Clinical trial NCT05715528
Conditions: COVID-19
Sponsor: Gilead Sciences
Start date: 2023-02-08; Completion date: 2024-01-23
Enrollment: 2011 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical study is to test if obeldesivir (GS-5245) is safe and effective for the treatment of coronavirus disease 2019 (COVID-19) in participants who have a standard risk of developing severe illness. This study will also measure how much obeldesivir gets into the blood and how long it takes for the body to get rid of it.

Detailed description:

Arms: arm 1: Participants will receive obeldesivir 350 mg twice daily for 5 days. arm 2: Participants will receive obeldesivir placebo twice daily for 5 days.
Interventions: intervention 1: Obeldesivir intervention 2: Obeldesivir Placebo
Intervention descriptions: intervention 1: Tablet administered orally without regard to food. intervention 2: Tablet administered orally without regard to food.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of GS-5245 for the Treatment 
of COVID-19 in Nonhospitalized Participants 
Short Title:
Study of GS-5245 in Nonhospitalized Participants With COVID-19 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
158222 
EU CT Number:
2023-503277-38
ClinicalTrials.gov 
Identifier:
NCT05715528
Indication:
COVID-19 
Protocol ID:
GS-US-611-6549
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol 
Version/Date:
Amendment 4:
12 December 2023 
Amendment History:
Original:
14 September 2022
Amendment 1:
05 December 2022
Amendment 2:
20 January 2023
Amendment 3:
21 March 2023
High-level summaries of the histories of amendments are provided 
in Appendix 11.8.
Country-specific 
Requirements:
Country-specific requirements, as applicable, are listed in 
Appendix 11.7.
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The information contained in this document, particularly unpublished data, is the property or 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 FIGURES........................................................................................................................................6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................................7
PROTOCOL SYNOPSIS..............................................................................................................................................10
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
1.5.
Risk/Benefit Assessment for the Study ...................................................................................................30
1.6.
Compliance..............................................................................................................................................31
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................32
3.
STUDY DESIGN.................................................................................................................................................34
3.1.
Study Design Overview...........................................................................................................................34
3.2.
Duration of Intervention..........................................................................................................................34
3.3.
Protocol-Specific Discontinuation Criteria .............................................................................................34
3.3.1.
Criteria for Early Discontinuation for the Individual Participants ........................................34
3.3.2.
Criteria for Early Discontinuation of the Study ....................................................................35
3.3.3.
Lost to Follow-up ..................................................................................................................35
3.4.
Definitions for Time of Primary Endpoint and End of Study .................................................................35
3.4.1.
Primary Endpoint...................................................................................................................35
3.4.2.
End of Study..........................................................................................................................36
3.5.
Source Data .............................................................................................................................................36
4.
PARTICIPANT POPULATION..........................................................................................................................37
4.1.
Number of Participants and Participant Selection...................................................................................37
4.1.1.
Participant Replacement........................................................................................................37
4.2.
Inclusion Criteria.....................................................................................................................................37
4.3.
Exclusion Criteria....................................................................................................................................38
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................40
5.1.
Randomization, Blinding, and Treatment Code Access..........................................................................40
5.1.1.
Randomization.......................................................................................................................40
5.1.2.
Blinding .................................................................................................................................40
5.1.3.
Planned Interim Internal Unblinding.....................................................................................40
5.1.4.
Procedures for Breaking the Blind on Treatment Codes.......................................................41
5.2.
Description and Handling........................................................................................................................41
5.2.1.
Formulation ...........................................................................................................................41
5.2.2.
Packaging and Labeling ........................................................................................................41
5.2.3.
Storage and Handling ............................................................................................................42
5.3.
Dosage and Administration .....................................................................................................................42
5.4.
Prior and Concomitant Medications........................................................................................................42
5.4.1.
Prior and Concomitant Medications That Are Prohibited.....................................................42


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5.5.
Accountability for Study Drug(s)............................................................................................................43
5.5.1.
Study Drug Return or Disposal .............................................................................................43
6.
STUDY PROCEDURES......................................................................................................................................44
6.1.
Informed Consent (and Assent as Applicable)........................................................................................44
6.1.1.
6.2.
Screening, Participant Enrollment, and Treatment Assignment .............................................................44
6.3.
Instructions for Study Procedures ...........................................................................................................45
6.3.1.
Adverse Events......................................................................................................................45
6.3.2.
Safety Assessments ...............................................................................................................45
6.3.3.
Pharmacokinetics...................................................................................................................48
6.3.4.
SARS-CoV-2 Rapid Antigen Test.........................................................................................48
6.3.5.
SARS-CoV-2 Serology .........................................................................................................48
6.3.6.
Clinical Virology...................................................................................................................48
6.3.7.
Patient-Reported Outcomes...................................................................................................49
6.3.8.
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
7.5.1.
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
8.1.1.
Primary Endpoint...................................................................................................................62
8.1.2.
Secondary Efficacy Endpoints ..............................................................................................62
8.2.
Planned Analyses.....................................................................................................................................63
8.2.1.
Interim Analysis ....................................................................................................................63
8.2.2.
Primary Analysis ...................................................................................................................64
8.2.3.
Final Analysis........................................................................................................................64
CCI
CCI
CCI


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8.3.
Analysis Conventions..............................................................................................................................64
8.3.1.
Analysis Sets .........................................................................................................................64
8.3.2.
Data Handling Conventions ..................................................................................................65
8.4.
Demographic and Baseline Characteristics Analysis..............................................................................65
8.5.
Efficacy Analysis.....................................................................................................................................66
8.5.1.
Primary Efficacy Analysis.....................................................................................................66
8.5.2.
Secondary Efficacy Analyses................................................................................................67
8.5.3.
Intercurrent Events ................................................................................................................67
8.6.
Safety Analysis........................................................................................................................................69
8.6.1.
Extent of Exposure ................................................................................................................69
8.6.2.
Adverse Events......................................................................................................................69
8.6.3.
Laboratory Evaluations .........................................................................................................69
8.7.
Adjustments for Multiplicity ...................................................................................................................70
8.8.
Pharmacokinetic Analysis .......................................................................................................................70
8.9.
Sample Size .............................................................................................................................................70
8.10.
Data Monitoring Committee....................................................................................................................70
9.
RESPONSIBILITIES...........................................................................................................................................72
9.1.
Investigator Responsibilities ...................................................................................................................72
9.1.1.
Good Clinical Practice...........................................................................................................72
9.1.2.
Financial Disclosure ..............................................................................................................72
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval................................................................................................................................72
9.1.4.
Informed Consent ..................................................................................................................72
9.1.5.
Confidentiality.......................................................................................................................73
9.1.6.
Study Files and Retention of Records ...................................................................................73
9.1.7.
Electronic Case Report Forms...............................................................................................75
9.1.8.
Investigator Inspections.........................................................................................................75
9.1.9.
Protocol Compliance .............................................................................................................75
9.2.
Sponsor Responsibilities .........................................................................................................................75
9.2.1.
Protocol Modifications ..........................................................................................................75
9.2.2.
Study Reports and Publications.............................................................................................76
9.3.
Joint Investigator/Sponsor Responsibilities ............................................................................................76
9.3.1.
Payment Reporting ................................................................................................................76
9.3.2.
Access to Information for Monitoring...................................................................................76
9.3.3.
Access to Information for Auditing or Inspections ...............................................................76
9.3.4.
Study Discontinuation ...........................................................................................................77
10.
REFERENCES.....................................................................................................................................................78
11.
APPENDICES......................................................................................................................................................80
11.1.
Investigator Signature Page.....................................................................................................................81
11.2.
Authorization Status of Study Interventions ...........................................................................................82
11.3.
Pandemic Risk Assessment and Mitigation Plan ....................................................................................83
11.4.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........86
11.5.
Underlying Medical Conditions Associated With Higher Risk for Severe COVID-19..........................89
11.6.
Patient Reported Outcomes .....................................................................................................................91
11.7.
Country-Specific Requirements ..............................................................................................................92
11.8.
Amendment History ................................................................................................................................93
11.8.1.
Amendment 4 (12 December 2023) ......................................................................................93
11.8.2.
Amendment 3 (21 March 2023) ............................................................................................93
11.8.3.
Amendment 2 (20 January 2023) ..........................................................................................94
11.8.4.
Amendment 1 (05 December 2022) ......................................................................................95


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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.......................................................42
Table 10.
Laboratory Analytes ................................................................................................................47
Table 11.
Handling of Intercurrent Events ..............................................................................................68
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ..........................................................................................................................15


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
1-OH-MDZ
1-hydroxymidazolam
AE
adverse event
AGM
African green monkey
ALT
alanine aminotransferase
ARA
acid-reducing agent
AUC
area under the concentration versus time curve
AUCinf
area under the concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/λz)
AUClast
area under the concentration versus time curve from time zero to the last 
quantifiable concentration
AUCtau
area under the concentration versus time curve over the dosing interval
AUCx-xx
partial area under the concentration versus time curve from time “x” to time “xx”
C24
concentration at 24 hours post-dose
CFR
Code of Federal Regulations
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
CSR
clinical study report
Ctau
observed drug concentration at the end of the dosing interval
CYP
cytochrome P450 enzyme
DAB
dabigatran
DAIDS
Division of AIDS
DDI
drug-drug interaction
DMC
data monitoring committee
EC50
half-maximal effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EU
European Union
FAM
famotidine
FAPS
Full Analysis Positive Set
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GD
gestation day


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Gilead
Gilead Sciences
GMR
geometric mean ratio
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
hazard 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
independent ethics committee
IND
investigational new drug
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
LLOQ
lower limit of quantitation
LPLV
last participant’s last visit
MAV
medically attended visit
MDZ
midazolam
MedDRA
Medical Dictionary for Regulatory Activities
MET
metformin
NOAEL
no observed-adverse-effect level
NRU
neutral red uptake
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
P-gp
P-glycoprotein
PIT
pitavastatin
PK
pharmacokinetic(s)
PROMIS-29
Patient-Reported Outcomes Measurement Information System-29
PRO
patient-reported outcome
RDV
remdesivir 
RNA
ribonucleic acid
RT-qPCR
reverse transcriptase-quantitative polymerase chain reaction
RWD
real-world data
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SSR
special situation report
t1/2
elimination half-life


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TK
toxicokinetic(s)
ULN
upper limit of normal
US
United States
WPAI + CIQ: COVID19
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 Nonhospitalized 
Participants 
Short Title: Study of GS-5245 in Nonhospitalized Participants With COVID-19
IND Number: 158222 
EU CT Number: 2023-503277-38
ClinicalTrials.gov Identifier: NCT05715528
Study Centers Planned: Approximately 300 centers globally
Objectives and Endpoints: 
Primary Objectives
Primary Endpoints 
•
To evaluate the efficacy of GS-5245 in reducing 
the duration of COVID-19 symptoms
•
Time to COVID-19 symptom alleviation by 
Day 29 
•
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
Secondary Objectives
Secondary Endpoints
•
To assess the impact of GS-5245 on time to 
resolution of COVID-19 symptoms 
•
To evaluate the impact of GS-5245 on moderate 
relapse of COVID-19 symptoms
•
Time to COVID-19 symptom resolution by 
Day 29 
•
Proportion of participants with moderate relapse 
of COVID-19 symptoms 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 hospitalizations or all-cause 
death
•
Proportion of participants with COVID-19–
related hospitalization or all-cause death by 
Day 29
•
To evaluate the antiviral activity of GS-5245 on 
SARS-CoV-2 nasal swab viral load at Day 5
•
Change from baseline in SARS-CoV-2 nasal 
swab viral load at Day 5
•
To evaluate the effect of GS-5245 on duration of 
viral shedding 
•
Time to antigen negativity


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•
To evaluate the effect of GS-5245 on viral 
rebound
•
Proportion of participants with viral antigen 
rebound
•
To evaluate the plasma PK of GS-441524 
(metabolite of GS-5245) 
•
To evaluate the impact of GS-5245 on relapse of 
COVID-19 symptoms
•
Plasma concentrations and PK parameters 
AUCtau, Ctau, and Cmax of GS-441524, as 
available
•
Proportion of participants with relapse of 
COVID-19 symptoms by Day 29
Study Design: This Phase 3 study will be a global randomized, double-blind, 
placebo-controlled study comparing the safety and efficacy of oral GS-5245 with placebo in 
nonhospitalized participants with COVID-19, without risk factors for progression to severe 
disease regardless of vaccination status. 
Randomization will be stratified by vaccination status (completed primary vaccination series: 
Yes or No).
Number of Participants Planned: Approximately 1900 participants may be enrolled. 
Target Population: Nonhospitalized participants ≥ 18 to < 65 years of age (at all sites), or 
aged ≥ 12 to < 18 years weighing ≥ 40 kg (US sites only after the first data monitoring 
committee [DMC] meeting has occurred), with COVID-19, without risk factors for 
progression to severe disease regardless of vaccination status.
Duration of Intervention: Participants will receive oral GS-5245 or placebo, twice daily, 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 to < 65 years (at all sites), or aged ≥ 12 to < 18 years weighing ≥ 40 kg (US 
sites only, after the first DMC meeting has occurred) at screening.
2) Willing and able to provide written informed consent (and assent as applicable). For 
participants ≥ 12 and < 18 years of age, a parent or legal guardian willing and able to 
provide written informed consent prior to performing study procedures.
3) SARS-CoV-2 infection confirmed, ≤ 3 days before randomization, by polymerase chain 
reaction, rapid antigen test, or an approved alternative assay. Serologic tests will not be 
accepted.
4) Willing and able to complete the COVID-19 Symptom Questionnaire prior to first dose 
and daily throughout study period.
5) Initial onset of COVID-19 signs/symptoms ≤ 3 days before randomization with ≥ 2 of the 
following targeted symptoms, at moderate or higher severity, present at randomization:
a) Stuffy or runny nose. 
b) Sore throat. 


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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.
6) Not currently hospitalized or requiring hospitalization.
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1) Any risk factors for progression to severe disease.
2) Planning to receive a direct acting antiviral or monoclonal antibody against SARS-CoV-2 
for the treatment of COVID-19.
3) Received any approved, authorized, or investigational direct acting antiviral drug or 
monoclonal antibody against SARS-CoV-2 for the treatment of COVID-19 < 28 days or 
< 5 half-lives, whichever is longer, before randomization.
4) Received any convalescent COVID-19 plasma or other antibody-based anti-SARS-CoV-2 
prophylaxis at any time prior to study entry.
5) Received an approved, authorized, or investigational COVID-19 vaccine (including 
booster dose) < 120 days before randomization.
6) Self-reported COVID-19 diagnosis < 120 days before randomization.
7) Anticipated need for hospitalization < 48 hours after randomization.
8) New oxygen requirement < 24 hours before randomization.
9) 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. 
10) Known history of chronic liver disease, limited to cirrhosis, nonalcoholic steatohepatitis, 
alcoholic liver disease, and autoimmune hepatitis.
11) Undergoing dialysis, or known history of chronic kidney disease.
12) Known history of any of the following abnormal laboratory results < 6 months before 
randomization, unless confirmed as not meeting the exclusion criteria below, at screening:
a) ALT ≥ 5  upper limit of normal (ULN).
b) Bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s syndrome).
c) CLcr < 60 mL/min or eGFR < 60 mL/min/1.73 m2.


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13) Persistent symptoms from previous COVID-19 illness that may interfere with the 
evaluation of response to the study drug. 
14) Positive urine pregnancy test at screening.
15) Breastfeeding (nursing).
16) Unwilling to use protocol-mandated contraception.
17) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
18) Requirement for ongoing therapy with or prior use of any prohibited medications.
19) Any other factor, including inability to complete the patient-reported outcome (PRO) 
questionnaire for the primary endpoint, making the participant, in the opinion of the 
investigator, unsuitable to participate in the study. 
20) Concurrent participation/enrollment in a separate therapeutic clinical study.
Study Procedures/Frequency: 
•
Screening: within 24 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 90 days after the first dose of study drug 
The schedule of study procedures is presented in Table 1. 
Test Product, Dose, and Mode of Administration: GS-5245 350 mg (1 tablet) administered 
orally twice daily without regard to food with approximately 240 mL of water for 5 days.
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 sample size of approximately 1900 participants (assuming 90% are CoV-2 positive at 
baseline as confirmed by the central laboratory) provides approximately 87% power to detect a 
median difference of 2 days in time to symptom alleviation, which is equal to a hazard ratio 
(HR) of 1.18 using a 2-sided significance level of 0.05, assuming the placebo group median 
time to symptom alleviation is 13 days. 
The median time to symptom alleviation and its 95% CI will be estimated by treatment group 
using the Kaplan-Meier method. A stratified log-rank test with stratification factor included 
will be used to compare the treatment difference in time to COVID-19 symptom alleviation.
In addition, a Cox proportional hazards regression model will be used to estimate the HR and 
its 2-sided 95% CI. Stratification factor will be included as a covariate in the Cox proportional 
hazards model.


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An interim analysis of efficacy and futility is planned after approximately 50% of planned 
participants complete the Day 29 assessment, or prematurely discontinue from the study. The 
DMC will conduct a review of safety and formal evaluation of futility and efficacy based on 
the unblinded interim analysis results.


