date or Day 29, whichever is earlier. If a participant 
prematurely discontinues from the study prior to Day 29 and prior to COVID-19-related 
hospitalization and then dies on or prior to Day 29, then date of the death and status will be used 
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hospitalization first and then dies, then date of the COVID-19–related hospitalization and status 
will be used for the primary analysis for this participant. If a participant has a 
non COVID-19-related hospitalization first and then dies without experiencing a 
COVID-19-related hospitalization, then date of the death and status will be used for the primary 
analysis for this participant. Handling of intercurrent events is defined in Section 6.4.
The number and percentage of participants with COVID-19–related hospitalization or all-cause 
death by Day 29 will be summarized.
6.2.
Secondary Endpoints
Key Secondary Efficacy Endpoints
The alpha-controlled secondary endpoints include the following:
•
Proportion of participants with all-cause hospitalization by Day 29
•
Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29
•
Proportion of participants with COVID-19–related MAVs by Day 29
•
Proportion of participants with all-cause death by Day 29
Medically attended visits are defined as any interactions with health care professionals other than 
study staff or designees including hospitalization; in-person emergency, urgent, or primary care 
visits; or any other in-person visit attended by the participant and a health care professional.
Other Secondary Efficacy Endpoints
•
Time to COVID-19 symptom alleviation by Day 15
•
Change from baseline (Day 1) in SARS-CoV-2 nasal swab viral load at Day 5
Symptom alleviation is defined as all targeted symptoms measured via the SIC questionnaire 
(Appendix 2) with a rating of 0, or at least 3 points decrease in rating from baseline, or an answer 
“No” to the question for at least 48 consecutive hours. A new version of the questionnaire that 
measures COVID-19 symptoms, COVID-19 Symptom Questionnaire, was introduced in 
protocol Amendment 1 but was not available to any participant by the time of stop of enrollment. 
Data for the COVID-19 Symptom Questionnaire were not collected.
Targeted symptoms are those listed below:
•
Nasal congestion (stuffy nose)
•
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•
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•
Shortness of breath (difficulty breathing)
•
Cough
•
Feeling generally unwell (run down)
•
Fatigue (tiredness)
•
Physical weakness
•
Feeling faint
•
Muscle aches/pains
•
Joint aches/pains
•
Headache
•
Chills
•
Uncontrollable body shaking/shivering
•
Fever
The first day of the 48 consecutive hours will be considered the symptom alleviation date. The 
date and time stamps at which participants complete the questionnaire each day are captured in 
electronic diary as “Form Saved Time” and will be used to determine whether the requirement 
of 48 continuous hours is satisfied.
A potential symptom alleviation is identified first and defined as all targeted symptoms with a 
rating of 0, or at least 3 points decrease in rating from baseline, or an answer “No” to the 
question, ie, without 48 consecutive hours confirmation. For participants with missing baseline 
symptoms data, all targeted symptoms need to have either a rating of 0 or an answer “No” to the 
question to be considered as potential symptom alleviation.
If there is any intercurrent event prior to Day 15 and prior to the time a participant achieves 
symptom alleviation, it will be handled per Section 6.4.
As the questionnaire recall time is the previous 24 hours, an additional consecutive 24 hour 
period is needed to achieve 48 consecutive hours of symptom alleviation. The duration for the 
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Yes 
Start 
Potential target 
symptom alleviation 
on Days X and X+l 
Duration:? 24 hours 
between completion times of 
COVID19 questionnaire on 
Day X and Day X+ 1 
No 
Potential symptom 
alleviation on Day X+2 
AND 
Duration :? 24 hours between 
completion times of COVID19 
questionnaire on Day X and 
Day X+2 
Yes 
Symptom Alleviation achieved 
on DayX 
Version 1.0 
No 
No missing day is allowed between first date and last date of potential symptom alleviation 
included in the calculation. 
The date-time of the first potential alleviation will be considered as the date-time of symptom 
alleviation and will be used for the calculation of time to symptom alleviation. Othe1wise, repeat 
the algorithm for the next potential symptom alleviation time. 
Details and examples of algorithm for symptom alleviation are provided in Appendix 3. 
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6.2.1. 
Analysis of Secondary Efficacy Endpoints 
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The F APS will be the primaiy analysis set for key secondaiy efficacy endpoints and time to 
COVID-19 symptom alleviation. The Virology Analysis Set will be the primaiy analysis set for 
SARS-CoV-2 nasal swab viral load. 
The key seconda1y endpoints will be tested in the following sequential order using a gatekeeping 
approach: 
1. Proportion of participants with all-cause hospitalization by Day 29 
2. Proportion of participants with COVID-19-related MA Vs or all-cause death by Day 29 
3. Propo1tion of pa1ticipants with COVID-19-related MA Vs by Day 29 
4. Propo1tion of pa1ticipants with all-cause death by Day 29 
The proportion of participants with all-cause hospitalization by Day 29, COVID-19-related 
MA Vs or all-cause death by Day 29, COVID-19 related MA Vs by Day 29, and all-cause death 
by Day 29 will be analyzed in a similar manner to the primaiy endpoint. 
All-cause death by Day 29 will also be compared between the 2 treatment groups using the 
Fisher's exact test. If a paiticipant prematurely discontinues from the study prior to Day 29 and 
the death status is missing, the paiticipant will not be included in the analysis. 
The Kaplan-Meier product limit method will be used to estimate, and stratified log-rank test will 
be used to compai·e the 2 treatment groups for the time to COVID-19 symptom alleviation by 
Day 15. In addition, a Cox propo1tional hazai·ds regression model with the stratification factors 
as covariates will be used to estimate the hazard ratio and its 2-sided 95% CI. 
Change from baseline in SARS-CoV-2 nasal swab viral load to each visit including Day 5 will 
be compai·ed between the 2 treatment groups using a mixed-effects model repeated measmes 
(MMRM) approach. Additionally, change in SARS-CoV-2 viral load from baseline at each 
postbaseline analysis visit will be provided. Descriptive statistics will be provided by treatment 
group as follows: (1) Baseline values, (2) Values at each ostbaseline anal sis visit 3 Change 
from baseline at each ostbaseline anal sis visit. 
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I 
I 
I 
I 
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6.4. 
Intercurrent Events 
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Handling of intercunent events for the efficacy endpoints related to hospitalization, MA Vs, 
death, symptom alleviation, SARS-CoV-2 viral load, or SARS-CoV-2 infectious viral titer are 
shown in Table 6-1. Intercunent events are events occuning after treatment initiation that affect 
either the inte1pretation or the existence of the measurement of an endpoint. An event ( eg, use of 
rescue medication) that occurs after an endpoint of interest ( eg, hospitalization) is not considered 
as an intercunent event. 
Table 6-1. 
Handling of Intercurrent Events 
Endpoint. 
Intercurrent event. 
Strategy 
Description 
Proportion of COVID-19- related 
Discontinue randomized 
hospitalization or all-cause death 
treatment prior to endpoint ( due 
by Day29 
to AE, lack of efficacy, 
Treatment 
Ignore the occwTence of 
investigator's discretion, 
policy 
intercw1·ent events (use 
Proportion of participants with 
noncompliance with study chug, 
observed outcome) 
all-cause hospitalization by 
protocol violation, pa1ticipant 
Day29 
decision, lost to follow-up) 
Propo1tion of participants with 
COVID-19-related MA Vs or 
all-cause death by Day 29 
Propo1tion of participants with 
Treatment 
Ignore the occurrence of 
Use of rescue medication 
intercw1·ent events (use 
COVID-19-related MA Vs by 
policy 
observed outcome) 
Day29 
Propo1tion of participants with 
all-cause death by Day 29 
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Endpoint
Intercurrent event
Strategy
Description
Hospitalization for the treatment 
of COVID-19 or all-cause death
Composite 
policy
Hospitalization for the 
treatment of COVID-19 
or all-cause death means 
never achieve symptom 
alleviation (censored at 
Day 14)
Discontinue randomized 
treatment prior to symptom 
alleviation (due to AE, lack of 
efficacy, investigator's discretion, 
noncompliance with study drug, 
protocol violation, participant 
decision, lost to follow-up)
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Time to COVID-19 symptom 
alleviation by Day 15
Use of rescue medication
Composite 
policy
Use of rescue medication 
means never achieve 
symptom alleviation 
(censor at Day 14)
Hospitalization for the treatment 
of COVID-19 or all-cause death
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Discontinue randomized 
treatment prior to endpoint (due 
to AE, lack of efficacy, 
investigator's discretion, 
noncompliance with study drug, 
protocol violation, participant 
decision, lost to follow-up)
Treatment 
policy
Ignore the occurrence of 
intercurrent events (use 
observed outcome)
Proportion of participants with 
negative SARS-CoV-2 nasal swab 
viral load at Days 3, 5, 10, 15
Proportion of participants with 
negative SARS-CoV-2 nasal swab 
infectious viral titer at Days 3, 5, 
10, 15
Use of rescue medication
Composite 
policy
Use of rescue medication 
means never achieve 
negativity
AE = adverse event; COVID-19 = coronavirus disease 2019; MAVs = medically attended visits
6.5.
Changes From Protocol-Specified Efficacy Analyses
An interim analysis of safety, futility and efficacy was planned in the protocol using the 
O’Brien-Fleming approach when 50% (1150 participants) of planned participants completed the 
Day 29 assessment or prematurely discontinued from the study. The second DMC meeting was 
to include review of the interim analysis results. Due to early stopping of enrollment of this 
study, the planned interim analysis was not conducted. The second and any following 
DMC meeting were not held.
The primary analysis set for efficacy analyses was specified as the FAS in the protocol, but will 
be the FAPS per FDA feedback.


