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
Phase: PHASE3
Conditions: COVID-19
Sponsor: Gilead Sciences

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The information contained in this document, particularly unpublished data, is the property or 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 
be unblinded to the participant treatment assignment.

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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 
algorithm for the new toxicity grade.

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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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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
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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
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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

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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

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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