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STUDY SCHEMA
Figure 1.
Study Schema
COVID-19 = coronavirus disease 2019; D = Day; EOS = end of study; PCR = polymerase chain reaction
Day I COVlD·l9 ymptomQuestionnaire 
must be completed prior 10 first dose 
.. 
D 
r:;i .;;;,, 
0, 
v
(±I ) 
12345678 
creeuing witlun 
2~hl:o5~:~7.~:~o _. 
first dose 
DIO 
Visit 
(±2) 
D15 
Visit 
(±2) 
10 II 12 13 14 IS 16 17 18 
Smdy Period (Study Days) 
Treatmeu1 
Period: 
COVID·l9 Symp1omQues1iounaire 10 be comple1ed 
on ALL study days (D l-29, D60 and D90) 
Days I lo 5 
• Day 29 visit will be in•person and require a mid.turbinate nasal swab collection for viral PCR 
if, any day after the Day 20 visit and p1ior to the Day 29 visit, the participant has: 
I moderate or severe symptom repo11ed on the COVID• 19 sympiom questionnaire 
or 
a positive rapid antigen test 
EOS Visit 
22 23 24 2S 26 27 28 29 
60 
90 * 
8 • 
* 
······················
• 
Oplional Obse1vational Real•\Vorld 
Subsudy: 12 months from EDS 
Ju.person 
Virtual 
In pmticipants who consent, real•world data may be 
followed out to 12 months from end of study (US only) 


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STUDY PROCEDURES TABLE 
Table 1.
Study Procedures Table
Study Visit
Day 3
Day 5
Day 
10
Day 
15
Day 
20
Day 29
Day 
60
EOS
Day 
90
Visit Window
Screeninga, b
Baseline
Day 1a
± 1 dayc
± 2 days
+ 5 days
± 7 days
Early 
Discontinuation 
Visit
Visit Type
In Persond
In 
Persone 
or 
Virtualf
Virtualf
In Persond
Written informed consent (and assent as 
applicable)
X
Medical historyh 
X
Document SARS-CoV-2 infection
X
Complete physical examinationi
X
X
X
X
Symptom-directed physical examination
X
X
Height and weight
X
Vital signsj
X
X
X
X
X
X
X
COVID-19 Symptom Questionnairek
X
X
X
X
X
X
X
X
X
X
WPAI + CIQ:COVID19 
X
X
X
X
X
X
PROMIS-29
X
X
X
X
X
Household contactsl
X
Chemistry, coagulation, and hematology 
panelsm
X
X
X
X
X
X
Urine or serum pregnancy testsn 
X
X
X
X
SARS-CoV-2 rapid antigen testo
X
X
X
X
X
X
X
Mid-turbinate nasal swabp
X
X
X
X
X
X
X
X
SARS-CoV-2 serology
X
CCI


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Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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Study Visit
Day 3
Day 5
Day 
10
Day 
15
Day 
20
Day 29
Day 
60
EOS
Day 
90
Visit Window
Screeninga, b
Baseline
Day 1a
± 1 dayc
± 2 days
+ 5 days
± 7 days
Early 
Discontinuation 
Visit
Visit Type
In Persond
In 
Persone 
or 
Virtualf
Virtualf
In Persond
Sparse PKq
X
X
X
MAV information/oxygen supplementation 
requirements
X
X
X
X
X
X
X
X
X
X
Study drug dispensation
X
Study drug dosing (GS-5245 or placebo)t
X
X
X
Study drug bottle returnu
X
X
X
Adverse events and concomitant medications
X
X
X
X
X
X
X
X
X
X
X
COVID-19 = coronavirus disease 2019; EOS = end of study; MAV = medically attended visit; PK = pharmacokinetic(s); PROMIS-29 = Patient-Reported Outcomes Measurement 
Information System-29; 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 24 hours of the Day 1 visit. The Day 1 visit may occur on the same day as screening. If screening and the Day 1 visit are the same day, do not 
repeat physical examination and vital signs.
b
Local screening laboratory tests including serum creatinine, creatinine clearance/estimated glomerular filtration rate, alanine aminotransferase, and bilirubin assessments at 
screening (prior to randomization) are not required unless deemed necessary by the investigator to confirm eligibility. Testing for influenza is also not required at screening. 
c
Day 3 and Day 5 visits should be conducted on separate calendar days. 
d
In-person visit is defined as a visit conducted at a medical facility or elsewhere by a health care provider (where permitted).
e
Day 29 visit will be an in-person visit and require a nasal swab collection, only if any day after the Day 20 visit and prior to the Day 29 visit the participant has ≥ 1 moderate 
or severe symptom reported on the COVID-19 symptom questionnaire or has a positive rapid antigen test.
f
Virtual visit is defined as an interaction with a health care professional using telephone or online-based interaction (eg, telehealth, webcast, video conferencing).
g
Long COVID-19 sequelae will be assessed using linked data between clinical study participant and real-world data (RWD). 
h
Medical history will include the date of first COVID-19 symptoms, overall COVID-19 symptoms, all COVID-19 vaccinations prior to screening, prior COVID-19 illness 
(including positive test type, month, and year), demographics, baseline characteristics, allergies, and all other relevant medical history. 
i
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. Urogenital and 
reproductive examination should only be completed if clinically indicated.
j
Vital signs include heart rate, respiratory rate, temperature, oxygen saturation, and blood pressure. 
k
The COVID-19 Symptom Questionnaire will be completed daily (at approximately the same time each day) from predose to Day 29 visit, then at Day 60 and Day 90 visits.
l
The number of contacts in the household and how many tested positive for COVID-19 to be recorded.
m
Baseline laboratory assessments should be collected prior to first study drug dose. 
CCI


GS-5245 
Protocol GS-US-611-654 9 
Gilead Sciences, Inc. 
Final 
Amendment4 
n 
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 
early discontinuation/unscheduled visits, these participants will have a senun pregnancy test via central laborato1y. At screening, a follicle-stimulating ho1mone test is 
required to confom the postrnenopausal state in participants younger than 54 years, who have stopped menstrnating for at least 12 months but do not have doctuuentation of 
ovarian hormonal faihu·e, as described in Appendix 11.4. 
o 
Rapid antigen tests will be self-collected daily on all visit and non-visit days, up to Day 15, thereafter, on Days 17, 19, 21, 23, 25, 27, and 29. 
p 
The samples will be used for SARS-Co V-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), potential infectious viral titer assessment, and potential 
resistance testing. Multiplex viral PCR will only be performed at Baseline/Day 1 visit. 
q 
Sparse PK samples will be collected at Day 1 visit (0.75 hotu·s postdose and 2 hotu·s postdose), Day 3 visit (predose [within 1 hour before dosing] and 0.75 hours postdose), 
and Day 5 visit (predose [within 1 hour before dosing] and 0.75 hours postdose); ± 20% time window will be applied for all postdose time points. On Days 1, 3, and 5, one of 
the 2 doses must be administered dtuing the in- erson visit. If a visit occtu·s on Da 6, PK sam !es should not be collected. 
r 
s 
e 1ca y attended visit information includes 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 nattu·e and cause of the visit should be 
identified. Medically attended visit information and oxygen supplementation information should be collected through EOS/Day 90 visit. 
Study drng dosing is twice daily for 5 days. 
u 
Study drng bottle should be returned by the pa1ticipant on Day 5, if the participant has already completed all doses of study drng. If the participant has study drng remaining 
by the conclusion of the Day 5 visit, the pa1ticipant must rettun the study drng bottle on the Day 10 visit. 
CONFIDENTIAL 
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12 December 2023 


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Amendment 4
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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}. There are currently no approved therapies for people with a standard 
risk of progression to severe disease but who may benefit from a shorter duration of illness as 
assessed by symptoms, ability to return to usual health and activities, or duration of 
infectiousness. 
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 drug-drug interactions and with few 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 standard risk of progressing to severe COVID-19, that is anticipated to fulfill 
an unmet medical need.


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Amendment 4
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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 and 
Section 1.2.1.1.2.
1.2.1.1.1.
Toxicology
1.2.1.1.1.1.
Fertility Study
The objectives of the fertility study (Gilead Study Number 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] phase/group) 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/group) 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 (GD) 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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Gilead Sciences, Inc. 
Amendment 4
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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 GS-5245 
administration. 
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) (TX-611-2026). Administration of GS-5245 is not considered to exhibit a 
photosafety risk.
1.2.1.1.2.
Clinical Studies of GS-5245 
1.2.1.1.2.1.
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 or placebo 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.


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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 participants (25%) in Cohort 5 (500 mg twice daily for 5 days).
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, electrocardiogram (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.


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Amendment 4
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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: 
The GS-441524 metabolite renal clearance (CLr) was 150 to 180 mL/min, which is above the 
typical estimated glomerular filtration rate (eGFR, 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 the first 24 hours postdose.
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).


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Protocol GS-US-611-6549
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Amendment 4
CONFIDENTIAL
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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 as 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 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 = 15,900 (18.4); Day 5 AUC0-12h = 21,500 (19.3).


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Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
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12 December 2023
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 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 high-fat meal 
decreased the rate but not the extent of GS-5245 absorption; thus, GS-5245 may be administered 
without regard to food. 
1.2.1.1.2.2.
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 drug-drug interactions (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 BID 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 and 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; 
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
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)
2700 (52.2)
2700 (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; 
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 was 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 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}, EU {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 study will evaluate GS-5245 compared with placebo in participants with a standard risk of 
disease progression for whom there are no existing therapies that are authorized or approved. 
While this standard risk population may have a low composite rate of COVID-19-related 
hospitalization or death, participants may benefit from effective antiviral therapy resulting in a 
shorter duration of illness as assessed by symptoms, a quicker ability to return to usual health 
and activities, and a shortened duration of infectiousness. 
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).
Following oral administration of GS-5245, the GS-441524 metabolite was the only circulating 
species. The plasma t1/2 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 1.2.1.1.2.1). 
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 


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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 the 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 was selected for evaluation in this Phase 3 study for the treatment 
of COVID-19 in participants at standard 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 
half-maximal 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. 
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 150 participants have reached Day 29 or prematurely discontinued 


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from the study and when approximately 50% of planned participants have completed the Day 29 
assessment, or prematurely discontinued from the study.
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 11.3 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 Objectives
Primary Endpoints
•
To evaluate the efficacy of GS-5245 in reducing 
the duration of COVID-19 symptoms
•
Time to COVID-19 symptom alleviation by 
Day 29 
•
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
Secondary Objectives
Secondary Endpoints
•
To assess the impact of GS-5245 on time to 
resolution of COVID-19 symptoms
•
Time to COVID-19 symptom resolution by 
Day 29
•
To evaluate the impact of GS-5245 on moderate 
relapse of COVID-19 symptoms 
•
To evaluate the efficacy of GS-5245 in reducing 
COVID-19–related medically attended visits 
(MAVs) or all-cause death
•
Proportion of participants with moderate relapse of 
COVID-19 symptoms by Day 29
•
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 hospitalizations or all-cause 
death
•
Proportion of participants with COVID-19–related 
hospitalization or all-cause death by Day 29
•
To evaluate the antiviral activity of GS-5245 on 
SARS-CoV-2 nasal swab viral load at Day 5
•
Change from baseline in SARS-CoV-2 nasal swab 
viral load at Day 5
•
To evaluate the effect of GS-5245 on duration of 
viral shedding 
•
Time to antigen negativity
•
To evaluate the effect of GS-5245 on viral rebound
•
Proportion of participants with viral antigen 
rebound
•
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
•
To evaluate the impact of GS-5245 on relapse of 
COVID-19 symptoms
•
Proportion of participants with relapse of 
COVID-19 symptoms by Day 29


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CCI


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3.
STUDY DESIGN
3.1.
Study Design Overview
This Phase 3 study will be a global, randomized, double-blind, placebo-controlled study 
comparing the safety and efficacy of oral GS-5245 with placebo in nonhospitalized participants 
with COVID-19, without risk factors for progression to severe disease, regardless of vaccination 
status. Participants aged ≥ 12 and < 18 (weighing ≥ 40 kg) will be enrolled only in participating 
US sites, and after conclusion of the first planned DMC meeting.
Randomization will be stratified by vaccination status (completed primary vaccination series: 
Yes or No).
An overview of the study design is shown in Figure 1.
3.2.
Duration of Intervention
Participants will receive oral GS-5245 or placebo for 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:
•
Any SAE suspected to be related to study drug.
•
Any ≥ Grade 3 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.
•
Baseline or on-treatment CLcr < 50 mL/min using the Cockcroft-Gault equation (for 
participants aged ≥ 18 to < 65 years of age) or eGFR < 50 mL/min/1.73 m2 using the Bedside 
Schwartz formula (for participants aged ≥ 12 to < 18 years of age). No confirmation repeat 
testing is required to meet this criterion. 
•
Baseline or on-treatment alanine aminotransferase (ALT) ≥ 5  upper limit of normal (ULN).


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•
Baseline or on-treatment bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s 
syndrome).
•
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.
•
Participant request to discontinue for any reason.
•
Participant noncompliance.
•
Pregnancy (refer to Appendix 11.4).
•
Discontinuation of the study by sponsor.
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, institutional review board (IRB), or independent ethics committee (IEC).
3.3.3.
Lost 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) (LPLV).
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), patient-reported outcomes (PROs), and interactive response technology (IRT).


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
Approximately 1900 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 to < 65 years (at all sites), or aged ≥ 12 to < 18 years weighing ≥ 40 kg (US sites 
only, after the first DMC meeting has occurred) at screening.
2) Willing and able to provide written informed consent (and assent as applicable). For 
participants ≥ 12 and < 18 years of age, a parent or legal guardian willing and able to provide 
written informed consent prior to performing study procedures.
3) SARS-CoV-2 infection confirmed, ≤ 3 days before randomization, by polymerase chain 
reaction (PCR), rapid antigen test, or an approved alternative assay. Serologic tests will not 
be accepted.
4) Willing and able to complete the COVID-19 symptom questionnaire prior to first dose and 
daily throughout the study period.
5) Initial onset of COVID-19 signs/symptoms ≤ 3 days before randomization with ≥ 2 of the 
following targeted symptoms, at moderate or higher severity, 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.


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h) Chills or shivering. 
i)
Feeling hot or feverish.
6) Not currently hospitalized or requiring hospitalization.
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria are not eligible to be enrolled in 
this study:
1) Any risk factors for progression to severe disease (Appendix 11.5).
2) Planning to receive a direct acting antiviral or monoclonal antibody against SARS-CoV-2 for 
the treatment of COVID-19.
3) Received any approved, authorized, or investigational direct acting antiviral drug or 
monoclonal antibody against SARS-CoV-2 for the treatment of COVID-19 < 28 days or 
< 5 half-lives, whichever is longer, before randomization.
4) Received any convalescent COVID-19 plasma or other antibody-based anti-SARS-CoV-2 
prophylaxis at any time prior to study entry.
5) Received an approved, authorized, or investigational COVID-19 vaccine (including booster 
dose) < 120 days before randomization.
6) Self-reported COVID-19 diagnosis < 120 days before randomization.
7) Anticipated need for hospitalization < 48 hours after randomization.
8) New oxygen requirement < 24 hours before randomization.
9) 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.
10) Known history of chronic liver disease, limited to cirrhosis, nonalcoholic steatohepatitis, 
alcoholic liver disease, and autoimmune hepatitis. 
11) Undergoing dialysis, or known history of chronic kidney disease 
12) Known history of any of the following abnormal laboratory results < 6 months before 
randomization, unless confirmed as not meeting the exclusion criteria below, at screening:
a) ALT ≥ 5  ULN.
b) Bilirubin ≥ 2  ULN (≥ 3  ULN for participants with Gilbert’s syndrome).


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c) CLcr < 60 mL/min or eGFR < 60 mL/min/1.73 m2.
13) Persistent symptoms from previous COVID-19 illness that may interfere with the evaluation 
of response to the study drug.
14) Positive urine pregnancy test at screening.
15) Breastfeeding (nursing).
16) Unwilling to use protocol-mandated contraception.
17) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
18) Requirement for ongoing therapy with or prior use of any prohibited medications (Table 9).
19) Any other factor, including inability to complete the PRO questionnaire for the primary 
endpoint, making the participant, in the opinion of the investigator, unsuitable to participate 
in the study. 
20) Concurrent participation/enrollment in a separate therapeutic clinical 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 vaccination status (completed primary vaccination series: Yes or No).
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 PK 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 Patient Safety who are responsible for safety 
signal detection, investigational new drug (IND) 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 datasets 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 participate 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 contains 10 tablets and polyester packing material. 
Each bottle 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 randomized to the GS-5245 group will receive GS-5245 350 mg (1 tablet) 
administered orally twice daily without regard to food for 5 days.
Participants randomized to the placebo group will receive placebo administered orally twice 
daily without regard to food for 5 days.
Study drug should be administered with approximately 240 mL of water.
5.4.
Prior and Concomitant Medications
5.4.1.
Prior and Concomitant Medications That Are Prohibited
Medications in Table 9 are prohibited while participants are taking study drug. 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).
There are no restrictions on the symptomatic treatment of COVID-19 other than those indicated 
in Table 9. There are no restrictions on concomitant medications based on the potential for PK 
DDI with GS-5245.
Table 9.
Prior and Concomitant Medications That Are Prohibited 
Medication Class
Prohibited Medicationsa 
COVID-19 medications
Nirmatrelvir/ritonavir, molnupiravir, ensitrelvir, IV RDV, monoclonal antibodies 
against COVID-19
COVID-19 = coronavirus disease 2019; IV = intravenous; RDV = remdesivir
a
Concomitantly with GS-5245.


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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 to capture the following information:
•
The date received, quantity, and condition of study drug bottles.
•
The date, participant number, and the quantity of study drug bottles dispensed.
•
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.


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STUDY PROCEDURES 
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The study procedures to be conducted for each paiticipant screened or emolled 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 (and Assent as Applicable) 
Written info1m ed consent (and assent as applicable) must be obtained from each paiticipant, or 
with a pai·ent or legal guai·dian who can provide infonned consent, before initiation of any 
screening procedure. After a paiticipant has provided info1med consent (and assent as 
applicable), the investigator and other study personnel will dete1mine if the pa1ticipant is eligible 
for paiticipation in the study (Section 4.2). The investigator must use the most cunent IRB- or 
!EC-approved consent fonn for doclllllenting written info1m ed consent. Each info1m ed consent 
(and assent as applicable) will be appropriately signed and dated by the paiticipant or the 
paiticipant's legally authorized representative and the person conducting the consent discussion, 
and also by an impaitial witness if required by IRB or IEC or local requirements. 
-
I 
I 
6.2. 
Screening, Participant Enrollment, and Treatment Assignment 
Paiticipants will be screened within 24 hours before emollment 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 24 hours for 
randomization into the study. 
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Entry into screening does not guarantee 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 participants are eligible to participate in 
the study prior to enrollment and continue to remain eligible throughout the study.
Laboratory tests including serum creatinine, CLcr/eGFR, ALT, and bilirubin are not required at 
screening unless deemed necessary by the investigator to confirm eligibility. Testing for 
influenza is also not required at screening. Pregnancy testing is required at screening for 
participants assigned female at birth and of childbearing potential as described in Table 1.
Once written informed consent has been obtained, all screening and admission tests and 
assessments have been completed (including recording the dates of COVID-19 vaccinations), 
and study eligibility has been confirmed, participants will be randomized to receive GS-5245 or 
placebo on Day 1. Whenever possible, screening, randomization, and Day 1 dosing should occur 
on the same day. 
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). Virtual visit is defined as an online-based interaction (eg, telehealth, webcast, 
video conferencing).
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 study 
procedures.
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.