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The secondaiy endpoints of all-cause hospitalization by Day 29 and COVID-19- related MA Vs 
by Day 29 were to be analyzed using a competing risk analysis approach, with death as the 
competing risk as described in the protocol. Competing risk analysis approach will not be used 
due to ve1y low event rate for deaths. 
Sensitivity analyses for the prima1y endpoint that were specified in the protocol will not be 
conducted. 
The questionnaires to assess the impact on work productivity, activities of daily living, and 
functionality, WPAI + CIQ: COVID-19 and PROMIS-29, were not available to any paiticipants 
by the time of stop of emollment. Data for these questionnaires were not collected and statistical 
analysis will not be conducted. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. SOC, 
high-level group term (HLGT), high-level term (HLT), PT, and lowest-level term (LLT) will be 
provided in the AE dataset.
7.1.2.
Adverse Event Severity
The severity of AEs will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. For each episode, 
the highest grade attained should be reported as defined in the grading scale. The DAIDS scale is 
available at the following location:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life threatening) or Grade 5 (fatal) according to toxicity criteria specified in the 
document above. The severity grade of events for which the investigator did not record severity 
will be categorized as “missing” for tabular summaries and data listings. The missing category 
will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the 
Gilead Global Patient Safety Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
Incidence of treatment-emergent adverse events (TEAEs) and laboratory abnormalities, and 
incidence of SAEs, and AEs leading to study drug discontinuation are secondary safety 
endpoints of this study.