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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 (See Appendix 11.5).
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 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.
•
Chemistry 
eGFR according to:
Participants aged ≥ 18 to < 65 years: 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)
Participants aged ≥ 12 and < 18 years: Bedside Schwartz formula. Height at 
screening will be used for all calculations using the Schwartz formula:
Adolescents:
(0.413  height in cm) = eGFR (mL/min/1.73 m2)
(serum creatinine in mg/dL)
•
Hematology
•
Coagulation 


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Table 10.
Laboratory Analytes
Safety Laboratory Measurements 
Chemistry
(Serum or Plasma)
Hematology
Coagulation
Other Laboratory 
Measurements
alkaline phosphatase, AST, 
ALT, total bilirubin, total 
protein, albumin, lactate 
dehydrogenase, creatine 
phosphokinase, bicarbonate, 
blood urea nitrogen, 
calcium, chloride, 
creatinine, glucose, lipase, 
magnesium, phosphorus, 
potassium, sodium, uric 
acid, creatinine clearance
hemoglobin, 
hematocrit, red blood 
cell count, platelet 
count, white blood cell 
count with differential 
(absolute and 
percentage) including
neutrophils, monocytes, 
eosinophils, basophils, 
lymphocytes
prothrombin time, 
partial 
thromboplastin 
time, international 
normalized ratio
serum and urine pregnancy tests
and serum follicle-stimulating 
hormone in amenorrhoeic 
participants < 54 years of age
Pharmacokinetics
Anti-SARS-CoV-2 antibodies
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 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 information about concomitant medications.
6.3.2.7.
Medically Attended Visits
Review of MAV information will occur at the times shown in Table 1. Medically attended visits 
are any in-person interaction 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.
6.3.2.8.
Pregnancy Tests
Urine and/or serum pregnancy tests will be performed for participants assigned female at birth 
and of childbearing potential at the times shown in Table 1. At screening, a follicle-stimulating 
hormone test is required to confirm the postmenopausal state in participants younger than 
54 years, who have stopped menstruating for at least 12 months but do not have documentation 
of ovarian hormonal failure, as described in Appendix 11.4. 
6.3.2.9
Household Contacts
Information regarding number of household contacts and number of contacts diagnosed with 
COVID-19 will be collected at the times shown in Table 1.


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Pharmacokinetics 
Final 
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Phaimacokinetic assessments will be conducted in all participants during an in-person visit as 
per Table 1. 
-
6.3.4. 
SARS-CoV-2 Rapid Antigen Test 
Rapid antigen tests will be perfonned by pa1ticipants on self-collected nasal swabs (anterior 
nares) to assess antigen positivity at the time points specified in Table 1. Results will be 
self-reported, with investigator confnmation by review of photographic documentation 
encouraged, but not required. 
6.3.5. 
SARS-CoV-2 Serology 
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 sainples collected during the study 
will be stored and retained for possible future biomai·ker-related testing. These stored samples 
may be used by Gilead or its reseai·ch partners for retesting anti-SARS-Co V-2 antibodies, for 
testing to leain 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 sainples may be retained in 
storage by Gilead for a period of up to 15 years. 
Sainples collected for biomai·ker assessments will be destroyed no later than 15 yeai·s after the 
end of the study or per country requirements (Section 9.1.4). 
6.3.6. 
6.3.6.1. 
6.3.6.1.1. 
Clinical Virology 
Virology Testing 
Virology Samples to Address the Study Objectives 
Mid-turbinate nasal swab sainples will be used to assess SARS-CoV-2 viral load by reverse 
ti·anscriptase-quantitative PCR (RT-qPCR). Once viral load testing is complete, the remnant 
sainples may be used to evaluate respirato1y viral coinfection, SARS-CoV-2 infectious viral titer, 
and the emergence of viral resistance (by SARS-CoV-2 sequencing and/or phenotypic testing). 
6.3.6.1.2. 
Virology Sample Storage 
Any remaining specimens from nasal swab sainples collected during the study will be stored and 
retained for possible future virology-related testing. These stored samples may be used by Gilead 
or its reseai·ch partners for viral genotyping/phenotyping assays or their development, for 
retesting the amount of vims present in the sample, or for testing to leain more about how the 
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study drug has worked or clinical laboratory 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.
6.3.7.
Patient-Reported Outcomes 
The COVID-19 symptom questionnaire is required for the primary, secondary, and exploratory 
endpoints of the study. The ability to complete the COVID-19 symptom questionnaire is required 
for enrollment. The Work Productivity and Activity Impairment + Classroom Impairment 
Questions: COVID-19 Infection Specific (WPAI + CIQ: COVID19), and Patient-Reported 
Outcomes Measurement Information System (PROMIS-29) are required for this study. All PRO 
data will be collected electronically on a device. The participant should read and answer the 
questionnaire individually without external assistance. Patient-reported outcomes are outlined in 
Appendix 11.6.
Patient-reported outcomes will be required at the time points shown in Table 1. The following 
PROs will be utilized for this study:
6.3.7.1.
COVID-19 Symptom Questionnaire 
The COVID-19 symptom questionnaire, 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 of Drugs and 
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. 
6.3.7.1.1.
Procedures to Minimize Missing COVID-19 Symptom Data
For the purposes of this study, it is important to minimize missing symptom data to ensure 
interpretable analyses for efficacy endpoints based on the symptom questionnaire. Therefore, the 
following steps are put in place to help participants remain compliant with questionnaire 
completion per protocol required time points:
•
Participants will receive reminders/notifications at regular intervals every day to complete 
questionnaire.
•
Site staff and the study monitor will review symptom questionnaire data completion reports 
to monitor compliance.
•
Site staff will contact participants with missing data (or their close contact in case of 
nonresponse, where feasible).
•
Participants will be provided with a Value Sheet (if available) to highlight the significance of 
symptom questionnaire data and importance of participant compliance for the purposes of 
this study.


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6.3.7.2. 
Work Productivity and Activity Impai1ment Questionnaire + Classroom 
Impaiiment Questions: COVID-19 Infection 
The WPAI + CIQ: COVID-19 Infection Specific is a questionnaire to measure impai1ments in 
both paid work and unpaid work, as well as educational impact. It measures absenteeism and 
presenteeism, as well as the impai1ments in unpaid activity because of health problem during the 
past 7 days. It has been validated to quantify work or education impaiiments for numerous 
diseases {Reilly 1993} . 
6.3.7.3. 
Patient-Reported Outcomes Measurement Info1mation System-29 
Up to 30% of people infected with SARS-Co V-2 have at least 1 symptom persisting longer than 
4 weeks {Azzolini 2022}. PROMIS-29 is a set of person-centered measures assessing physical, 
mental, and social health {HealthMeasures 2022} . The tool has been used to dete1mine the 
prevalence and characteristics of impaiiment after recove1y from acute COVID-19 {Romano 
2022}. --
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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). 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 90 visit or early discontinuation visit, as applicable) for assessments and procedures 
specified in Table 1. 
6.6.
Poststudy Care
The long-term care of the participants will remain the responsibility of their primary treating 
physicians. 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. 
Any remaining specimens from nasal swab samples collected during 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 virus present in the sample, or for testing to learn more about how the 
study drug has worked or clinical laboratory 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.


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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 ICF 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, 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 
90 days after first 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 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).


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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 Situation 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 SSR 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 Section 7.4.2.2 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 start of the study to 
30 days after the last study drug 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 Section 7.4.1. 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 11.4 for Pregnancy Precautions, Definition for Childbearing Potential, and 
Contraceptive Requirements.


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Gilead Reporting Requirements 
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Depending on relevant local legislation or regulations, including the applicable US FDA CFR, 
the EU Regulation 536/2014 and relevant updates, and other countiy-specific legislation or 
regulations, Gilead may be required to expedite to worldwide regulato1y agencies the repo1ts of 
SAEs, which may be in the fonn of line listings, serious adverse drng reactions, or suspected 
unexpected serious adverse reactions. In accordance with the EU Regulation 536/2014, Gilead or 
a specified designee will notify worldwide regulato1y agencies and the relevant IEC in concerned 
Member States of applicable suspected unexpected serious adverse reactions as outlined in 
cmTent regulations. 
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
infonnation 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 diug. The investigator should notify 
the IRB/IEC of suspected unexpected serious adverse reaction repo1ts as soon as is practical, 
where this is required by local regulato1y agencies, and in accordance with the local institutional 
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7.6. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laborato1y abnonnalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laborato1y abnonnalities ( eg, clinical cheinistiy , hematology, urinalysis) that require 
medical or surgical intervention or lead to study diug inte1n1ption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laborato1y or other abnonnal 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 laborato1y abnonnality is part of a 
syndi·ome, record the syndi·ome or diagnosis ( eg, aneinia), not the laborato1y result (ie, decreased 
hemoglobin). 
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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
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.
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 (for 
participants ≥ 18 to < 65 years of age) or eGFR < 50 mL/min/1.73 m2 by Bedside Schwartz 
formula (for participants ≥ 12 and < 18 years of age) will be discontinued from study drug 
whether considered related to the study drug or not (refer to Section 3.3.1.1). No confirmation 
repeat testing is required to meet this criterion.
Recurrence of laboratory abnormalities considered unrelated to study drug may not require 
permanent discontinuation but requires discussion with the Gilead medical monitor.


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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.
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.
8.1.1.
Primary Endpoint
The primary endpoint is the time (days) to COVID-19 symptom alleviation by Day 29 on the 
targeted symptoms measured via the COVID-19 symptom questionnaire. Symptom alleviation is 
defined as follows: all targeted symptoms scored moderate or severe at baseline are scored as 
mild or none for at least 48 consecutive hours and all targeted symptoms scored mild or none at 
baseline are scored as none for at least 48 consecutive hours; the first day of the 48 consecutive 
hours will be considered the symptom alleviation date. 
Targeted symptoms are those listed below:
•
Stuffy or runny nose.
•
Sore throat. 
•
Shortness of breath (difficulty breathing).
•
Cough.
•
Low energy or tiredness.
•
Muscle or body aches.
•
Headache.
•
Chills or shivering. 
•
Feeling hot or feverish.
8.1.2.
Secondary Efficacy Endpoints
8.1.2.1.
Key Secondary Efficacy Endpoints
The alpha-controlled secondary endpoints include the following:
•
Time to COVID-19 symptom resolution by Day 29.


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COVID-19 symptom resolution is defined as all targeted symptoms scored as none for at least 
48 consecutive hours. The first day of the 48 consecutive hours will be considered the date of 
symptom resolution. The time to COVID-19 symptom resolution is the time (days) from the first 
dose date to the date of symptom resolution.
•
Proportion of participants with moderate relapse of COVID-19 symptoms by Day 29.
COVID-19 symptom relapse is defined as the first day of at least 2 consecutive diary entries 
(regardless of missing entries in between) where there is any symptom (regardless of severity) 
after achieving short symptom recovery, or if a participant is hospitalized for COVID-19 after 
achieving short symptom recovery. 
Short symptom recovery is defined as the first day of at least 2 consecutive diary entries 
(regardless of missing entries in between) where all targeted symptoms are absent. If a 
hospitalization for COVID-19 event occurs prior to the short recovery day, this participant is 
considered not having short symptom recovery for 28 days. 
COVID-19 moderate symptom relapse is defined as having at least 1 symptom being moderate 
or severe OR at least 2 mild symptoms OR a hospitalization for COVID-19, observed on a day 
during COVID-19 symptom relapse (first day of symptom relapse to Day 28). 
•
Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29. 
Medically attended visits are defined as any interactions with health care professionals other than 
study staff or designees including hospitalization; in-person emergency, urgent, or primary care 
visits; or any other in-person visit attended by the participant and a health care professional. The 
nature and cause of the visit should be identified.
•
Proportion of participants with 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 trial 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. 
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.


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8.2.1.1.
Data Monitoring Committee Analysis 
A planned interim analysis of safety and efficacy is planned after approximately 50% of the 
planned participants reach Day 29 or prematurely discontinue from the study (see Section 8.10). 
8.2.2.
Primary Analysis
The unblinded primary analysis will be conducted after all participants have completed the 
Day 29 assessments or discontinued from the study prematurely, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized for 
the analysis. This analysis will serve as the final analysis of the primary efficacy endpoint and 
key secondary efficacy endpoints. If the study is stopped based on interim efficacy analysis 
recommendations from the DMC, the interim analysis will be considered the primary analysis.
8.2.3.
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. 
8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
Efficacy
The Full Analysis Set (FAS) will include all participants who (1) are randomized into the study 
and (2) have received at least 1 dose of study drug. Participants will be grouped according to the 
treatment to which they were randomized.
The Full Analysis Positive Set (FAPS) includes all participants who are (1) randomized into the 
study, (2) have received at least 1 dose of study drug, and (3) are SARS-CoV-2 positive at 
baseline as confirmed by the central laboratory. Participants will be grouped according to the 
treatment to which they were randomized. 
8.3.1.2.
Safety
The primary analysis set for safety analyses is defined as the Safety Analysis Set, which will 
include all participants who (1) are randomized into the study and (2) have received at least 
1 dose of study drug. Participants will be grouped according to the treatment they received.
All data collected during treatment plus 30 days will be included in the safety summaries.
8.3.1.3.
Virology
The Virology Analysis Set will include all participants who (1) are randomized into the study, 
(2) have received at least 1 dose of study treatment, and (3) have a baseline SARS-CoV-2 viral 


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load greater than or equal to the lower limit of quantification (LLOQ). Participants will be 
grouped according to the ti·eatment they received. 
8.3.1.4. 
Phaimacokinetics 
The PK Analysis Set will include all randomized paii icipants 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. 
-
8.3.1.6. 
Biomai·kers 
The Biomai·ker Analysis Set will include all randomized paiiicipants who received at least 1 dose 
of study drng and have a sample collected for biomarker evaluation. 
8.3.2. 
Data Handling Conventions 
Natural logai·ithm ti·ansfo1mation for PK pai·ameters will be applied for PK analysis. 
For summaiy statistics, PK concenti·ation values below the limit of quantitation will be ti·eated as 
zero at predose and one-half of the LLOQ for postdose time points. 
Laborato1y 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 laborato1y test is < 20, a value of 
19 will be assigned). 
Missing data can have an impact upon the inte1pretation of the study data. In general, values for 
missing data will not be imputed. However, a missing preti·eatment laborato1y result would be 
ti·eated as nonnal (ie, no toxicity grade) for the laborato1y abno1mality summa1y . 
All available data for paiiicipants 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 Sllllllnai-ized using standai·d descriptive 
methods. 
Demographic Sllilllllai·ies will include sex, race/ethnicity, randomization sti·atification group, and 
age. For categorical demographic and baseline chai·acteristics, a Cochran-Mantel-Haenszel test 
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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 Efficacy Analysis
The time to COVID-19 symptom alleviation is defined as follows: 
•
For participants with symptom alleviation by Day 29 (event), time to COVID-19 symptom 
alleviation is calculated as symptom alleviation date minus the first dose date plus 1.
•
For participants who complete Day 29 of the study or discontinue from the study before 
Day 29 without symptom alleviation (censored), the time will be calculated as the last date 
on which the symptom alleviation is assessed by Day 29 minus the first dose date plus 1 or 
Day 28 whichever occurs first.
Handling of intercurrent events is defined in Section 8.5.3.
The median time to symptom alleviation and its 95% CI will be estimated by treatment group 
using the Kaplan-Meier method. A stratified log-rank test with stratification factor included will 
be used to compare the treatment difference in time to COVID-19 symptom alleviation. 
The proportion of participants with symptom alleviation using Kaplan-Meier estimates will be 
provided in tables and plots by treatment. 
In addition, a Cox proportional hazards regression model will be used to estimate the hazard ratio 
(HR) and its 2-sided 95% CI. Stratification factor will be included as a covariate in the Cox 
proportional hazards model. 
The FAPS will be used for the primary efficacy endpoint analysis. The primary analysis for the 
primary efficacy endpoint will be repeated using the FAS.
Sensitivity analysis associated with the primary endpoint may be performed:
•
A sensitivity analysis using a competing risk analysis approach will be provided, with 
intercurrent events (death or COVID-19–related hospitalization) as the competing risk. 
•
Missing symptom alleviation status will be imputed using multiple imputation assuming 
missing at random.
•
Depending on the percentage of participants with other concomitant respiratory viral 
coinfection(s) at baseline, a sensitivity analysis may be conducted using the respiratory viral 
coinfection status (yes/no) at baseline as an additional stratification factor in the stratified 
log-rank test and as an additional covariate in the Cox proportional hazards model.


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8.5.2.
Secondary Efficacy Analyses
8.5.2.1.
Key Secondary Efficacy Endpoints
Four alpha-controlled secondary efficacy endpoints are considered as the key secondary 
endpoints and will be tested in the following sequential order using a gatekeeping approach: 
•
Time to COVID-19 symptom resolution by Day 29.
•
Proportion of participants with moderate relapse of COVID-19 symptoms by Day 29.
•
The proportion of participants with COVID-19–related MAVs or all-cause death by Day 29.
•
Proportion of participants with COVID-19–related hospitalization or all-cause death by 
Day 29.
The time to COVID-19 symptom resolution will be analyzed in a similar manner to the primary 
endpoint using the FAPS.
Proportion of participants with moderate relapse of COVID-19 symptoms will be estimated with 
95% CIs including participants in the FAPS who have achieved short symptom recovery. 
The proportion of participants with MAVs or all-cause death by Day 29 in the FAPS will be 
summarized using Kaplan-Meier estimates and compared between treatment groups using the 
log-rank test. Similar analysis methods will be used for the proportion of participants with 
COVID-19–related hospitalization or all-cause death by Day 29.
Handling of intercurrent events for key secondary efficacy endpoints is defined in Section 8.5.3. 
8.5.3.
Intercurrent Events
Handling of intercurrent events for the primary endpoint and secondary efficacy endpoints 
relevant to symptom duration and main clinical outcome measures (eg, hospitalization/death) are 
shown in Table 11.


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Table 11.
Handling of Intercurrent Events
Endpoint
Intercurrent event
Strategy
Description
Hospitalization for the treatment 
of COVID-19 or all-cause death
Composite 
policy
Hospitalization for the treatment of 
COVID-19 or all-cause death means 
never achieve symptom 
alleviation/resolution (censored at 
Day 28)
Discontinue randomized 
treatment prior to symptom 
alleviation/resolution (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 29
Time to COVID-19 
symptom resolution by 
Day 29
Use of rescue medication
Composite 
policy
Use of rescue medication means 
never achieve symptom 
alleviation/resolution (censor at Day 
28)
Hospitalization for the treatment 
of COVID-19 or all-cause death 
after short symptom recovery
Composite 
policy
Hospitalization for the treatment of 
COVID-19 or all-cause death means 
moderate relapse/relapse
Discontinue randomized 
treatment after short symptom 
recovery (due to AE, lack of 
efficacy, investigator's 
discretion, noncompliance with 
study drug, protocol violation, 
participant decision, lost to 
follow-up)
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
Proportion of 
participants with 
moderate relapse of 
COVID-19 symptoms 
by Day 29
Proportion of 
participants with 
relapse of COVID-19 
symptoms by Day 29
Use of rescue medication after 
short symptom recovery
Composite 
policy
Use of rescue medication means 
moderate relapse/relapse
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 
COVID-19-related 
MAVs or all-cause 
death by Day 29
Use of rescue medication
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
AE = adverse event; COVID-19 = coronavirus disease 2019


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8.6.
Safety Analysis
Descriptive summaries will be provided for the primary safety endpoints of treatment-emergent 
AEs and laboratory abnormalities and incidence of SAEs and AEs leading to study drug 
discontinuation. No formal statistical comparison of safety endpoints between treatment groups 
is planned. All safety data collected on or after the first dose date of study drug 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 MedDRA. 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). 
The DAIDS scale is available at:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline up to 30 days after the date of the last 
dose of study drug 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.


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8.7.
Adjustments for Multiplicity
The overall 2-sided type I error rate of 0.05 for the primary efficacy endpoint 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 in a sequential manner only if the primary efficacy endpoint is met). 
An example O’Brien-Fleming stopping boundary at 50% of planned participants reaching 
Day 29 or prematurely discontinuing from the study is: reject the null hypothesis with 1-sided 
P value ≤ 0.0015 or reject the alternative hypothesis with 1-sided P value > 0.3495. The actual 
stopping boundaries will depend on the exact timing of the interim analysis. If the efficacy 
stopping boundary is crossed at the interim analysis, the primary endpoint will not be tested 
again at the primary analysis.
8.8.
Pharmacokinetic Analysis 
Plasma concentrations and PK parameters AUCtau, Ctau, and Cmax (and others, as available) for 
GS-441524 (metabolite of GS-5245) will be listed and summarized using descriptive statistics by 
treatment. Exposure-response analysis for safety and/or efficacy may be conducted, if needed 
and sufficient data are available. 
8.9.
Sample Size
A total sample size of approximately 1900 participants (assuming 90% are CoV-2 positive at 
baseline as confirmed by the central laboratory) provides approximately 87% power to detect a 
median difference of 2 days in time to alleviation of targeted symptoms, which is equal to an HR 
of 1.18 using a 2-sided significance level of 0.05 assuming the placebo group median time to 
symptom alleviation is 13 days. The estimate of median time to COVID-19 symptom alleviation 
is based on the EPIC-SR study.
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 interim analysis using the 
Lan-DeMets approach with O’Brien-Fleming type spending function).
8.10.
Data Monitoring Committee 
A multidisciplinary DMC consisting of non-Gilead personnel will review the progress of the 
study, perform interim reviews of safety data, and provide recommendation to Gilead whether 
the nature, frequency, and severity of AEs associated with study treatment warrant the early 
termination 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.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 


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the study. If the DMC recommends stopping the study for futility or efficacy, a Gilead Oversight 
Committee will be unblinded to review the DMC recommendation.
•
The first DMC meeting will be based on data collected after the first 150 participants have 
reached Day 29 or prematurely discontinued from the study, and will include safety data.
•
Enrollment of adolescent participants (aged ≥ 12 to < 18 years), at US sites only, may 
commence after conclusion of the first DMC meeting.
The second DMC meeting will occur when approximately 50% of planned participants complete 
the Day 29 assessment, or prematurely discontinue from the study. The DMC meeting will 
include review of safety and formal evaluation of futility and efficacy. 
The significance level for futility and efficacy will be determined using the O’Brien-Fleming 
approach at the interim analysis and the final analysis. The overall significance level is set at 
5% (2 sided). 


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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 Gilead 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, the EU, 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 Gilead. 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.


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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.
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.
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.
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.


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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 Nonhospitalized Participants 
GS-US-611-6549, Amendment 4 Protocol, 12 December 2023
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Sr Assoc Clinical Development 
Director
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.
Authorization Status of Study Interventions
Study 
Intervention 
Name
Category
Authorized in 
at Least 
1 Country 
Following EU 
Regulation 
No. 536/2014
Authorized 
in at Least 1 
ICH Country
Authorized by 
Swissmedic
GS-5245
Study drug
No
No
No
EU = European Union; ICH = International Council for Harmonisation (of Technical Requirements for Pharmaceuticals for 
Human Use) 


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11.3.
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 Gilead or delegate if they foresee shortage in study drug inventory or if 
there is any interruption in local shipping service. Gilead 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 patient-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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b) Study monitors may be unable to carry out source data review, 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-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 86
12 December 2023
11.4.
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 Day 1 and 15 visits. 


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 87
12 December 2023
Duration of required contraception for participants assigned female at birth and of childbearing 
potential in this clinical study should start from the screening visit until 14 days after the last 
study dose. 
Participants assigned female at birth and of childbearing potential must agree to 1 of the 
following contraceptive methods:
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the participant’s preferred and usual 
lifestyle. 
Or
Consistent and correct use of 1 of the following methods of birth control listed below: 
•
Hormonal or nonhormonal intrauterine device (IUD) 
•
Subdermal contraceptive implant
•
Bilateral tubal occlusion (upon medical assessment of surgical success)
•
Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success)
Or 
Participants assigned female at birth and of childbearing potential who wish to use a hormonally 
based method must use it in conjunction with a barrier method, preferably a male condom. 
Hormonal methods are restricted to those associated with the inhibition of ovulation. Hormonally 
based contraceptives and barrier methods permitted for use in this protocol are as follows:
•
Hormonal methods (each method must be used with a barrier method, preferably male 
condom)
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Transdermal contraceptive patch
Contraceptive vaginal ring
•
Barrier methods (each method must be used with a hormonal method)
Male condom (with or without spermicide)
Female condom (with or without spermicide)
Diaphragm with spermicide


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 88
12 December 2023
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. 


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 89
12 December 2023
11.5.
Underlying Medical Conditions Associated With Higher Risk for Severe 
COVID-19
•
Obesity (body mass index [BMI] ≥ 30 kg/m2 for those ≥ 18 years or > 95th percentile in those 
≥ 12 but < 18 years of age).
•
Diabetes mellitus, type 1 and type 2.
•
Heart failure, coronary artery disease, or cardiomyopathies.
•
Chronic kidney disease, or undergoing dialysis.
•
Chronic liver disease, limited to cirrhosis, nonalcoholic steatohepatitis (NASH), alcoholic 
liver disease, and autoimmune hepatitis.
•
Chronic lung diseases limited to: 
Chronic obstructive pulmonary disease.
Interstitial lung disease.
Cystic fibrosis.
Pulmonary hypertension.
Bronchiectasis.
•
Current pulmonary embolism.
•
Moderate to severe asthma (or asthma of any severity participants ≥ 12 and < 18 years of 
age).
•
Active pulmonary tuberculosis.
•
Cerebrovascular disease.
•
Down syndrome.
•
Pregnancy.
•
One or more of the following immunocompromising conditions or immunosuppressive 
treatments:
Receiving chemotherapy or other therapies for cancer.
Hematologic malignancy (active or in remission).


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 90
12 December 2023
History of a hematopoietic stem cell or a solid organ transplant.
Human immunodeficiency virus infection: not on antiretroviral therapy or with cluster of 
differentiation 4+ cell count < 200 cells per cubic millimeter.
Primary immunodeficiencies.
Taking systemic immunosuppressive agents (eg, high-dose corticosteroids [ie, ≥ 20 mg of 
prednisone or equivalent per day when administered for 2 or more weeks], alkylating 
agents, antimetabolites, transplant-related immunosuppressive drugs, cancer 
chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor 
(TNF) blockers, and other biologic agents that are immunosuppressive or 
immunomodulatory).


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 91
12 December 2023
11.6.
Patient Reported Outcomes


GS-5245 
Protocol GS-US-611-654 9 
Gilead Sciences, Inc. 
11.7. 
Country-Specific Requirements 
Additional Countiy-Specific Requirements for the United States 
Country-Specific Requirements 
To achieve broad access and for generalizability of study results, included adolescents 
(age :C::12 to < 18 years) in the US only at pa1t icipating sites. Enrolment may 
commence after the first DMC meeting. 
CONFIDENTIAL 
Page 92 
Final 
Amendment4 
Protocol Section 
Sections 6.1.1, 6.3.8, 
and 7.5.l 
Table 1, 
Sections 3.3.1.1, 4.2, 
4.3, 6.1, 6.1.1, 6.3.2.5, 
and 8.10 
12 December 2023 


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 93
12 December 2023
11.8.
Amendment History
High-level summaries of the history of this study’s amendments are provided in tabular form in 
the subsections below (from most recent amendment to oldest), with changes listed in each table 
in order of importance. Minor changes such as the correction of typographic errors, grammar, or 
formatting are not detailed.
A separate tracked change (red-lined) document comparing protocol amendment 3 to this 
amendment will be made available upon the publication of this protocol.
11.8.1.
Amendment 4 (12 December 2023)
Rationale for Key Changes Included in Amendment 4
Affected Sections
Key secondary endpoints were reordered to reflect the current clinical outcomes 
of COVID-19.
Synopsis, Sections 
2, 8.1.2.1, and 8.5.2.1 
The definition of the primary efficacy analysis set was clarified.
Sections 8.3.1.1, 8.5.1, and 
8.5.2.1
The definition of the virology analysis set was clarified.
Section 8.3.1.3
The futility stopping boundary and study power were revised to align with 
primary efficacy analysis set clarification.
Synopsis, Sections 8.7 and 
8.9
Minor changes included to provide clarification. 
Throughout, as needed
11.8.2.
Amendment 3 (21 March 2023)
Rationale for Key Changes Included in Amendment 3
Affected Sections
Revision of exclusion criteria and the list of underlying medical conditions 
associated with higher risk for severe COVID-19 to align with current clinical 
practice and COVID-19 epidemiology per FDA communication. 
Synopsis, Section 4.3, and 
Appendix 11.5
Provided clarification on pregnancy reporting period for both participant 
pregnancies and partner pregnancies to ensure alignment throughout the protocol.
Section 7.4.2.3 and 
Appendix 11.4
Given recently available phototoxicity results demonstrating that GS-5245 is not 
considered a photosafety risk, text previously included regarding UV protection 
measure recommendations have been removed. Recently available PK data have 
also been included. 
Sections 1.2.1.1.1.2, 
1.2.1.1.2.2, and 5.3 
Addition of visit windows for Study Days 3 and 5 to allow participants greater 
scheduling flexibility, moved serum pregnancy test from screening visit to Day 1 
visit, as urine pregnancy test at screening is already being performed, and 
clarification of study drug bottle return on Day 10.
Table 1
Addition of definitions for medically attended visits and COVID-19–related 
hospitalization.
Section 8.1.2.1
Prior and concomitant medications that are prohibited was expanded to include 
ensitrelvir.
Section 5.4.1
A list of study interventions and their authorization status is provided as per 
template update. 
Appendix 11.2
Minor changes included to correct typographic errors. 
Throughout, as needed


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 94
12 December 2023
11.8.3.
Amendment 2 (20 January 2023)
Rationale for Key Changes Included in Amendment 2
Affected Sections
Patient-reported outcome (PRO) tools were updated to minimize participant 
noncompliance with data reporting and interference of missing data with endpoint 
interpretability, per Food and Drug Administration (FDA) advice. Procedures to 
minimize missing PRO data were added.
Appendix 11.5 and 
Section 6.3.7.1.1
Secondary and 
 were updated to reflect revised objectives 
incorporating FDA feedback. Symptom relapse and symptom alleviation 
definitions, addition of evaluation of impact of SARS-CoV-2 lineage on key 
endpoints, and sensitivity analysis using the respiratory viral coinfection status 
(yes/no) at baseline was added for the primary efficacy analysis were added.
Synopsis, Sections 2, 8.1.1, 
8.1.2.1, 8.5.1, and 8.5.3
Inclusion criterion “5” was updated to indicate the severity of disease symptoms 
as per FDA guidance.
Additionally, exclusion criterion “12” was updated to exclude participants with 
prior or current elevated bilirubin level (≥ 2  ULN; ≥ 3  ULN for participants 
with Gilbert’s syndrome).
Synopsis, Section 4.2
Data of Phase 1 drug-drug interaction (DDI) were added and the restrictions on 
coadministration of acid-reducing agents removed, and hormonal contraceptive 
measures amended, to reflect DDI study conclusions. 
Sections 1.2.1.1.2.2, and 
5.4.1, and Appendix 11.3
Clarification was added noting a Gilead internal unblinded team will be involved 
in planned interim unblinding only upon DMC recommendation. 
Synopsis and Section 5.1.3
PK parameters were specified for the PK analysis of GS-441524 (metabolite of 
GS-5245).
Synopsis, Sections 2 and 8.8
Clarification was added regarding the PK samples collections for the participants 
in the
 
Table 1 (footnote “p”) and 
Section 6.3.3.1
Additional text was included regarding UV protection measure recommendation 
(pending phototoxicity evaluation of GS-5425).
Section 5.3
Clarification regarding discontinuation of participants from the study drug in case 
of Grade 4 clinically significant laboratory abnormality or clinical event, and was 
similarly updated for Grade 3. 
Sections 7.7.1.4 and 7.7.1.3
A clarification was added regarding the type of nasal swab samples to be collected 
per FDA feedback.
Study schema, Table 1, 
Sections 6.3.4 and 6.3.6.1.1
Minor changes included to correct typographic errors. 
Throughout, as needed
CCI
CCI


GS-5245
Protocol GS-US-611-6549
Final
Gilead Sciences, Inc. 
Amendment 4
CONFIDENTIAL
Page 95
12 December 2023
11.8.4.
Amendment 1 (05 December 2022)
Rationale for Key Changes Included in Amendment 1
Affected Sections
Expansion in scope of study from Phase 2 to Phase 3.
Throughout, as needed
Change in primary, secondary, and
 endpoints to reflect Phase 3 
objectives.
Synopsis, Tables 1 and 8, 
Sections 2, 6, and 8
Changes to the visit schedule to optimize characterization of viral kinetics and 
detection of any potential resistance-associated mutations.
Table 1 and Section 6
Inclusion and exclusion criteria were revised to incorporate FDA feedback on the 
study population. 
Synopsis, Sections 4.2, 4.3, 
and Appendix 11.4
An optional observational long COVID-19 assessment using observational data 
(obtain, store, and use existing health records data to assess long COVID-19 
symptoms and conditions) to evaluate the potential effect of GS-5245 on the 
incidence and persistence of long COVD-19 sequelae is only applicable to 
participants in the Unites States (US) at participating sites.
Sections 6.1.1, 6.3.8, and 
7.5.1
To achieve broad access and for generalizability of study results, included 
adolescents (age ≥ 12 to < 18 years) in the US only at participating sites. 
Enrolment may commence after the first DMC meeting.
Table 1, Sections 3.3.1.1, 
4.2, 4.3, 6.1, 6.1.1, 6.3.2.5, 
and 8.10
Minor changes to correct typographic errors. 
Throughout, as needed
CCI-


protocol GS-US-611-6549 amd-4
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
13-Dec-2023
00:17:30
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of GS-5245 for the 
Treatment of COVID-19 in Nonhospitalized Participants
Name of Test Drug:
Obeldesivir (ODV, GS-5245)
Study Number:
GS-US-611-6549
Protocol Version (Date):
Amendment 4:             12 December 2023
Analysis Type:
Primary Analysis and Final Analysis
Analysis Plan Version:
V1.0
Analysis Plan Date:
11 January 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