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7.1.5.1.
Definition of Treatment-Emergent Adverse Events
TEAEs are defined as 1 or both of the following:
•
Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug
•
Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:
•
The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and
•
The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, HLT (if applicable), PT, and treatment group. For other AE categories 
described below, summaries will be provided by SOC, PT, and treatment group:
•
Grade 3 or higher TEAEs
•
All treatment-emergent treatment-related AEs
•
Grade 3 or higher treatment-emergent treatment-related AEs
•
All treatment-emergent SAEs
•
All treatment-emergent treatment-related SAEs
•
All treatment-emergent AEs leading to premature discontinuation from study drug 


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TEAE and treatment-related TEAE will be summarized by SOC, PT, severity, and treatment 
group.
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described above will be provided by treatment group. All 
treatment-emergent deaths observed in the study will also be included in this summary. 
Treatment-emergent death refers to deaths that occurred between the first dose date and the last 
dose date plus 30 days (inclusive).Multiple events will be counted only once per participant in 
each summary. Adverse events will be summarized and listed first in alphabetic order of SOC 
(and HLT within each SOC if applicable), and then by PT in descending order of total frequency 
within each SOC. For summaries by severity grade, the most severe grade will be used for those 
AEs that occurred more than once in an individual participant during the study.
In addition to the above summary tables, all TEAEs, Grade 3 or higher TEAEs, 
treatment-emergent treatment-related AEs, Grade 3 or higher treatment-emergent 
treatment-related AEs, and treatment-emergent SAEs, will be summarized by PT only, in 
descending order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
Treatment-related AEs
•
All AEs with severity of Grade 3 or higher
•
All SAEs
•
All Deaths
•
Treatment-related SAEs
•
All AEs leading to premature discontinuation of study drug
7.1.7.
Additional Analysis of Adverse Events
The following categories of AEs will be summarized by treatment group:
•
Renal dysfunction: Acute renal failure Standard MedDRA Query (SMQ) (broad)
•
Hepatic findings: Liver toxicity KUR list
The number and percentage of participants who experienced any of the above events will be 
summarized for each treatment group by category and PT.


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TEAEs will also be summarized for the subgroups for safety endpoints (ie, age, sex at birth, race, 
region, BMI and baseline eGFR) defined in Section 3.4.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days. 
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. SARS-CoV-2 viral load result of 
“Inconclusive” will not be included in numeric summary. Hemolyzed test results will not be 
included in the analysis, but they will be listed in by-participant laboratory listings.
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, and coagulation separately. Values 
falling outside of the relevant reference range and/or having a severity grade of 1 or higher on 
the DAIDS Grading Scale will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for selected laboratory tests in 
Hematocrit, Hemoglobin, Absolute Neutrophil Count, Absolute Lymphocyte Count, Platelet 
Count, White Blood Cells, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), 
Total bilirubin, Serum Creatinine, eGFR: Creatinine Clearance by Cockcroft-Gault, and 
International Normalized Ratio (INR) as follows:
•
Baseline values 
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of study drug. Change from baseline to a postbaseline visit will be defined as 
the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) change from baseline values for selected laboratory tests listed above will be 
plotted using a line plot by treatment group and each postbaseline visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.


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7.2.2.
Graded Laboratory Values
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Event, Version 2.1 
(July 2017) will be used to assign toxicity grades (0 to 4) to laboratory results for analysis. 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any 
abnormality of at least Grade 1 observed within the time frame specified above will be 
considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group; participants will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:
•
Treatment-emergent laboratory abnormalities
•
Treatment-emergent Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with nonmissing postbaseline values up to 30 days after last dosing date.
A by-participant listing of all laboratory abnormalities and treatment-emergent Grade 3 or 4 
laboratory abnormalities will be provided by participant ID number and visit in chronological 
order. This listing will include all test results that were collected throughout the study for the lab 
test of interest, with all applicable severity grades and abnormal flags displayed.
For the INR of prothrombin time and activated partial thromboplastin time (aPTT), protocol 
specified toxicity grading scale depends on the upper limit of normal range (ULN). While the 
ULN of INR and aPTT depends on whether the participant is taking anticoagulant medication or 
not (ie, Not taking oral anticoagulant: 0.8 – 1.2; Taking oral anticoagulant: 2.0 – 3.0), this 
information is not collected by the reference laboratory. As a result, INR and aPTT will be 
graded by assuming participant is not taking an oral anticoagulant, which is a conservative 
approach that may lead to over-reporting of abnormalities for INR and aPTT.
Abnormalities in coagulation parameters will be included for INR and aPTT.