GS-5245
GS-US-611-6549
Statistical Analysis Plan – Primary Analysis and Final Analysis
Version 1.0
11 January 2024
GILEAD CONFIDENTIAL INFORMATION
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................8
1.2.
Study Design .............................................................................................................................................9
1.3.
Sample Size and Power ...........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................11
2.1.
Interim Analyses......................................................................................................................................11
2.1.1.
DMC Analysis.......................................................................................................................11
2.2.
Primary Analysis .....................................................................................................................................11
2.3.
Final Analysis..........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................12
3.1.
Analysis Sets ...........................................................................................................................................12
3.1.1.
All Randomized Analysis Set................................................................................................12
3.1.2.
Full Analysis Set....................................................................................................................12
3.1.3.
Full Analysis Positive Set......................................................................................................12
3.1.4.
Virology Analysis Set............................................................................................................13
3.1.5.
Antigen Analysis Set .............................................................................................................13
3.1.6.
Safety Analysis Set................................................................................................................13
3.1.7.
Pharmacokinetic Analysis Set ...............................................................................................13
3
3.2.
Subject Grouping.....................................................................................................................................13
3.3.
Strata and Covariates...............................................................................................................................14
3.4.
Examination of Subject Subgroups .........................................................................................................14
3.5.
Multiple Comparisons .............................................................................................................................15
3.6.
Missing Data and Outliers.......................................................................................................................15
3.6.1.
Missing Data..........................................................................................................................15
3.6.2.
Outliers ..................................................................................................................................15
3.7.
Data Handling Conventions and Transformations ..................................................................................15
3.8.
Analysis Visit Windows..........................................................................................................................18
3.8.1.
Definition of Study Day ........................................................................................................18
3.8.2.
Analysis Visit Windows........................................................................................................18
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................22
4.
SUBJECT DISPOSITION ...................................................................................................................................24
4.1.
Subject Enrollment and Disposition........................................................................................................24
4.2.
Extent of Study Drug Exposure...............................................................................................................25
4.2.1.
Duration of Exposure to Study Drug.....................................................................................25
4.2.2.
Total Number of Tablets Administered.................................................................................25
4.3.
Protocol Deviations .................................................................................................................................25
4.4.
Assessment of COVID-19 Impact...........................................................................................................26
5.
BASELINE CHARACTERISTICS .....................................................................................................................27
CCI• 


GS-5245 
GS-US-611-654 9 
Statistical Analysis Plan - Prima1y Analysis and Final Analysis 
Version 1.0 
5.1. 
Demographics and Baseline Characteristics ........................................................................................... 27 
5.2. 
Other Baseline Characteristics ................................................................................................................ 27 
5.3. 
Medical Histo1y ....................................................................................................................................... 28 
6. 
EFFICACY ANALYSES ..................................................................................................................................... 29 
6.1. 
Pri1nruy Efficacy Endpoint ...................................................................................................................... 29 
6.1.1. 
Definition of the Prima1y Efficacy Endpoint ........................................................................ 29 
6.1.2. 
Statistical Hypothesis for the Primruy Efficacy Endpoint ..................................................... 31 
6.1.3. 
Primruy Analysis of the Prima1y Efficacy Endpoint.. ........................................................... 31 
6.1.4. 
Secondruy Analyses of the Prima1y Efficacy Endpoint ........................................................ 31 
6.2. 
Secondruy Endpoints ............................................................................................................................... 32 
6.2.1. 
Anal sis ofSecondru End oints .......................................................................................... 34 
6.4. 
Intercwl'ent Events .................................................................................................................................. 38 
6.5. 
Changes From Protocol-Specified Efficacy Analyses ............................................................................ 39 
7. 
SAFETY ANALYSES ........................................................................................................................................ .40 
7 .1. 
Adverse Events and Deaths .................................................................................................................... .40 
7 .1.1. 
Adverse Event Dictiona1y .................................................................................................... .40 
7.1.2. 
Adverse Event Severity ........................................................................................................ .40 
7.1.3. 
Relationship of Adverse Events to Study Dmg .................................................................... .40 
7 .1.4. 
Serious Adverse Events ........................................................................................................ .40 
7 .1.5. 
Treatinent-Emergent Adverse Events ................................................................................... .40 
7 .1. 5.1. 
Definition of Treatinent-Emergent Adverse Events ....................................... .41 
7.1.5.2. 
Inco1nplete Dates ............................................................................................ .41 
7.1.6. 
Swrunaries of Adverse Events and Deaths ............................................................................ 41 
7 .1. 7 
Additional Analysis of Adverse Events ................................................................................ 42 
7.2. 
Laborato1y Evaluations .......................................................................................................................... .43 
7.2.1. 
Swrunaries ofNwneric Laborat01y Results ......................................................................... .43 
7.2.2. 
Graded Laborato1y Values .................................................................................................... 44 
7 .2.2.1. 
Treatinent-Emergent Laborat01y Abnonnalities ............................................. 44 
7.2.2.2. 
Swnmaries ofLaborat01y Abnonnalities ........................................................ 44 
7.2.3. 
Liver-Related Laborato1y Evaluations ................................................................................. .45 
7.3. 
Body Weight and Vital Signs ................................................................................................................. .45 
7 .4. 
Prior and Concomitant Medications ....................................................................................................... .46 
7.4.1. 
Prior Medications ................................................................................................................. .46 
7.4.2. 
Conco1nitant Medications ..................................................................................................... .46 
7.5. 
Other Safety Measures ........................................................................................................................... .47 
7.6. 
Changes From Protocol-Specified Safety Analyses ............................................................................... .47 
8. 
PHARMACOKINETIC (PK) ANALYSES ........................................................................................................ .48 
8.1. 
PK Sample Collection ............................................................................................................................ .48 
8.2. 
PK Analyses Related to Intensive PK Srunpling .................................................................................... .48 
8.2.1. 
Estimation of PK Parruneters ................................................................................................ .48 
8.2.2. 
PK Parameters ...................................................................................................................... .49 
8.3. 
PK Analyses Related to Sparse PK Srunpling ......................................................................................... 50 
9. 
REFERENCES ..................................................................................................................................................... 51 
10. SOFTWARE ......................................................................................................................................................... 52 
11. SAP REVISION ................................................................................................................................................... 53 
12. APPENDICES ...................................................................................................................................................... 54 
11 Janua1y 2024 
GILEAD CONFIDENTIAL INFORMATION 
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Statistical Analysis Plan – Primary Analysis and Final Analysis
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GILEAD CONFIDENTIAL INFORMATION
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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Vital Signs..................................................................................19
Table 3-2.
Analysis Visit Windows for SARS-CoV-2 Mid-turbinate Nasal Swab..................................19
Table 3-3.
Analysis Visit Windows for Hematology, Chemistry, and Coagulation Laboratory 
Tests.........................................................................................................................................20
Table 3-4
Urine or Serum Pregnancy Tests.............................................................................................20
Table 3-5.
Analysis Visit Windows for SARS-CoV-2 Rapid Antigen Test Collected after Day 
15 .............................................................................................................................................21
Table 3-6.
Analysis Visit Windows for Questionnaires ...........................................................................21
Table 6-1.
Handling of Intercurrent Events ..............................................................................................38
Table 8-1.
Pharmacokinetic Parameters for Analyte ................................................................................49
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ..........................................................................................................................10


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Statistical Analysis Plan – Primary Analysis and Final Analysis
Version 1.0
11 January 2024
GILEAD CONFIDENTIAL INFORMATION
Page 5 of 71
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CoV
coronavirus
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
DAIDS
Division of AIDS
DMC
data monitoring committee
ECG
electrocardiogram
ET
early termination
FAS
Full Analysis Set
FAPS
Full Analysis Positive Set
GCP
Good clinical practice
Hb
hemoglobin
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
IXRS
interactive voice or web response system
LLT
lowest-level term
LLOQ
Lower limit of quantitation
LOD
Limit of detection
LOQ
limit of quantitation
MAV
medically attended visit
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model repeated measures
ODV
Obeldesivir, GS-5245
PT
preferred term
Q1, Q3
first quartile, third quartile
SAE
serious adverse event
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SD
standard deviation
SE
Standard error
SI (units)
international system of units


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Statistical Analysis Plan – Primary Analysis and Final Analysis
Version 1.0
11 January 2024
GILEAD CONFIDENTIAL INFORMATION
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SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WHO
World Health Organization


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GS-US-611-6549
Statistical Analysis Plan – Primary Analysis and Final Analysis
Version 1.0
11 January 2024
GILEAD CONFIDENTIAL INFORMATION
Page 7 of 71
PHARMACOKINETIC ABBREVIATIONS
AUCtau
area under the concentration versus time curve over the dosing interval
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve


GS-5245
GS-US-611-6549
Statistical Analysis Plan – Primary Analysis and Final Analysis
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) of the Primary analysis and the 
Final Analysis for Study GS-US-611-6549. The Primary analysis will be performed after all 
participants reach Day 29 or prematurely discontinue from the study. The Final Analysis will be 
performed after all participants have completed the study or prematurely discontinue from the 
study.
This SAP is based on the study protocol Amendment 4 dated 12 December 2023 and the 
electronic case report form (eCRF). The SAP will be finalized prior to data finalization for the 
primary analysis. Any critical changes (eg, changes related to the primary efficacy endpoint) 
made after the finalization of this SAP will be documented in the final clinical study report 
(CSR).
1.1.
Study Objectives
Primary Objectives
•
To evaluate the efficacy of GS-5245 in reducing the duration of COVID-19 symptoms
•
To evaluate the safety and tolerability of GS-5245 administered in nonhospitalized participants with COVID-
19
Secondary Objectives
•
To assess the impact of GS-5245 on time to resolution of COVID-19 symptoms
•
To evaluate the impact of GS-5245 on moderate relapse of COVID-19 symptoms
•
To evaluate the efficacy of GS-5245 in reducing COVID-19–related medically attended visits (MAVs) or all-
cause death
•
To evaluate the efficacy of GS-5245 in reducing COVID-19–related hospitalizations or all-cause death
•
To evaluate the antiviral activity of GS-5245 on SARS-CoV-2 nasal swab viral load at Day 5
•
To evaluate the effect of GS-5245 on duration of viral shedding 
•
To evaluate the effect of GS-5245 on viral rebound
•
To evaluate the plasma PK of GS-441524 (metabolite of GS-5245) 
•
To evaluate the impact of GS-5245 on relapse of COVID-19 symptoms


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1.2. 
Study Design 
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This Phase 3 study is a global, randomized, double-blind, placebo-controlled study comparing 
the safety and efficacy of oral ODV with placebo in nonhospitalized participants, aged ::::: 12 to 
< 65 years, with COVID-19, without risk factors for progression to severe disease, regardless of 
vaccination status. 
Randomization will be stratified by vaccination status ( completed primaiy vaccination series: 
Yes or No). 
An overview of the study design is shown in Figure 1. 
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Figure 1. 
Study Schema 
Doy I COVI0-19 Symplom Q\lcstiow.utu< 
mus1 be <"0mple-1~ prior to firSf dose 
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10 11 12 L1 11 I:c; lti 17 l8 19
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S1t1d1 Penod (Study D•ys) 
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0uALL s ludy da)'S{Ol-29_. 060 aud 090) 
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Days l to S 
t Day 29 vi.sit will be in-pt'rson and re<Luire a u1id-t11rbi1111e nasal swab colleciion for viral PCR 
if, auy clay aRei 11,e Day 20 visit and J)lior 10 1he Day 29 \'isil, lhe p;u1icipa111 bas: 
:=:: I moderate or severe symptomreponedon lheCOVID-19 syruplomquestionnai.re 
or 
• a positive rapid a111igeu icsl 
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In-person 
' 
Vu1ual 
* 
lo participanls wboconscat. rca14 wortd dala may be 
folJowcd out to 12 mouths from c:ndof .study(US 011.ly) 
COVID-19 = coronavims disease 2019; D = Day; EOS = end of study; PCR = polymerase chain reaction 
Approximately 1900 paiiicipants will be randomized into the study. Participants who meet 
randomization eligibility criteria will be randomized in a 1: 1 ratio to ODV or placebo staiiing on 
Day 1. 
The schedule of study procedures is presented in Appendix 1. 
1.3. 
Sample Size and Power 
A total sample size of approximately 1900 paiiicipants ( assuming 90% ai·e SARS-Co V-2 
positive at baseline as confmned by the centrnl laborato1y) provides approximately 87% power 
to detect a median difference of 2 days in time to alleviation of tai·geted symptoms, which is 
equal to a hazard ratio (HR) of 1.18 using a 2-sided significance level of 0.05 assuming the 
placebo group median time to symptom alleviation is 13 days. The estimate of median time to 
COVID-19 symptom alleviation is based on the EPIC-SR study. 
The sample size calculation was perfo1med using softwai·e EAST (Version 6.5, module for 
log-rank test given accrnal duration and study duration and 1 interim analysis using the 
Lan-DeMets approach with O'Brien-Fleming type spending function). 
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
Prior to 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.
2.1.1.
DMC Analysis
An external multidisciplinary DMC will review the progress of the study and perform interim 
reviews of the safety data in order to protect participant welfare and preserve study integrity. To 
ensure the best interests of the participants, the DMC will make recommendations to the sponsor 
if the nature, frequency, and severity of adverse effects associated with the study treatment 
warrant the early termination of the study, the continuation of the study, or the continuation of 
the study with modifications.
The DMC’s role and responsibilities and the scope of analysis are provided in a mutually agreed 
upon charter, which defines the DMC membership, meeting logistics, and meeting frequency.
A planned interim analysis of futility based upon the primary endpoint was conducted when 
approximately 50% of the planned participants reached Day 29 or prematurely discontinued from 
the study. The significance level for futility was determined using the O’Brien-Fleming 
approach. The DMC recommended the study to continue without any modifications. 
2.2.
Primary Analysis
The unblinded primary analysis of the primary endpoint will be conducted after all participants 
have completed the Day 29 assessments or discontinued from the study prematurely, outstanding 
data queries have been resolved or adjudicated as unresolvable, and the data have been cleaned 
and finalized for the analysis. This analysis will serve as the primary analysis of the primary 
efficacy endpoint and key secondary efficacy endpoints. 
2.3.
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.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-participant listings will be presented for all participants in the All Randomized Analysis Set 
and sorted by participant ID number, visit date, and time (if applicable). Data collected on log 
forms, such as AEs, will be presented in chronological order within the participant. The 
treatment group to which participants were randomized will be used in the listings. Age, sex at 
birth, race, ethnicity, and country will be included in the listings, as space permits.
SARS-CoV-2 viral load will be used throughout the SAP for SARS-CoV-2 RT-qPCR viral load. 
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. Participants included in each analysis set will be 
determined before the study blind is broken for analysis. The analysis set will be identified and 
included as a subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion will be 
summarized by treatment group and overall.
A listing of reasons for exclusion from analysis sets will be provided by participant.
Good clinical practice (GCP) noncompliance observations were identified at 1 study center (Site 
20189) that randomized 32 participants into this study. The observations were considered critical 
or major. Therefore, the 32 participants from Site 20189 will be excluded from the efficacy, 
safety, virology, and PK analyses; these participants will only be included in the All Randomized 
Analysis Set.
3.1.1.
All Randomized Analysis Set
All Randomized Analysis Set includes all participants who were randomized in the study.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all participants, except those from Site 20189, who (1) are 
randomized into the study and (2) have received at least 1 dose of study drug. 
3.1.3.
Full Analysis Positive Set
The Full Analysis Positive Set (FAPS) includes all participants, except those from Site 20189, 
who (1) are randomized into the study, (2) have received at least 1 dose of study drug, and (3) 


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are SARS-CoV-2 positive at baseline as confnmed by Cepheid's Xpe1t Xpress CoV-2/Flu/RSV 
plus test or SARS-CoV-2 RT-qPCR test from central lab. This is the primaiy analysis set for 
efficacy analyses. 
3.1.4. 
Virology Analysis Set 
The Virology Analysis Set includes all pa1ticipants, except those from Site 20189, who (1) are 
randomized into the study, (2) have received at least 1 dose of study diug, and (3) have a 
baseline SARS-CoV-2 viral load ~ Lower limit of quantification (LLOQ). Refer to Section 3.4 
for the definition of LLOQ. 
3.1.5. 
Antigen Analysis Set 
The Antigen Analysis Set includes all paiticipants, except those from Site 20189, who (1) are 
randomized into the study, (2) have received at least 1 dose of study diug, and (3) have at least 1 
SARS-Co V-2 rapid antigen test positive from Day 1 to Day 5 and SARS-Co V-2 PCR positive at 
baseline per F APS. 
3.1.6. 
Safety Analysis Set 
The Safety Analysis Set includes all paiticipants, except those from Site 20189, who (1) are 
randomized into the study and (2) have received at least 1 dose of study dmg. 
3.1.7. 
Pharmacokinetic Analysis Set 
The Phaimacokinetic (PK) Analysis Set will include all randomized paiticipants, except those 
from Site 20189, who took at least 1 dose of study dmg and have at least 1 nonmissing 
concentration value repo1ted by the PK laborato1y for GS-441524. This is the primaiy analysis 
set for all PK analyses. 
-
3.2. 
Subject Grouping 
For analyses based on the All Randomized Analysis Set, F APS, Virology Analysis Set, or 
Antigen Analysis Set, pait icipants will be grouped according to the treatment to which they were 
randomized. For analyses based on the Safety Analysis Set, pait icipants will be grouped 
according to the actual treatment received. The actual treatment received will differ from the 
randomized treatment only when their actual treatment differs from randomized treatment for the 
entire treatment duration. 
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For the PK Analysis Set and the PK Substudy Analysis Set, participants will be grouped 
according to the actual treatment they received.
3.3.
Strata and Covariates
Participants will be randomly assigned to treatment groups via the interactive voice or web 
response system (IXRS) in a 1:1 ratio using a stratified randomization schedule. Stratification 
will be based on vaccination status (completed primary vaccination series): Yes or No.  
Stratification discrepancies will be reviewed and assessed. The values recorded in the clinical 
database will be used for analyses in case there are discrepancies between the IXRS and the 
clinical database. Based on the assessment of stratification discrepancies, a sensitivity analysis of 
the primary endpoint may be performed.
The primary efficacy endpoint will be evaluated using stratification factors as covariates or 
stratification variables for analyses, as specified in Section 6. In addition, observed imbalances 
between treatment groups in other baseline characteristics may be considered as covariates in 
sensitivity analyses of efficacy endpoints.  
If 5 events or less across both treatment groups are observed within 1 or more stratum, efficacy 
analyses including stratification factors will be evaluated in the same analyses without using 
stratification factors.
3.4.
Examination of Subject Subgroups
Subgrouping of participants based on randomization stratification factor will be explored for 
subgroup analyses. In addition, the primary and select secondary efficacy endpoint(s), and 
selected safety endpoints may be examined using the following subgroups:
•
Age: ≥ 12 – < 18, ≥ 18 – < 65, ≥ 65 years
•
Sex at birth: Male vs Female
•
Race: (a) Asian, (b) Black, (c) White, (d) Other
•
Ethnicity: Hispanic vs non-Hispanic 
•
Region: US vs ex-US
•
Baseline SARS-CoV-2 viral load: < 6 log10 copies/mL vs ≥ 6 log10 copies/mL 
•
Baseline SARS-CoV-2 viral load: ≥ LLOQ vs < LLOQ. Baseline SARS-CoV-2 viral load 
result of ‘No SARS-CoV2 detected’, ‘Inconclusive’, ‘< 2228 cp/mL SARS-CoV2 detected’ 
are considered <LLOQ; numerical results are considered as ≥ LLOQ. Participants for whom 
the baseline SARS-CoV-2 viral load sample was collected with less than specified volume of 
test solution will not be included for analysis.