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7.2.3.
Liver-Related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized using 
the number and percentage of participants who were reported to have the following laboratory test 
values for postbaseline measurements:
•
AST: (a) > 3 times of the ULN; (b) > 5 × ULN; (c) > 10 × ULN; (d) > 20 × ULN
•
ALT: (a) > 3 × ULN; (b) > 5 × ULN; (c) > 10 × ULN; (d) > 20 × ULN
•
AST or ALT: (a) > 3 × ULN; (b) > 5 × ULN; (c) > 10 × ULN; (d) > 20 × ULN
•
Total bilirubin: (a) > 1 × ULN; (b) > 2 × ULN
•
Alkaline phosphatase (ALP) > 1.5 × ULN
•
AST or ALT > 3 × ULN and total bilirubin: (a) > 1.5 × ULN; (b) > 2 × ULN
•
AST or ALT > 3 × ULN and total bilirubin > 2 × ULN and ALP < 2 × ULN
The summary will include data from all postbaseline visits up to 30 days after the last dose of study 
drug. For individual laboratory tests, participants will be counted once based on the most severe 
postbaseline value. For both the composite endpoint of ALT or AST and total bilirubin, and the 
composite endpoint of ALT or AST, total bilirubin, and ALP, participants will be counted once when 
the criteria are met at the same postbaseline visit date. The denominator is the number of participants 
in the Safety Analysis Set who have nonmissing postbaseline values of all relevant tests at the same 
postbaseline visit date.
Listings of liver-related laboratory tests will be provided.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for vital signs (including heart rate, 
respiratory rate, temperature, oxygen saturation, and blood pressure) as follows:
•
Baseline value
•
Values at each postbaseline analysis window visit
•
Change from baseline at each postbaseline analysis window visit
A baseline value will be defined as the last available value collected on or prior to the date of first 
dose of study drug. Change from baseline to a postbaseline visit will be defined as the postbaseline 
value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as described in 
Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of body weight, BMI, and vital signs will be provided by participant 
ID number and visit in chronological order.


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7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the Gilead-modified World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications with a start date prior to the first dosing date of 
study drug, regardless of when the stop date is. If a partial start date is entered, the medication 
will be considered prior unless the month and year (if day is missing) or year (if day and month 
are missing) of the start date are after the first dosing date. Medications with a completely 
missing start date will be considered as prior medications.
Prior medications will not be summarized.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a participant took study drug. 
Day 1 to Day 29 medications are defined as medications taken from Day 1 to Day 29. Use of 
concomitant medications and Day 1 to Day 29 medications will be summarized separately by 
preferred name using the number and percentage of participants for each treatment group. A 
participant reporting the same medication more than once will be counted only once when 
calculating the number and percentage of participants who received that medication. The 
summary will be ordered by preferred term in descending overall frequency. For drugs with the 
same frequency, sorting will be done alphabetically. COVID-19 rescue medications 
(see Appendix 3) taken postbaseline will be listed and summarized if there are sufficient data.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Day 1 to Day 29 medications will follow the same logic of concomitant medications 
using Day 29 instead of last dosing date of study drug. Summaries will be based on the 
Safety Analysis Set. No formal statistical testing is planned.
All reported medications will be provided in a by-participant listing sorted by participant 
ID number and administration date in chronological order.


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7.5.
Other Safety Measures
A by-participant listing of participant pregnancies during the study will be provided by 
participant ID number. No additional safety measures are specified in the protocol.
7.6.
Changes From Protocol-Specified Safety Analyses
Treatment-emergent AEs were defined in the protocol as any AEs with an onset date on or after 
the study drug start date and no later than 30 days after permanent discontinuation of study drug. 
In this SAP, any AEs leading to premature discontinuation of study drug are added in addition to 
the protocol definition of TEAEs.
There are no deviations from the protocol-specified safety analyses.


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PHARMACOKINETIC ANALYSES 
8.1. 
PK Sample Collection 
Version 1.0 
Sparse PK blood samples will be collected during an in-person visit for all participants. 
I 
I 
I 
8.2. 
PK Analyses Related to Intensive PK Sampling 
Concentrntions of GS-441524 in plasma will be detennined using validated bioanalytical assays. 
Due to limited number of paiiicipants with intensive PK data, PK pai·aineters will not be 
detennined in pa1iicipants in the PK Substudy Analysis Set for this study. Summa1y of PK 
parameters will not be provided. 
Individual pa1iicipant concentrntion data for GS-441524 will be listed and summarized using 
descriptive statistics by treatment. Summaiy statistics (n, mean, SD, coefficient of variation 
[%CV], median, min, max, geometric mean, 5th percentile, 95th percentile, Ql, and Q3) will be 
presented for individual paiiicipant concentration data by time point. 
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Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number of participants 
with concentration BLQ will be presented for each time point. For summary statistics, 
BLQ values will be treated as 0 at predose and one-half of the lower LOQ for postdose time 
points.
The following tables will be provided for each analyte by treatment:
•
Individual participant concentration data and summary statistics
The following figures may be provided for each analyte by treatment:
•
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)
•
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤ LOQ will not be 
displayed in the figures and remaining points connected.
PK sampling details by participant, including procedures, differences in scheduled and actual 
draw times, and sample age will be provided in listings.
8.3.
PK Analyses Related to Sparse PK Sampling
Individual participant concentration data from participants in the PK Analysis Set for GS-441524 
will be listed and summarized using descriptive statistics. PK concentration data from samples 
out of window will be listed but will not be included in the summary statistics. 
Summary statistics (n, mean, SD, %CV, median, min, max, 5th percentile, 95th percentile, Q1, 
Q3, geometric mean, %CV, and 95% CI for geometric mean) will be presented by day and by 
nominal time point.
Sparse and intensive PK sampling data from this study may be combined with data from other 
studies in a meta-population analysis using mixed-effect modeling techniques. Details of the 
population PK analysis will be provided in a separate document prepared by the PK scientist.
8.4.
Changes From Protocol-Specified PK Analyses
PK parameters will not be determined for this study. Summary and listing of PK parameters for 
GS-441524, as specified in the protocol, will not be provided.