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•
Baseline SARS-CoV-2 seropositivity: overall positive, defined as any one of the anti-spike 
antibody or anti-nucleocapsid antibody is positive, vs overall negative, defined as both 
anti-spike antibody and anti-nucleocapsid antibody negative if both results are available or 1 
test result is negative if only 1 test result is available.    
•
BMI: < 25 kg/m2 vs ≥ 25 kg/m2
•
Baseline eGFR: ≥ 90, ≥ 60 - < 90, ≥ 30 - < 60, < 30 regardless of unit. Creatinine Clearance 
by Cockcroft-Gault formula is used for participants ≥ 18 years old. Bedside-Schwartz 
formula is used for participants ≥ 12 and < 18 years old.
Other subgroups may be considered based on imbalances between treatment groups observed in 
other baseline characteristics.
3.5.
Multiple Comparisons
The overall 2-sided type I error rate of 0.05 for the primary efficacy endpoint 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 in a sequential manner only if the primary efficacy endpoint is met). 
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
Participants with missing outcomes for the primary endpoint due to premature discontinuation 
from the study will be censored at the last COVID-19 questionnaire assessment date.
For missing last dosing date of study drug, imputation rules are described in Section 4.2. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process. No sensitivity 
analyses to evaluate the impact of outliers on efficacy or safety outcomes are planned. Unless 
specified otherwise, all data will be included in the analyses.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:


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•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a participant, then age derived based on date of birth and the 
First dose date will be used instead. If an enrolled participant was not dosed with any study drug, 
the randomization date will be used instead of the First dose date. For screen failures, the date 
the first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (eg, estimates of creatinine clearance, age at 
date of AE) will be based on age derived from date of birth and the date of the measurement or 
event, unless otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.
•
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper LOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the lower or upper LOQ, 
respectively).
SARS-CoV-2 viral load results that are below LLOQ but have a positive signal will be reported 
as “<2228cp/mL SARSCoV2 detected” and those that are below lower limit of detection (LOD) 
and negative will be reported as “No SARS-CoV2 detected”. The data will be imputed as 
follows:
•
A value of 1114 copies/mL (half of the LOQ 2228 copies/mL) will be used to calculate 
descriptive statistics if the datum is reported as “<2228cp/mL SARSCoV2 detected”.
•
A value of 746.5 copies/mL (1/2 of the LOD 1493 copies/mL) will be used to calculate 
descriptive statistics if the datum is reported as “No SARS-CoV2 detected”.
SARS-CoV-2 infectious viral titer result will be imputed as follows:


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•
A value of 100 PFU/mL (half of the LOQ 200 PFU/mL) will be used to calculate descriptive 
statistics if the datum is reported as “< 200 PFU/mL” and the corresponding qualitative result 
is “Positive”
•
A value of 50 PFU/mL (1/4 of the LOQ 200 PFU/mL) will be used to calculate descriptive 
statistics if the datum is reported as “< 200 PFU/mL” and the corresponding qualitative result 
is “Negative”
Numerical result of SARS-CoV-2 viral load and infectious viral titer results from samples 
collected with less than specified volume of test solution will not be included in viral load or 
infectious viral titer analyses. The positive or negative result of these samples will not be 
impacted.
Any SARS-CoV-2 viral load and infectious viral titer samples collected on or after the day when 
the participants are receiving additional COVID-19 treatments (see Appendix 2) will be excluded 
from the viral load or infectious viral titer analysis.
Base 10 logarithm transformation will be used for analyzing SARS-CoV-2 viral load and SARS-
CoV-2 infectious viral titer.
Sparse PK concentration values that are below the limit of quantitation (BLQ) will be presented 
as “BLQ” in the data listing.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters. 
Concentration values that are BLQ will be presented as “BLQ” in the concentration data listing 
and PK concentration summary tables. Values that are BLQ will be treated as 0 at predose time 
points, and one-half the value of the LOQ at postdose time points for summary purposes. Values 
that are 0 or characters will be excluded from the calculation of geometric means. 
The following conventions will be used for the presentation of summary and order statistics for 
PK concentrations: 
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:
•
For assessment dates on or after the first dosing date: Assessment Date – First Dosing 
Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date 
Therefore, Study Day 1 is the day of first dose of study drug administration.
Last Dose Date is defined as the maximum, nonmissing, nonzero dose end date of treatment 
recorded on the Study Drug Administration eCRF form with “Study Drug Permanently 
Withdrawn” box checked for participants who prematurely discontinued or completed study drug 
according to the Study Drug Completion eCRF. Refer to Section 4.2 for missing date imputation, 
if necessary.
Last Study Date is the latest of the study drug start dates and end dates, the in-person or virtual 
visit dates, the vital sign collection dates, questionnaire collection dates and the laboratory 
collection dates, and the death date (if applicable, for participants who died during the study, the 
death date will be the Last Study Date. For participants who died after completing the study or 
after prematurely discontinuing the study, the death date will not be considered for the Last 
Study Date).
Baseline value is defined as the last value obtained on or prior to the first dose date unless 
otherwise specified (see Section 3.8.3).
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for Vital signs are provided in Table 3-1.


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Table 3-1.
Analysis Visit Windows for Vital Signs
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
7
Day 10
10
8
12
Day 15
15
13
22
*If the nominal visit is a scheduled visit and the assessment is done on Day 4 (Study Day = 4), assign to Day 3 or Day 5 analysis 
window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on Day 4, 
assign to Day 3 analysis window. 
The analysis windows for SARS-CoV-2 mid-turbinate nasal swab are provided in Table 3-2.
Table 3-2.
Analysis Visit Windows for SARS-CoV-2 Mid-turbinate Nasal Swab
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
7
Day 10
10
8
12
Day 15
15
13
17
Day 20
20
18
23
Day 29
29
24
43
*If the nominal visit is a scheduled visit and the assessment is done on Day 4 (Study Day = 4), assign to Day 3 or Day 5 analysis 
window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on Day 4, 
assign to Day 3 analysis window. 
The analysis windows for hematology, chemistry, and coagulation laboratory tests are provided 
in Table 3-3.


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Table 3-3.
Analysis Visit Windows for Hematology, Chemistry, and Coagulation 
Laboratory Tests
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
4*
Day 5
5
4*
7
Day 10
10
8
12
Day 15
15
13
22
*If the nominal visit is a scheduled visit and the assessment is done on Day 4 (Study Day = 4), assign to Day 3 or Day 5 analysis 
window based on the nominal visit label. If the nominal visit is an unscheduled visit or early discontinuation visit on Day 4, 
assign to Day 3 analysis window. 
The analysis windows for urine or serum pregnancy tests are provided in Table 3-4.
Table 3-4
Urine or Serum Pregnancy Tests
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 15
15
2
22
SARS-CoV-2 rapid antigen tests will be self-collected daily on all visit and non-visit days, up to 
Day 15, thereafter, on Days 17, 19, 21, 23, 25, 27, and 29. Windows are not assigned and results 
will be summarized for each applicable Study Day through Day 15. For assessment from Day 17 
to Day 29 nominal visits, the analysis windows are provided in Table 3-5.


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Table 3-5.
Analysis Visit Windows for SARS-CoV-2 Rapid Antigen Test 
Collected after Day 15
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Day 17
17
16
17
Day 19
19
18
19
Day 21
21
20
21
Day 23
23
22
23
Day 25
25
24
25
Day 27
27
26
27
Day 29
29
28
43
The COVID-19 Symptom Questionnaire will be completed daily from predose at Day 1 to 
Day 29 visit, then at Day 60 and Day 90 visits. Windows are not assigned and results will be 
summarized for each applicable Study Day through Day 29. For the Day 60 and Day 90 nominal 
visits, the analysis windows are provided in Table 3-6.
The WPAI + CIQ:COVID-19 Questionnaire will be completed at Days 1, 10, 29, 60, and 90 and 
PROMIS-29 Questionnaire will be completed at Days 1, 29, 60, and 90. The analysis windows 
are provided in Table 3-6.
Table 3-6.
Analysis Visit Windows for Questionnaires 
Visit Window Study Day
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 10*
10
8
12
Day 29*
29
24
43
Day 60
60
53
67
Day 90
90
83
97
* for WPAI + CIQ:COVID-19 and PROMIS-29 questionnaires as applicable
The number of contacts in the household and how many tested positive for COVID-19 will be 
recorded on Day 15 visit. Study day 13 to 22 will be assigned to Day 15 analysis visit for 
household contact diagnosed with COVID-19.  


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3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline questionnaire data, the last nonmissing value on or prior to the first dosing date 
of study drug will be selected. If there are multiple records on or prior to the first dose date, 
the record prior to and closest to the first dose date and time will be used if available; 
otherwise the record after and closest to the first dose date and time will be used.
•
For baseline data other than questionnaires, the last nonmissing value on or prior to the first 
dosing date of study drug will be selected, unless specified differently. If there are multiple 
records on the same day, the baseline value will be selected as follows: 
o
For continuous data:
■
For SARS-CoV-2 viral load and SARS-CoV-2 infectious viral titer, if there is more 
than 1 record on the selected day, the latest value will be selected. If there are 
multiple records with the same time or no time recorded on the same day, the 
geometric mean value (copies/mL) will be taken.
■
For other continuous data, the average of the measurements will be taken.
o
For categorical data:
■
For SARS-CoV-2 positivity based on RT-qPCR, positivity based on infectious viral 
titer and Multiplex viral PCR, the worst severity (ie, a positive result) will be 
selected. 
■
For other categorical data, the lowest severity will be selected.
•
For postbaseline values 
o
The record closest to the nominal day for that visit will be selected
o
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected. 
o
If there is more than 1 record on the selected day, values will be selected for analysis as 
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■
 For SARS-CoV-2 viral load and SARS-CoV-2 infectious viral titer, if there is more 
than 1 record on the selected day, the latest value will be selected. If there are 
multiple records with the same time or no time recorded on the same day, the 
geometric mean value (copies/mL) will be taken. 
■
For time to symptom alleviation and time to symptom resolution, all records within 
the analysis visit window will be used.
■
For postbaseline questionnaire data (not for time to event endpoint), if there is more 
than 1 record on the selected day, the latest value will be selected.
■
For time to antigen negativity and antigen rebound, all records within the analysis 
visit window will be used.
■
For other parameters, if there is more than 1 record on the selected day, the average 
will be taken for continuous data and the worst severity will be taken for categorical 
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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A table of key study dates will be provided, including first participant screened, first participant 
randomized, last participant randomized, last participant last visit for the primary endpoint, and 
last participant last visit.
A summary of participant enrollment will be provided by treatment group for each investigator 
within a country or region, and overall using the All Randomized Analysis Set. The summary 
will present the number and percentage of participants enrolled. For each column, the 
denominator for the percentage calculation will be the total number of participants analyzed for 
that column.
The number and percentage of participants enrolled by randomized stratum will be summarized 
using stratum assignment based on the clinical database. The denominator will be the number of 
participants in the All Randomized Analysis Set. A listing of participants with discrepancies 
between IXRS and the clinical database will be provided if applicable. 
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of participant disposition will be provided by treatment group and overall for all 
screened participants. This summary will include the number of participants screened, screen 
failure participants who were not randomized, participants who met all eligibility criteria and 
were not randomized with reasons participants not randomized, participants randomized, 
participants randomized but never treated, participants from Site 20189, participants in the Safety 
Analysis Set, participants in the FAS, and participants in the FAPS.
In addition, the number and percentage of the participants in the following categories will be 
summarized: 
•
Completed study drug as recorded on the Study Drug Completion form
•
Did not complete study drug with reasons for premature discontinuation of study drug as 
recorded on the Study Drug Completion form
•
Continuing study up to the data cut date
•
Completed study
•
Did not complete the study with reasons for premature discontinuation of study as recorded 
on the Study Completion form
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 


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


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic data (eg, sex, race, race category, ethnicity, age, and age group 
[≥ 12 - < 18, ≥ 18 - < 65, ≥ 65 years) and baseline characteristics (eg,  BMI [kg/m2]) will be 
summarized by treatment group and overall using descriptive statistics (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) for continuous data and by the number and percentage of 
participants for categorical data. The summaries of demographic data and baseline participant 
characteristics will be provided for the Safety Analysis Set and FAPS.
For categorical data, the Cochran-Mantel-Haenszel (CMH) test (ie, general association statistic 
for nominal data and row mean scores for ordinal data) will be used to compare the 2 treatment 
groups. For continuous data, the 2-sided Wilcoxon rank sum test will be used to compare the 
2 treatment groups. 
Similar summaries will be produced for the following subgroups: completed primary vaccination 
series (Yes or No) and region: (US vs ex-US).
A by-participant demographic listing will be provided.
5.2.
Other Baseline Characteristics
The following baseline disease characteristics will be summarized by treatment group and 
overall using descriptive statistics for the Safety Analysis Set and FAPS:
•
Randomization stratum: completed primary vaccination series (Yes or No)
•
Duration of COVID-19 symptoms prior to first dose of study drug
•
Duration from first positive SARS-CoV-2 diagnostic test to first dose of study drug
•
Number of targeted COVID-19 symptoms at baseline
•
Count and percentage of category for each COVID-19 symptom at baseline
o
None, Mild, Moderate, and Severe for targeted symptoms and Nausea;
o
No vomit/diarrhea, 1-2 times, 3-4 times, 5 or more times for Vomit and Diarrhea;
o
The same as usual, Less than usual, No sense for Sense of smell and sense of taste
•
Total scores of targeted COVID-19 symptoms at baseline, where 0 = None, 1 = Mild, 
2 = Moderate, and 3 = Severe 
•
Baseline COVID-19 vaccination status: Ever vs Never


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•
Baseline seropositivity: overall positive, defined as any one of the anti-spike antibody 
positive or anti-nucleocapsid antibody is positive, vs overall negative, defined as both 
anti-spike antibody and anti-nucleocapsid antibody negative if both results are available 
or 1 test result is negative if only 1 test result is available. 
•
Baseline respiratory viral coinfections: None; Yes subdivided into: Influenza A; Influenza B; 
respiratory syncytial virus (RSV)
•
Baseline SARS-CoV-2 viral load (as a continuous variable, and a categorical variable 
< 6 log10 copies/mL vs ≥ 6 log10 copies/mL)
•
Baseline eGFR: ≥ 90, ≥ 60 - < 90, ≥ 30 - < 60, < 30 regardless of unit. Creatinine Clearance 
by Cockcroft-Gault formula is used for participants ≥ 18 years old. Bedside-Schwartz 
formula is used for participants ≥ 12 and < 18 years old. 
For categorical data, the CMH test (general association statistic for nominal data and row mean 
scores for ordinal data) will be used to compare the 2 treatment groups. For continuous data, the 
2-sided Wilcoxon rank sum test will be used to compare the 2 treatment groups. 
Similar summaries will be produced for the following subgroups: completed primary vaccination 
series (Yes or No).
5.3.
Medical History
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed, or before the first dose of study drug and not related to a 
protocol-associated procedure is considered to be preexisting and should be documented as 
medical history. General medical history data will be collected at screening. It will be coded 
using the current version of MedDRA. A summary table will present the percentages of 
participants reporting each medical history preferred term, sorted first in alphabetical order by 
system organ class (SOC) and then by preferred term (PT) in descending order of total frequency 
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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary endpoint is the time (days) to COVID-19 symptom alleviation by Day 29 on the 
targeted symptoms measured via the COVID-19 symptom questionnaire. Symptom alleviation is 
defined as follows: all targeted symptoms scored moderate or severe at baseline are scored as 
mild or none for at least 48 consecutive hours and all targeted symptoms scored mild or none at 
baseline are scored as none for at least 48 consecutive hours; the first day of the 48 consecutive 
hours will be considered the symptom alleviation date. 
Targeted symptoms are those listed below:
•
Stuffy or runny nose
•
Sore throat 
•
Shortness of breath (difficulty breathing)
•
Cough
•
Low energy or tiredness
•
Muscle or body aches
•
Headache
•
Chills or shivering 
•
Feeling hot or feverish
The date and time stamps at which participants complete the questionnaire each day are captured 
in electronic-diary as “Form Saved Time” and will be used to determine whether the requirement 
of 48 continuous hours is satisfied. 
A potential symptom alleviation is identified first and defined as all targeted symptoms scored 
moderate or severe at baseline are scored as mild or none and all targeted symptoms scored mild 
or none at baseline are scored as none, ie, without 48 consecutive hours confirmation. For 
participants with missing baseline symptoms data, all targeted symptoms need to be scored as 
none to be considered as potential symptom alleviation.  
If there is any intercurrent event prior to Day 29 and the time a participant achieves symptom 
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As the questionnaire recall time is the previous 24 hours, an additional consecutive 24 hour 
period is needed to achieve 48 consecutive hours of symptom alleviation. The duration for the 
second consecutive 24 hours is calculated as shown in the flowchart: 
Yes 
Start 
Potential target 
symptom alleviation 
on Days X and X+l 
Duration 
24 hours 
between completion times of 
COVID19 questionnaire on 
Day X and Day X+l 
No 
Potential symptom 
alleviation on Day X+2 
AND 
Duration~ 24 hours between 
completion times of COVID19 
questionnaire on Day X and 
Day X+2 
Yes 
Symptom Alleviation achieved 
on DayX 
No 
No missing day is allowed between first date and last date of potential symptom alleviation 
included in the calculation. 
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The date-time of the first potential alleviation will be considered as the date-time of symptom 
alleviation and will be used for the calculation of time to symptom alleviation. Otherwise, repeat 
the algorithm for the next potential symptom alleviation time. 
Details and examples of algorithm for the symptom alleviation are provided in Appendix 2.  
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
Null hypothesis: There is no difference in time to COVID-19 symptom alleviation by Day 29 
between the 2 treatment groups.
Alternative hypothesis: There is a difference in time to COVID-19 symptom alleviation by 
Day 29 between the 2 treatment groups.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The median time to symptom alleviation and its 95% confidence interval (CI) will be estimated 
by treatment group using the Kaplan-Meier method. A stratified log-rank test with stratification 
factor included will be used to compare the treatment difference in time to COVID-19 symptom 
alleviation. 
For participants with symptom alleviation by Day 29 (event), time to COVID-19 symptom 
alleviation is calculated as symptom alleviation date/time minus the first dose date/time 
(expressed as days with 8 decimal places). In the analysis output, 1 decimal place in days will be 
used for display purposes. For participants who complete Day 29 of the study or discontinue 
from the study before Day 29 without symptom alleviation (censored) and without intercurrent 
events, the time will be calculated as the last date/time on which the symptom alleviation is 
assessed by Day 29 minus the first dose date/time or Day 28, whichever occurs first.
Handling of intercurrent events is defined in Section 6.4.
The proportion of participants with symptom alleviation using Kaplan-Meier estimates will be 
provided in tables and plots by treatment. 
In addition, a Cox proportional hazards regression model will be used to estimate the HR and its 
2-sided 95% CI. Randomization stratification factor will be included as a covariate in the Cox 
proportional hazards model. 
The FAPS will be used for the primary efficacy endpoint analysis. The primary analysis will be 
repeated using the FAS. 
6.1.4.
Secondary Analyses of the Primary Efficacy Endpoint
Sensitivity analyses may be conducted using the following alternative approaches for the primary 
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•
A sensitivity analysis using a competing risk analysis approach, with intercurrent events 
(death or COVID-19–related hospitalization) as the competing risk, if there are sufficient 
intercurrent events. 
•
Missing symptom alleviation status imputed using multiple imputation assuming missing at 
random.
•
Depending on the percentage of participants with other concomitant respiratory viral 
coinfection(s) at baseline, a sensitivity analysis may be conducted using the respiratory viral 
coinfection status (yes/no) at baseline as an additional stratification factor in the stratified 
log-rank test and as an additional covariate in the Cox proportional hazards model.
•
Restricted mean time to symptom alleviation for each treatment group will be provided.
6.2.
Secondary Endpoints 
Key Secondary Efficacy Endpoints:
The alpha-controlled secondary endpoints include the following:
•
Time to COVID-19 symptom resolution by Day 29.
COVID-19 symptom resolution is defined as all targeted symptoms scored as none for at least 
48 consecutive hours. The first day of the 48 consecutive hours will be considered the date of 
symptom resolution. The time to COVID-19 symptom resolution is the time (expressed as days 
with 8 decimal places) from the first dose date/time to the date/time of symptom resolution.
•
Proportion of participants with moderate relapse of COVID-19 symptoms by Day 29.
COVID-19 symptom relapse is defined as the first day of at least 2 consecutive diary entries 
(regardless of missing entries in between) where there is any symptom (regardless of severity) 
after achieving short symptom recovery, or if a participant is hospitalized for COVID-19 or dies 
after achieving short symptom recovery. Short symptom recovery is defined as the first day of at 
least 2 consecutive diary entries (regardless of missing entries in between) where all targeted 
symptoms are absent. If a hospitalization for COVID-19 or death event occurs prior to the short 
recovery day, this participant is considered as not having short symptom recovery for 28 days. 
COVID-19 moderate symptom relapse is defined as having at least 1 symptom being moderate 
or severe OR at least 2 mild symptoms OR a hospitalization for COVID-19 or death, observed 
on a day during COVID-19 symptom relapse (first day of symptom relapse to Day 28). 
•
Proportion of participants with COVID-19–related MAVs or all-cause death by Day 29. 
Medically attended visits are defined as any interactions with health care professionals other than 
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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.
•
Proportion of participants with 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 trial execution. The date and 
duration (if there is 1 day difference between the start date and end date) of hospital admission, 
and primary reason for hospitalization (including if the hospitalization is related to COVID-19) 
will be recorded. 
Other secondary efficacy endpoints include: 
•
Change from baseline in SARS-CoV-2 nasal swab viral load at Day 5
•
Time to antigen negativity
o
Antigen negativity is defined as 2 consecutive negative SARS-CoV-2 rapid antigen test 
(regardless if there is missing data in between), or negative test at last available sample 
for participants who completed or discontinued from the study after at least 1 positive 
antigen test.  Antigen negativity through Day 29 will be derived using rapid antigen test 
data included for analysis as defined in Table 3-5. 
o
The time to antigen negativity is defined (in days) as the number of days to the first date 
of 2 consecutive dates achieving a negative result:  
First date of 2 consecutive dates achieving negative result – First dose date +1. 
Participants without a negative antigen test will be censored at the last non-missing antigen 
test date.
•
Proportion of participants with viral antigen rebound through Day 29
o
Viral antigen rebound is defined as any positive SARS-CoV-2 rapid antigen test after 
antigen negativity
•
Proportion of participants with relapse of COVID-19 symptoms by Day 29


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6.2.1.
Analysis of Secondary Endpoints
The FAPS will be the primary analysis set for secondary endpoints. The Virology Analysis Set 
will be the primary analysis set for SARS-CoV-2 endpoints. The Antigen Analysis Set will be 
the primary analysis for antigen related endpoints. 
The key secondary endpoints will be tested in the following sequential order using a gatekeeping 
approach. 
•
Time to COVID-19 symptom resolution by Day 29.
•
Proportion of participants with moderate relapse of COVID-19 symptoms by Day 29.
•
The proportion of participants with COVID-19–related MAVs or all-cause death by Day 29.
•
Proportion of participants with COVID-19–related hospitalization or all-cause death by 
Day 29.
The time to COVID-19 symptom resolution will be analyzed in a similar manner to the primary 
endpoint using the FAPS.
Proportion of participants with moderate relapse of COVID-19 symptoms by Day 29 will be 
estimated with 95% CIs including participants in the FAPS who have achieved short symptom 
recovery and compared between treatment groups using the Fisher’s exact test. 
The proportion of participants with MAVs or all-cause death by Day 29 in the FAPS will be 
summarized using Kaplan-Meier estimates and compared between treatment groups using the 
log-rank test. Similar analysis methods will be used for the proportion of participants with 
COVID-19–related hospitalization or all-cause death by Day 29.
Change from baseline in SARS-CoV-2 nasal swab viral load to each visit including Day 5 will 
be compared between treatment groups using a mixed-effects model repeated measures 
(MMRM) approach. The analysis will be repeated in subgroups based on baseline viral load (< 6 
log10 copies/mL, ≥ 6 log10 copies/mL).
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 antigen negativity through Day 29. Count and 
percentage of participants with viral antigen rebound through Day 29 will be summarized among 
those who achieve antigen negativity by treatment group and compared between treatment 
groups using the Fisher’s exact test.
Proportion of participants with relapse of COVID-19 symptoms will be estimated with 95% CIs 
and compared between treatment groups using the Fisher’s exact test, including participants in 
the FAPS who have achieved short symptom recovery.


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6.4.
Intercurrent Events
Handling of intercurrent events for the primary endpoint and secondary efficacy endpoints are 
shown in Table 6-1. Intercurrent events are events occurring after treatment initiation that affect 
either the interpretation or the existence of the measurements of an endpoint. An event (eg. use 
of rescue medication) that occurs after an endpoint of interest (eg. symptom alleviation) is not 
considered as an intercurrent event. 
Table 6-1.
Handling of Intercurrent Events
Endpoint
Intercurrent event
Strategy
Description
Hospitalization for the treatment 
of COVID-19 or all-cause death
Composite 
policy
Hospitalization for the treatment of 
COVID-19 or all-cause death means 
never achieve symptom 
alleviation/resolution (censored at 
Day 28)
Discontinue randomized 
treatment prior to symptom 
alleviation/resolution (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 29
Time to COVID-19 
symptom resolution by 
Day 29
Use of rescue medication
Composite 
policy
Use of rescue medication means never 
achieve symptom alleviation/resolution 
(censor at Day 28)
Hospitalization for the treatment 
of COVID-19 or all-cause death 
after short symptom recovery
Composite 
policy
Hospitalization for the treatment of 
COVID-19 or all-cause death means 
moderate relapse/relapse
Discontinue randomized 
treatment after short symptom 
recovery (due to AE, lack of 
efficacy, investigator's discretion, 
noncompliance with study drug, 
protocol violation, participant 
decision, lost to follow-up)
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
Proportion of 
participants with 
moderate relapse of 
COVID-19 symptoms by 
Day 29
Proportion of 
participants with relapse 
of COVID-19 symptoms 
by Day 29
Use of rescue medication after 
short symptom recovery
Composite 
policy
Use of rescue medication means 
moderate relapse/relapse
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 
COVID-19-related 
MAVs or all-cause death 
by Day 29
Use of rescue medication
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)


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Endpoint
Intercurrent event
Strategy
Description
Hospitalization for the treatment 
of COVID-19 or all-cause death 
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
Discontinue randomized 
treatment prior to antigen 
negativity (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 antigen 
negativity
Use of rescue medication 
Composite 
policy
Use of rescue medication means never 
achieve antigen negativity (censor at 
Day 28)
Hospitalization for the treatment 
of COVID-19 or all-cause death 
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
Discontinue randomized 
treatment prior to antigen rebound 
(due to AE, lack of efficacy, 
investigator's discretion, 
noncompliance with study drug, 
protocol violation, participant 
decision, lost to follow-up)
Treatment 
policy
Ignore the occurrence of intercurrent 
events (use observed outcome)
Proportion of 
participants with viral 
antigen rebound
Use of rescue medication after 
antigen negativity
Composite 
policy
Use of rescue medication means 
antigen rebound
AE = adverse event; COVID-19 = coronavirus disease 2019
6.5.
Changes From Protocol-Specified Efficacy Analyses
An interim analysis of futility and efficacy was planned in the protocol using the 
O’Brien-Fleming approach when 50% of planned participants completed the Day 29 assessment, 
or prematurely discontinued from the study. The assessment of stopping the study for efficacy 
was not conducted and the interim analysis assessed futility only. 
Participants from Site 20189 with GCP noncompliance observations will be excluded from 
efficacy, safety, virology, and PK analyses.
  


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lowest-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
The severity of AEs will be graded using the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017. For each episode, 
the highest grade attained should be reported as defined in the grading scale. The DAIDS scale is 
available at the following location:
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life threatening) or Grade 5 (fatal) according to toxicity criteria specified in 
the document above. The severity grade of events for which the investigator did not record 
severity will be left as “missing” for data listings.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Patient Safety 
Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
Proportion of participants with treatment-emergent AEs (TEAEs) is the primary safety endpoint 
of the study. No statistical comparison will be provided for proportion of participants with 
TEAE.


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7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:
•
Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug.
•
Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:
•
The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and
•
The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, or with the onset date missing and the AE is 
marked as ongoing, will be considered to be treatment emergent. In addition, an AE with the 
onset date missing and incomplete stop date with the same or later month and year (or year alone 
if month is not recorded) as the first dosing date of study drug will be considered treatment 
emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, High lever term (HLT), PT, and treatment group. For other AEs 
described below, summaries will be provided by SOC, PT, and treatment group: 
•
Grade 3 or higher treatment-emergent AEs
•
All treatment-emergent treatment-related AEs
•
Grade 3 or higher treatment-emergent treatment-related AEs
•
All treatment-emergent SAEs
•
All treatment-emergent treatment-related SAEs
•
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Treatment-emergent AE and treatment related TEAE will be summarized by system organ class, 
PT, Severity, and treatment group.
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described above, and treatment emergent deaths will be provided 
by treatment group. Treatment-emergent death refers to deaths that occurred between the first 
dose date and the last dose date plus 30 days (inclusive).
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC (and HLT within each SOC if 
applicable) and then by PT in descending order of total frequency within each SOC. For 
summaries by severity grade, the most severe grade will be used for those AEs that occurred 
more than once in a given participant during the study.
In addition to the above summary tables, all treatment-emergent AEs, treatment-emergent AEs 
with Grade 3 or higher, treatment-emergent treatment-related AEs, and treatment-emergent 
treatment-related AEs with Grade 3 or higher, will be summarized by PT only, in descending 
order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs
•
Treatment-Related AEs 
•
AEs with severity of Grade 3 or higher
•
SAEs
•
Treatment-Related SAEs 
•
Deaths
•
AEs leading to premature discontinuation of study drug
7.1.7
Additional Analysis of Adverse Events
The following categories of AEs will be summarized by treatment group:
•
Renal dysfunction: Acute renal failure Standard MedDRA Query (SMQ) (broad)
•
Hepatic findings: Liver toxicity KUR list
The number and percentage of participants who experienced any of the above events will be 
summarized for each treatment group by category and PT.


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TEAEs will also be summarized for each treatment group by PT for following subgroups defined 
in Section 3.4: Age, Baseline eGFR, Sex, Race, Region, and BMI. 
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days, 
or all available data at the time of the database snapshot. The analysis will be based on values 
reported in conventional units. When values are below or above the LOQ, they will be listed as 
such, and the closest imputed value will be used for the purpose of calculating summary statistics 
as specified in Section 3.7. SARS-CoV-2 viral load result of “Inconclusive” will not be included 
in numeric summary. 
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, and coagulation separately. Values 
falling outside of the relevant reference range and/or having a severity grade of 1 or higher on 
the DAIDS Grading Scale will be flagged in the data listings, as appropriate.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for selected laboratory tests 
(Hemoglobin, Hematocrit, Absolute Neutrophil Count, Absolute Lymphocyte Count, Platelet 
Count, White Blood Cells, ALT, AST, Total bilirubin, Serum Creatinine, eGFR (Creatinine 
Clearance by Cockcroft-Gault for participants ≥ 18 years old; Bedside-Schwartz for participants 
≥ 12 and < 18 years old), INR) as follows:
•
Baseline values 
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of study drug. Change from baseline to a postbaseline visit will be defined as 
the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) change from baseline values for selected laboratory tests listed above, will be 
plotted using a line plot by treatment group and each postbaseline visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
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7.2.2.
Graded Laboratory Values
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Event, Version 2.1 
(July 2017) will be used to assign toxicity grades (0 to 4) to laboratory results for analysis. 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for participants who have permanently discontinued study drug, 
or the last available date in the database snapshot for other participants. If the relevant baseline 
laboratory value is missing, any abnormality of at least Grade 1 observed within the time frame 
specified above will be considered treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and treatment group; participants will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:
•
Treatment-emergent laboratory abnormalities
•
Treatment-emergent Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with nonmissing postbaseline values up to 30 days after last dosing date.
A by-participant listing of all laboratory abnormalities and treatment-emergent Grade 3 or 4 
laboratory abnormalities will be provided by participant ID number and visit in chronological 
order. 
For the international normalized ratio (INR) of prothrombin time and activated partial 
thromboplastin time (aPTT), protocol specified toxicity grading scale depends on the upper limit 
of normal range (ULN). While the ULN of INR and aPTT depends on whether the participant is 
taking anticoagulant medication or not (ie, Not taking oral anticoagulant: 0.8 – 1.2; Taking oral 
anticoagulant: 2.0 – 3.0), this information is not collected by the reference laboratory. As a 
result, INR and aPTT will be graded by assuming participant is not taking an oral anticoagulant, 
which is a conservative approach that may lead to over-reporting of abnormalities for INR and 
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7.2.3.
Liver-Related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of participants who were reported to have the following 
laboratory test values for postbaseline measurements:
•
Alanine aminotransferase (ALT): (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, 
(d) > 20 × ULN
•
Aspartate aminotransferase (AST): (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, 
(d) > 20 × ULN
•
ALT or AST: (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, (d) > 20 × ULN
•
Total bilirubin: (a) > 1 × ULN, (b) > 2 × ULN
•
Alkaline phosphatase (ALP) > 1.5 × ULN
•
ALT or AST > 3 × ULN and total bilirubin: (a) > 1.5 × ULN, (b) > 2 × ULN
•
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN and ALP < 2 × ULN
For individual laboratory tests, participants will be counted once based on the most severe 
postbaseline value. For both the composite endpoint of ALT or AST and total bilirubin, and the 
composite endpoint of ALT or AST, total bilirubin, and ALP, participants will be counted once 
when the criteria are met at the same postbaseline visit date. The denominator is the number of 
participants in the Safety Analysis Set with nonmissing postbaseline value of the tests in 
evaluation at the same postbaseline visit date. 
Listings of liver-related laboratory tests will be provided.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight and vital signs 
(including heart rate, respiratory rate, temperature, oxygen saturation, and blood pressure) as 
follows:
•
Baseline value
•
Values at each postbaseline analysis window 
•
Change from baseline at each postbaseline analysis window
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of body weight, BMI, vital signs will be provided by participant ID 
number and visit in chronological order. 
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the Gilead-modified World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications with a start date prior to the first dosing date of 
study drug, regardless of when the stop date is. If a partial start date is entered the medication 
will be considered prior unless the month and year (if day is missing) or year (if day and month 
are missing) of the start date are after the first dosing date. Medications with a completely 
missing start date will be considered as prior medications.
A summary of prior medications will not be provided.
7.4.2.
 Concomitant Medications
Concomitant medications are defined as medications taken while a participant took study drug. 
Day 1 to Day 29 medications are defined as medication taken from Day 1 to Day 29. Use of 
concomitant medications and Day 1 to Day 29 medications will be summarized separately by 
preferred name using the number and percentage of participants for each treatment group. A 
participant reporting the same medication more than once will be counted only once when 
calculating the number and percentage of participants who received that medication. The 
summary will be ordered by preferred term in descending overall frequency. For drugs with the 
same frequency, sorting will be done alphabetically. COVID-19 rescue medications (see 
Appendix 2) taken postbaseline will be listed and summarized if there are sufficient data.  
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication. If a partial start date is entered, any medication with the month and year (if day is 
missing) or year (if day and month are missing) after the study drug stop date will be excluded 
from the concomitant medication summary. Medications with completely missing start and stop 
dates will be included in the concomitant medication summary, unless otherwise specified. 