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9.
REFERENCES
Ferdinands JM, Rao S, Dixon BE, Mitchell PK, DeSilva MB, Irving SA, et al. Waning 2-Dose 
and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated 
Emergency Department and Urgent Care Encounters and Hospitalizations Among 
Adults During Periods of Delta and Omicron Variant Predominance - VISION 
Network, 10 States, August 2021-January 2022. MMWR Morb Mortal Wkly Rep 
2022;71 (7):255-63.
Pfizer Inc. Pfizer Reports Additional Data on PAXLOVID™Supporting Upcoming New Drug 
Application Submission to U.S. FDA [Press Release]. 2022:
Thompson MG, Natarajan K, Irving SA, Rowley EA, Griggs EP, Gaglani M, et al. Effectiveness 
of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency 
Department and Urgent Care Encounters and Hospitalizations Among Adults 
During Periods of Delta and Omicron Variant Predominance - VISION Network, 
10 States, August 2021-January 2022. MMWR Morb Mortal Wkly Rep 2022;71 
(4):139-45.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
Phoenix WinNonlin® 8.2. Pharsight Corporation, Princeton, NJ, USA.
East® 6.5. Cytel, Waltham, MA, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
Draft Version 1.0
(13 Nov 2023)
Original Version
3.8.3
Addition of selection of baseline 
for SARS-CoV-2 data
Align with selection of analysis 
record for postbaseline
6.1.3
Updated primary analysis of the 
primary efficacy endpoint
Provide additional analysis of 
the primary efficacy endpoint
6.4
Addition of handling of 
intercurrent events for the 
SARS-CoV-2 related efficacy 
endpoints
Clarify the impact of 
intercurrent events on 
SARS-CoV-2 related efficacy 
endpoints and the 
corresponding handling rules
7.1.6
Revised section with removal of 
sections 7.1.6.1 and 7.1.6.2
Update to clarify the summaries 
of AE incidence by severity
Version 1.0
(22 Jan 2024)
8.2
Removal of sections 8.2.1 and 
8.2.2, and any analyses of PK 
parameters
Update to clarify that PK 
parameters will not be 
determined or analyzed for this 
study


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APPENDICES 
Appendix 1. 
Schedule of Assessments 
Study Visit 
Visit Window 
Screening• 
Baseline/ 
Day 13,b 
Day3b 
Day Sb 
Day 10 
Day l Sb 
Day 29 
± 1 day< 
± 2 days 
+ 5 days 
In Persond 
In 
Visit Type 
In Persond 
or Virtual• 
Persond 
In Persond 0 1· Virtual• 
Written informed consent 
Medical histo1yf 
Document SARS-CoV-2 infection 
Complete physical examinationg 
Symptom-directed physical examination 
Height and weight 
Vital signsh 
Screening ALT, bilimbin, semm creatinine, 
and CLc/eGFRi 
Chemistty, coagulation, and hematology panelsi 
Urine or semm pregnancy testsk 
Mid-turbinate nasal swab1 
SARS-CoV-2 serology 
MA V infonnation/oxygen supplementation 
requirement" 
CONFIDENTIAL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Version 1.0 
Early 
Discontinuation 
Visitb 
In Persond 
X 
X 
X 
X 
X 
X 
22 Janua1y 2024 


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Study Visit
Day 3b
Day 5b
Day 10
Day 15b
Day 29
Visit Window
Screeninga
Baseline/
Day 1a, b
± 1 dayc
± 2 days
+ 5 days
Early 
Discontinuation 
Visitb
Visit Type
In Persond
In Persond 
or Virtuale
In 
Persond
In Persond or Virtuale
In Persond
COVID-19 Symptom Questionnairep
X
X
X
X
X
X
X
PROMIS-29
X
X
X
X
WPAI + CIQ: COVID19
X
X
X
X
Study drug dispensation
X
Study drug dosing (GS-5245 or placebo)
X
X
X
Study drug bottle returnq
X
X
X
X
X
Adverse events and concomitant medications
X
X
X
X
X
X
X
X
ALT = alanine aminotransferase; CLcr = creatinine clearance; COVID-19 = coronavirus disease 2019; ED = early discontinuation; eGFR = estimated glomerular filtration rate; 
MAV = medically attended visit; PCR = polymerase chain reaction; PK = pharmacokinetic(s); PROMIS-29 = Patient-Reported Outcomes Measurement Information System-29; 
RT-qPCR = reverse transcriptase-quantitative polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WPAI + CIQ:COVID19 = Work 
Productivity and Activity Impairment + Classroom Impairment Questions: COVID-19 Infection
a
Screening window is within 48 hours of the Day 1 visit. Day 1 visit may occur on the same day as screening. If the Day 1 and screening visits are the same day, do not repeat 
physical exam and vital signs.
b
Laboratory tests for safety will be performed on Days 1 and 5, on Days 3 and 15 when an in-person visit is conducted, and at early discontinuation.
c
Day 3 and Day 5 visits should be conducted on separate calendar days.
d
In-person is defined as a visit at a medical facility or elsewhere by a health care provider (where permitted).
e
Virtual visit is defined as an interaction with a health care professional using telephone or online-based interaction (eg, telehealth, webcast, video conferencing).
f
Medical history will include the date of first COVID-19 symptoms, overall COVID-19 symptoms, all COVID-19 vaccinations prior to screening, exposure source, 
demographics, baseline characteristics, allergies, and all other medical history.
g
A complete physical examination must include source documentation of general appearance and the following body systems: head, neck, and thyroid; eyes, ears, nose, throat, 
mouth, and tongue; chest (excluding breasts); respiratory; cardiovascular; lymph nodes, abdomen; skin, hair, nails; musculoskeletal; and neurological. For participants with 
compensated cirrhosis, a complete physical exam must also include a clinical assessment of ascites (absent, slight, or moderate) and a clinical assessment of hepatic 
encephalopathy (Absent, Grade I, Grade II, Grade III, or Grade IV), as described in Section 6.3.2.1 of the protocol. Urogenital and reproductive examination should only be 
completed if clinically indicated.
h
Vital signs include heart rate, respiratory rate, temperature, oxygen saturation, and blood pressure. Vital signs are collected at in-person visits only.
i
Screening: Serum ALT, bilirubin, serum creatinine, and CLcr/eGFR assessments at screening (prior to dosing) are not required unless deemed necessary by the investigator to 
confirm eligibility, using a local laboratory. See Appendix 11.4 of the protocol for country-specific requirements.
j
All required baseline laboratory assessments should be collected prior to first study drug dose.


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k 
At screening, a mine pregnancy test will be performed at the local laboratory for participants assigned female at birth and of childbea1ing potential. On Day 1, Day 15, and 
ED visits, these pa1ticipants will have a serum pregnancy test performed via the central laboratory for in-person visits or a urine pregnancy test for virtual visits. At screening, 
a follicle-stimulating ho1mone test is required to confirm the postmenopausal state in participants younger than 54 years, who have stopped menstmating for at least 
I 
r 
12 months but do not have documentation of ovarian hormonal faihu·e, as described in Appendix 11.3 of the protocol. 
A mid-ttubinate nasal swab will be collected at in-person visits and used for SARS-Co V-2 RT-qPCR, potential multiplex viral PCR, potential infectious viral titer assessment, 
and otential resistance testino. The nasal swab must be collected b clinic/stud 
ersonnel in erson. For viitual visits on Da s 3, 10, or 15 no sam !es will be collected. 
o 
Me 1ca y at.ten e v1S1t rn ormation rnc u es any rnteractions w1 
1ea t 1 care pro ess1ona s o er t an stu y sta or es1gnees rnc u rng hospitalization; in-person 
emergency, m·gent, or primary care visits; or any other in-person visit attended by the pa1t icipant and a health care professional. The nattu·e and cause of the visit should be 
identified. Medically attended visit information and oxygen supplementation information should be collected through Day 29. 
p 
The COVID-19 symptom questionnaire should be completed daily (at approxiniately the same time each day) from predose (prior to first dose on Day 1) through Day 15, and 
on Day 29. If a pa1ticipant discontinues from the study early, the pa1ticipant should complete this questionnaii·e during the early discontinuation visit. 
q 
Study dmg bottle should be returned by the pa1ticipant on Day 5, if the participant has already completed both doses of study dmg. If the participant has study dmg at the end 
of the Day 5 visit, the participant may return the study dmg bottle on Day 10. If the Day 10 visit is viitual, dmg accountability should be pe1fon11ed virtually and the 
pa1ticipant will be instmcted on returning the study dmg bottle. 
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Appendix 2.
Patient Reported Outcomes
CONFIDENTIAL: SIC Version 2.0 
May 29, 2020 
Symptoms of Infection with Coronavirus-19 (SIC) 
The following questions ask about symptoms people with coronavirus-19 infection may experience. Answer 
each question carefully by choosing 'Yes' if you have experienced the symptom or 'No' if you have not 
experienced the symptom in the last 24 hours. If you choose 'yes', select the rating that best matches your 
experience. 
In the last 24 hours, 
have you 
experienced ... 
Feeling generally 
How severe was this feeling (generally unwell or run down) in the last 24 hours? 
unwell (run down) 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Fatigue (tiredness) 
How severe was your fatigue (tiredness) in the last 24 hours? 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Physical weakness 
How severe was your feeling of physical weakness in the last 24 hours? 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Cough 
How severe was your cough in the last 24 hours? 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Shortness of breath 
How severe was your shortness of breath (difficulty breathing) in the last 24 hours? 
(difficulty breathing) 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Sore throat 
How severe was your sore throat in the last 24 hours? 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Nasal congestion 
How severe was your nasal congestion (stuffy nose) in the last 24 hours? 
(stuffy nose) 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Wheezing (whistling 
How severe was your wheezing (whistling sound while breathing) in the last 24 hours? 
sound while 
breathing) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 


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SIC Version 1 0 
Mav 29 2020 
In the last 24 hours, 
have you 
experienced ... 
Runny nose 
How severe was your runny nose in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Sneezing 
How severe was your sneezing in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Chest congestion 
How severe was your chest congestion (mucus in chest) in the last 24 hours? 
(mucus in chest) 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Chest pain/ 
How severe was your chest pain/pressure/tightness in the last 24 hours? 
pressure/tightness 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Muscle aches/pains 
How severe were your muscle aches or pains in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Joint aches/pains 
How severe were the aches or pains in your joints in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Headache 
How severe was you r headache in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Feeling faint 
How severe was your feeling offaintness in the last 24 hours? 
D Yes 
No 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Problems thinking 
How severe were your problems thinking clearly/brain fog in the last 24 hours? 
clearly/brain fog 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
2 


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SIC Version 1 0 
Mav 29 2020 
In the last 24 hours, 
have you 
experienced ... 
Chills 
How severe were your chills in the last 24 hours? 
D Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Skin rash 
How severe was your skin rash in the last 24 hours? 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Eye 
How severe was your eye irritation/discharge in the last 24 hours? 
irritation/discharge 
Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Diarrhea 
How severe was your diarrhea in the last 24 hours? 
D Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Vomiting 
How severe was your vomiting in the last 24 hours? 
Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Nausea 
How severe was your nausea in the last 24 hours? 
Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
Abdominal/stomach 
pain 
How severe was your abdominal/stomach pain in the last 24 hours? 
Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Worst possible 
Loss of appetite 
How severe was your loss of appetite in the last 24 hours? 
Yes 
No 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
None 
Wcrst possible 
In the last 24 hours, have you 
exoerienced ... 
Fever 
What was your highest temperature in the last 24 hours? __ °F 
Yes 
No 
3 


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SIC Version 1.0 
May29 2020 
In the last 24 hours, have vou experienced ... 
Uncontrollable body shaking/shivering 
Yes 
No 
Decreased sense of sm el I 
D Yes 
No 
Decreased sense of taste 
Yes 
No 
Red or bruised looking feet or toes 
Yes 
No 
4 


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Appendix 3.
Programming Specifications
1) Symptom alleviation and time to symptom alleviation
SIC questionnaire is shown in Appendix 2.
1. Targeted symptoms are those listed below. Only targeted symptoms will be evaluated in 
deriving of the secondary endpoint in time to COVID-19 symptom alleviation by Day 15.
•
Nasal congestion (stuffy nose)
•
Runny nose
•
Sore throat
•
Shortness of breath (difficulty breathing)
•
Cough
•
Feeling generally unwell (run down)
•
Fatigue (tiredness)
•
Physical weakness
•
Feeling faint
•
Muscle aches/pains
•
Joint aches/pains
•
Headache
•
Chills
•
Uncontrollable body shaking/shivering
•
Fever
2. Alleviation of all targeted symptoms:
▪Symptom with a rating of 0 at postbaseline
▪Symptom with a nonmissing rating at baseline has a decrease of at least 3 points in 
rating at postbaseline
▪Symptom with an answer “No” to the question at postbaseline


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and
▪for 48 consecutive hours (SAS datetime format dd:hh:mm:ss will be used for the 
duration)
o
A potential symptom alleviation is identified first without 48 consecutive hours 
confirmation. Participants with missing baseline symptoms data, all targeted 
symptoms need to have a rating of 0 or an answer “No” to the question for 
symptom alleviation.
o
Since the questionnaire recall time is over the last 24 hours, an additional 
consecutive 24 hours is needed to achieve consecutive 48 hours symptom 
alleviation, the reference start time of the second 24 hours is the assessment time 
of the first potential symptom alleviation.
o
No missing assessment is allowed between the first date and the last date of 
potential symptom alleviation included in the calculation.
o
The last day potentially able to meet the definition of alleviation is Day 14.
Examples of counting additional 24 consecutive hours:
Study Day
Example
1
2
3
4
5
6
7
8
9
Day and 
time of 
symptom 
alleviation 
Time
18:00
9:00
10:00
1
PSA
N
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 
10:00 ≥ 24 hrs
Time
9:00
10:00
2
PSA
.
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 
10:00 ≥ 24 hrs, 
Missing symptoms 
on Day 2 has no 
impact.
Time
18:00
9:00
8:00
8:30
3
PSA
N
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 
8:00 <24 hrs, so 
check for next day
Day 3 9:00 to Day 5 
8:30 ≥ 24 hrs
Time
18:00
9:00
8:00
8:30
10:00
10:00
4
PSA
N
Y
Y
N
Y
Y
Y
Y
Y
Day 6 
10:00
Day 3 9:00 to Day 4 
8:00 <24 hrs, so 
check for next day
Day 5 is not a PSA 
so need to check 
later date


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Study Day
Example
1
2
3
4
5
6
7
8
9
Day and 
time of 
symptom 
alleviation 
Time
18:00
9:00
.
9:00
10:00
10:00
5
PSA
N
Y
.
Y
Y
Y
Y
Y
Y
Day 5 9:00
no missing data is 
allowed within 
consecutive 24 hrs, 
need to restart the 
clock; Day 5 
9:00 – Day 6 
10:00 ≥24 hrs
Time
18:00
8:00
8:00
8:30
10:00
10:00
6
PSA
N
Y
Y
N
Y
Y
Y
Y
Y
Day 3 8:00
Day 3 8:00 to Day 4 
8:00 ≥ 24 hrs, 
symptom alleviation 
achieved even if 
symptoms reported 
on Day 5 
Time
18:00
9:00
8:00
9:00
10:00
10:00
8:00
7
PSA
N
N
N
N
N
N
N
Censored at Day 8 
8:00 if prematurely 
discontinued from 
study after Day 8
 PSA – potential symptom alleviation; Y – Yes; N – No; Yellow – symptom alleviation ≥ 48 hours; Tan – symptom alleviation 
< 48 hours
Note: If a participant answered “No” to the question for all symptoms at baseline, 
alleviation status will not be derived, and the participant is excluded from the analysis.
If a participant had nonmissing results for symptoms at baseline and symptoms for Day 2 
and later are all missing, the participant is considered as censored at 23:59 on Day 1.
If a participant has no SIC questionnaire data reported from Day 1 to Day 15, the 
participant is excluded from the analysis.
For all participants in ADEFF, the symptom alleviation status will be set to “Not 
Achieved Alleviation” with corresponding numeric value 0 at baseline, although 
symptom alleviation is not evaluated at baseline.
3. Time to alleviation of symptoms (unit = day, keep 8 decimals from date/time calculation 
in dataset, use 1 decimal place for TFLs)
•
For participants with symptom alleviation by Day 15, use the first event of participant 
level alleviation status equals Yes,
Date and Time of alleviation – Date and time of first dose.
•
For participants who complete Day 15 of the study without symptom alleviation, time 
to symptom alleviation will be censored at Day 14,


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Date and time of Day 14 SIC questionnaire assessment – Date and time of first dose.
Use Day 14 23:59 if no Day 14 SIC questionnaire assessment.
•
For participants who have nonmissing results for symptoms for at least 1 day after 
Day 1 and discontinue from the study before Day 15 without symptom alleviation, 
time to symptom alleviation will be censored at the last SIC questionnaire 
assessment,
Date and time of last SIC questionnaire assessment – Date and time of first dose.
•
For participants with missing time of first dose, missing time is imputed using the 
time of SIC questionnaire assessment on the first dose date or 12:00 whichever occurs 
first.
4. Additional censoring rules due to Intercurrent event:
Hospitalization for the treatment of COVID-19 or all-cause death or Use of rescue 
medication (see definition in #2)
Date and Time of Day 14 SIC questionnaire assessment – Date and time of first dose.
Use Day 14 23:59 if no Day 14 SIC questionnaire assessment.
2) COVID-19 Rescue Medications
Details of COVID-19 rescue medications are provided in the table below.
Drug Class
Dictionary 
Level
Prohibited PREF 
Codes
Prohibited Ingredient, PREF, 
and/or ATC Decodes
Bamlanivimab and Etesevimab
PREF
15665101001
BAMLANIVIMAB;ETESEVIMAB
Bamlanivimab
PREF
15343501001
BAMLANIVIMAB
Bamlanivimab
PREF
15665101001
BAMLANIVIMAB;ETESEVIMAB
Casirivimab and Imdevimab
PREF
15585401001
CASIRIVIMAB;IMDEVIMAB
Cilgavimab and Tixagevimab
PREF
15616901001
CILGAVIMAB;TIXAGEVIMAB
Molnupiravir
PREF
15326101001
MOLNUPIRAVIR
Nirmatrelvir and Ritonavir
PREF
15892101001
NIRMATRELVIR;RITONAVIR
Remdesivir
PREF
14269001001
REMDESIVIR
Sotrovimab
PREF
15464401001
SOTROVIMAB
Bebtelovimab
PREF
16033001001
BEBTELOVIMAB
Ensitrelvir
PREF
16350701001
ENSITRELVIR
Ensitrelvir
PREF
16350702001
ENSITRELVIR FUMARIC ACID
ATC = anatomical therapeutic chemical; PREF = preferred 


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Additional medication may be included during final review of concomitant medications prior 
to data finalization.
3) Population, denominator, and numerator for efficacy endpoints summaries of proportion
Endpoint / Summary
Population / Denominator 
Numerator 
Proportion of COVID-19–related 
hospitalization or all cause death by Day 29
Proportion of participants with all-cause 
hospitalization by Day 29
Proportion of participants with 
COVID-19-related MAVs or all-cause 
death by Day 29
Proportion of participants with 
COVID-19-related MAVs by Day 29
Proportion of participants with all-cause 
death by Day 29
FAPS
Based on KM estimate, no 
explicit denominator used
Total number of events by 
selected visits
Note: Proportions from KM 
estimate differ from proportion 
calculated directly from number 
of event and participants at risk
Proportion of participants with negative 
SARS-CoV-2 nasal swab viral load at 
Days 3, 5, 10, and 15
Participants in the Virology 
analysis set who had 
SARS-CoV-2 nasal swab 
collected and nonmissing result 
of viral load reported at 
selected visits
Number of participants with 
negative SARS-CoV-2 nasal 
swab viral load
Proportion of participants with negative 
SARS-CoV-2 infectious viral titer at 
Days 3, 5, 10, and 15
Participants in the Virology 
analysis set who had 
SARS-CoV-2 nasal swab 
collected and nonmissing result 
of SARS-CoV-2 infectious 
viral titer reported at selected 
visits
Number of participants with 
negative SARS-CoV-2 
infectious viral titer
4) Definition of Hospitalization
MAVs type of Emergency Room, non-ICU Hospitalization, ICU Hospitalization, and 
Hospitalization (unknown ward) could meet criteria for hospitalization if one of the 
following conditions is met:
•
If the duration of the MAV is greater than 24 hours. 
•
If the duration is missing and end date of the MAV is 1 day after the start date.
Time to hospitalization is calculated as Start date of Hospitalization – First dose date + 1.


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5) SARS-CoV-2 positive at baseline
SARS-CoV-2 positive at baseline is defined as test result from central lab.
•
Cepheid’s Xpert Xpress CoV-2/Flu/RSV plus (Multiplex) test result is positive for 
SARS-CoV-2 or
•
SARS-CoV-2 RT-qPCR test result is numerical viral load result or “<2228cp/mL 
SARSCoV2 detected”, regardless the sample was collected with less than specified 
volume of test solution.


GS-US-611-6273-Final Analysis-SAP-v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
24-Jan-2024
01:01:34
Global Development
Lead (GDL) eSigned
24-Jan-2024
17:55:34
PPD
PPD