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Day 1 to Day 29 medications will follow the same logics of concomitant medication using 
Day 29 instead of last dosing date of study drug. Summaries will be based on the Safety Analysis 
Set. No formal statistical testing is planned.
All reported medications will be provided in a by-participant listing sorted by participant ID 
number and administration date in chronological order.
7.5.
Other Safety Measures
A by-participant listing of participant pregnancies during the study will be provided by 
participant ID number. No additional safety measures are specified in the protocol.
7.6.
Changes From Protocol-Specified Safety Analyses
Treatment-emergent AEs are defined in the protocol as any AEs with an onset date on or after 
the study drug start date and no later than 30 days after permanent discontinuation of study drug. 
In the SAP, any AEs leading to premature discontinuation of study drug are added in addition to 
the protocol definition of TEAEs. There are no other deviations from the protocol-specified 
safety analyses.
Participants from Site 20189 with GCP noncompliance observations will be excluded from 
efficacy, safety, virology, and PK analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
PK analyses will be included in the SAP for the final analysis of the study.
8.1.
PK Sample Collection
Pharmacokinetic assessments will be conducted in all participants during an in-person visit.
Approximately 30 participants at participating sites will have intensive PK samples collected. 
For participants in the optional intensive PK substudy, sparse PK samples will not be collected 
on the days of intensive PK sampling.
•
Sparse PK assessments
o
Day 1: 0.75 hours postdose and 2 hours postdose 
o
Day 3: predose [within 1 hour before dosing] and 0.75 hours postdose
o
Day 5: predose [within 1 hour before dosing] and 0.75 hours postdose
Note: ± 20% time window will be applied for all postdose time points. On Days 1, 3, and 
5, 1 of the 2 doses must be administered during the in-person visit. If a visit occurs on 
Day 6, PK samples should not be collected.
•
Intensive PK assessments
Day 1 (first dose) and/or Day 5 visit (morning or evening dose) at 0.25, 0.5, 0.75, 1.5, 3, and 
4 hours postdose; At Day 5 visit, an additional sample will be collected predose (within 
1.0 hour before dosing).
Note: ± 20% time window will be applied for all postdose time points. On Days 1 and 5, 
1 of the 2 doses must be administered during the in-person visit. If a visit occurs on 
Day 6, PK samples should not be collected.
8.2.
PK Analyses Related to Intensive PK Sampling
Pharmacokinetic parameters will be determined for participants in the PK Substudy Analysis Set. 
Concentrations of GS-441524 in plasma will be determined using validated bioanalytical assays.
8.2.1.
Estimation of PK Parameters
Pharmacokinetic parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear up log down rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.


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All predose sample times before time-zero will be converted to 0.  Pre-dose concentration values 
on Day 5 will also be used as 12-hours postdose values to allow for AUCtau estimation.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.2.2.
PK Parameters
Pharmacokinetic parameters will be generated for all subjects in the PK Substudy Analysis Set. 
The analytes and parameters presented in Table 8-1 will be used to evaluate the PK objectives of 
the study. The PK parameters to be estimated in this study are listed and defined in the PK 
Abbreviations section.
Table 8-1.
Pharmacokinetic Parameters for Analyte 
Analyte
Parameters
GS-441524
AUCtau, Ctau, and Cmax 
Individual participant concentration data and individual participant PK parameters for 
GS-441524 will be listed and summarized using descriptive statistics by treatment. Summary 
statistics (n, mean, SD, coefficient of variation [%CV], median, min, max, geometric mean, 
5th percentile, 95th percentile, Q1, and Q3) will be presented for both individual participant 
concentration data by time point and individual participant PK parameters by treatment. 
Moreover, the geometric mean, %CV for the geometric mean,  95% CI, and the mean and SD of 
the natural log-transformed values will be presented for individual participant PK parameter 
data. 
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number of participants 
with concentration BLQ will be presented for each time point. For summary statistics, BLQ 
values will be treated as 0 at predose and one-half of the lower LOQ for postdose time points. 
Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter.


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The following tables will be provided for each analyte by treatment:
•
Individual participant concentration data and summary statistics
•
Individual participant plasma PK parameters and summary statistics
•
Individual participant plasma PK parameters and summary statistics by baseline Creatinine 
clearance categories. 
The following figures may be provided for each analyte by treatment:
•
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)
•
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤ LOQ will not be 
displayed in the figures and remaining points connected.
Pharmacokinetic sampling details by participant, including procedures, differences in scheduled 
and actual draw times, and sample age will be provided in listings.
8.3.
PK Analyses Related to Sparse PK Sampling
Individual participant concentration data from Participants in the PK Analysis Set for GS-441524 
will be listed and summarized using descriptive statistics. Summary statistics (n, mean, SD, 
coefficient of variation [%CV], median, min, max, 5th percentile, 95th percentile, Q1, Q3, 
geometric mean, %CV, and 95% CI for geometric mean) will be presented by day and by 
nominal time point.
Sparse and intensive PK sampling data from this study may be combined with data from other 
studies in a meta-population analysis using mixed-effect modeling techniques. Details of the 
population PK analysis will be provided in a separate document.


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9.
REFERENCES
HealthMeasures, National Institutes of Health (NIH). PROMIS Adult Profile Scoring Manual. 
Available at: 
https://www.healthmeasures.net/images/PROMIS/manuals/Scoring_Manuals_/PR
OMIS_Adult_Profile_Scoring_Manual.pdf. Accessed: 09 June 2023. Last 
Updated: 10 September.  2021:


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


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision
Draft Version 1.0 
(14 Nov 2023)
Original version
Version 1.0
(11 Jan 2024)
6.5
Remove text of change in FAPS 
and Virology analysis set and 
remove reorder of key secondary 
endpoints. 
The changes are included in 
protocol amendment 4
1.3
The futility stopping boundary 
and study power were revised 
To align with primary efficacy 
analysis set clarification
3.8.3
Addition of selection of baseline 
for SARS-CoV-2 data
Align with selection of analysis 
record for postbaseline
3.1.7, 3.1.8, 
8
Addition of PK analysis sets and 
PK analyses for final analysis
Update to include analysis for 
the final analysis
6.3
Addition of analyses for SARS-
CoV-2 infectious viral titer and 
subgroup analysis by lineage for 
final analysis
Update to include analysis for 
the final analysis


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12.
APPENDICES
Appendix 1.
SCHEDULE OF ASSESSMENTS
Study Visit
Screeninga, b
Baseline
Day 1a
Day 3
Day 5
Day 
10
Day 
15
Day 
20
Day 29
Day 
60
EOS
Day 
90
Early 
Discontinuation 
Visit
Visit Window
± 1 dayc
± 2 days
+ 5 days
± 7 days
Visit Type
In Persond
In 
Persone 
or 
Virtualf
Virtualf
In Persond
Written informed consent (and assent as 
applicable)
X
Medical historyh 
X
Document SARS-CoV-2 infection
X
Complete physical examinationi
X
X
X
X
Symptom-directed physical examination
X
X
Height and weight
X
Vital signsj
X
X
X
X
X
X
X
COVID-19 Symptom Questionnairek
X
X
X
X
X
X
X
X
X
X
WPAI + CIQ:COVID19 
X
X
X
X
X
X
PROMIS-29
X
X
X
X
X
Household contactsl
X
Chemistry, coagulation, and hematology 
panelsm
X
X
X
X
X
X
Urine or serum pregnancy testsn 
X
X
X
X
SARS-CoV-2 rapid antigen testo
X
X
X
X
X
X
X
CCI


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Study Visit
Screeninga, b
Baseline
Day 1a
Day 3
Day 5
Day 
10
Day 
15
Day 
20
Day 29
Day 
60
EOS
Day 
90
Early 
Discontinuation 
Visit
Visit Window
± 1 dayc
± 2 days
+ 5 days
± 7 days
Visit Type
In Persond
In 
Persone 
or 
Virtualf
Virtualf
In Persond
Mid-turbinate nasal swabp
X
X
X
X
X
X
X
X
SARS-CoV-2 serology
X
Sparse PKq
X
X
X
MAV information/oxygen 
supplementation requirements
X
X
X
X
X
X
X
X
X
X
Study drug dispensation
X
Study drug dosing (ODV or placebo)t
X
X
X
Study drug bottle returnu
X
X
X
Adverse events and concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
COVID-19 = coronavirus disease 2019; EOS = end of study; MAV = medically attended visit; PK = pharmacokinetic(s); PROMIS-29 = Patient-Reported Outcomes Measurement 
Information System-29; 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 24 hours of the Day 1 visit. The Day 1 visit may occur on the same day as screening. If screening and the Day 1 visit are the same day, do not 
repeat physical examination and vital signs.
b
Local screening laboratory tests including serum creatinine, creatinine clearance/estimated glomerular filtration rate, alanine aminotransferase, and bilirubin assessments at 
screening (prior to randomization) are not required unless deemed necessary by the investigator to confirm eligibility. Testing for influenza is also not required at screening. 
c
Day 3 and Day 5 visits should be conducted on separate calendar days. 
d
In-person visit is defined as a visit conducted at a medical facility or elsewhere by a health care provider (where permitted).
e
Day 29 visit will be an in-person visit and require a nasal swab collection, only if any day after the Day 20 visit and prior to the Day 29 visit the participant has ≥ 1 moderate 
or severe symptom reported on the COVID-19 symptom questionnaire or has a positive rapid antigen test.  
f
Virtual visit is defined as an interaction with a health care professional using telephone or online-based interaction (eg, telehealth, webcast, video conferencing).
g
Long COVID-19 sequelae will be assessed using linked data between clinical study participant and real-world data (RWD). 
h
Medical history will include the date of first COVID-19 symptoms, overall COVID-19 symptoms, all COVID-19 vaccinations prior to screening, prior COVID-19 illness 
(including positive test type, month, and year), demographics, baseline characteristics, allergies, and all other relevant medical history. 
CCI


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A complete physical examination must include sotu·ce 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 netu·ological. Urogenital and 
reproductive examination should only be completed if clinically indicated. 
J 
Vital signs include heart rate, respirnto,y rnte, tempernture, oxygen sattu·ation, and blood pressm·e. 
k 
The COVID-19 Symptom Questionnaire will be completed daily (at approxiniately the same time each day) from predose to Day 29 visit, then at Day 60 and Day 90 visits. 
I 
The number of contacts in the household and how many tested positive for COVID-19 to be recorded. 
m 
Baseline laboratory assessments should be collected prior to first study dmg dose. 
n 
At screening, a mine pregnancy test will be performed at the local laborntory for participants assigned female at birth and of childbea,ing potential. On Day 1, Day 15, and 
early discontinuation/unscheduled visits, these participants will have a semm pregnancy test via centrnl laborato,y. At screening, a follicle-stimulating ho,mone test is 
required to confom the postmenopausal state in participants younger than 54 years, who have stopped menstrnating for at least 12 months but do not have doctuuentation of 
ovarian hormonal faihu·e, as described in Appendix 11.4. 
o 
Rapid antigen tests will be self-collected daily on all visit and non-visit days, up to Day 15, thereafter, on Days 17, 19, 21, 23, 25, 27, and 29. 
p 
The samples will be used for SARS-Co V-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), potential infectious viral titer assessment, and potential 
resistance testing. Multiplex viral PCR will only be performed at Baseline/Day 1 visit. 
q 
Sparse PK samples will be collected at Day 1 visit (0.75 hotu·s postdose and 2 hotu·s postdose), Day 3 visit (predose [within 1 hour before dosing] and 0.75 hours postdose), 
and Day 5 visit (predose [within 1 hour before dosing] and 0.75 hours postdose); ± 20% time window will be applied for all postdose time points. On Days 1, 3, and 5, one of 
the 2 doses must be administered dming the in- erson visit. If a visit occtu·s on Da 6 PK sam !es should not be collected. 
r 
s 
Me ,ca y attended visit information includes any interactions with health care professionals other than study staff or designees including 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 EOS/Day 90 visit. 
Study drng dosing is twice daily for 5 days. 
u 
Study drng bottle should be returned by the pa,ticipant on Day 5, if the participant has already completed all doses of study drng. If the participant has study drng remaining 
by the conclusion of the Day 5 visit, the pa,ticipant must rettun the stt1dy drng bottle on the Day 10 visit. 
11 Janua1y 2024 
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Appendix 2.
PROGRAMMING SPECIFICATIONS
1) Symptom alleviation and time to symptom alleviation, COVID-19 symptom questionnaire is 
shown in Appendix 3. 
1. Targeted symptoms are those listed below, only targeted symptoms will be evaluated in 
deriving of the primary endpoint.
•
Stuffy or runny nose
•
Sore throat 
•
Shortness of breath (difficulty breathing)
•
Cough
•
Low energy or tiredness
•
Muscle or body aches
•
Headache
•
Chills or shivering 
•
Feeling hot or feverish
2. Alleviation of all targeted symptoms: 
■
Symptom scored as Moderate or Severe at baseline is scored as None or Mild at 
postbaseline
■
Symptom scored as Mild at baseline is scored as None at postbaseline
■
Symptom scored as None or missing at baseline is scored as None at postbaseline
and
■
for 48 consecutive hours (SAS datetime format dd:hh:mm:ss will be used for the 
duration)
○
A potential symptom alleviation is identified first and defined as all targeted 
symptoms scored moderate or severe at baseline are scored as mild or none and 
all targeted symptoms scored mild or none at baseline are scored as none, i.e. 
without 48 consecutive hours confirmation. Participants with missing baseline 
symptoms data, all targeted symptoms need to be scored as none for symptom 
alleviation. 
○
Since the questionnaire recall time is over the last 24 hours, an additional 
consecutive 24 hours is needed to achieve consecutive 48 hours symptom 
alleviation, the reference start time of the second 24 hours is the assessment time 
of the first potential symptom alleviation.
○
No missing assessment is allowed between the first date and the last date of 
potential symptom alleviation included in the calculation.


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○
The last day potentially able to meet the definition of alleviation is Day 28.
Examples of counting additional 24 consecutive hours:
Study Day
Example
1
2
3
4
5
6
7
8
9
…
Day and 
time of 
symptom 
alleviation
Time
18:00
9:00
10:00
1
PSA
N
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 10:00 ≥ 24 
hrs
Time
9:00
10:00
2
PSA
.
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 10:00 ≥ 24 
hrs, Missing symptoms on Day 2 
has no impact.
Time
18:00
9:00
8:00
8:30
3
PSA
N
Y
Y
Y
Y
Y
Y
Y
Y
Day 3 9:00
Day 3 9:00 to Day 4 8:00 <24 hrs, 
so check for next day
Day 3 9:00 to Day 5 8:30 ≥ 24 hrs
Time
18:00
9:00
8:00
8:30
10:00 10:00
4
PSA
N
Y
Y
N
Y
Y
Y
Y
Y
Day 6 
10:00
Day 3 9:00 to Day 4 8:00 <24 hrs, 
so check for next day
Day 5 is not a PSA so need to 
check later date
Time
18:00
9:00
.
9:00
10:00 10:00
5
PSA
N
Y
.
Y
Y
Y
Y
Y
Y
Day 5 9:00
no missing is allowed within 
consecutive 24 hrs, need to restart 
the clock;. Day 5 9:00 – Day 6 
10:00 ≥24 hrs
Time
18:00
8:00
8:00
8:30
10:00 10:00
6
PSA
N
Y
Y
N
Y
Y
Y
Y
Y
Day 3 8:00
Day 3 8:00 to Day 4 8:00 ≥ 24 
hrs, symptom alleviation achieved 
even if   symptoms reported on 
Day 5 
Time
18:00
9:00
8:00
9:00
10:00 10:00 8:00
7
PSA
N
N
N
N
N
N
N
.
.
Censored at Day 8 8:00
PSA – potential symptom alleviation; Y- Yes; N – No; Yellow – symptom alleviation ≥ 48 hours; Tan - symptom alleviation < 48 
hours
Note: If a participant’s all symptoms are None at baseline, alleviation status will not be 
derived and the participant is excluded from the analysis. 
If a participant’s baseline symptoms are Mild or higher and symptoms from Day 2 and 
later are all missing, the participant is considered as censored at 23:59 on Day 1. 
If a participant has no COVID-19 symptom questionnaire data reported from Day 1 to 
Day 29, the participant is excluded from the analysis. 
3. Time to alleviation of symptoms (unit = day, keep 8 decimals from date/time calculation 
in dataset, use 1 decimal place for TFLs)
•
For participants with symptom alleviation by Day 29, use the first event of participant 
level alleviation status equals Yes.  
Date and Time of alleviation – Date and time of first dose. 
•
For participants who complete Day 29 of the study without symptom alleviation, time to 
symptom alleviation will be censored at Day 28 


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Date and Time of Day 28 COVID-19 questionnaire assessment - Date and time of 
first dose  
 Use Day 28 23:59 if no Day 28 COVID-19 questionnaire assessment
•
For participants who discontinue from the study before Day 29 without symptom 
alleviation, time to symptom alleviation will be censored at last COVID-19 questionnaire 
assessment
Date and Time of last COVID-19 questionnaire assessment - Date and time of 
first dose.
•
For participants with missing time of first dose, missing time is imputed using time of 
COVID-19 questionnaire assessment on the first dose date or 12:00 whichever occurs 
first
 5. Additional censoring rules due to Intercurrent event:
•
Hospitalization for the treatment of COVID-19 or all cause death or Use of rescue 
medication (see definition in #20)
Date and Time of Day 28 COVID-19 questionnaire assessment - Date and time of 
first dose.
Use Day 28 23:59 if no Day 28 COVID-19 questionnaire assessment.
 
2) COVID-19 Rescue medications
Details of COVID-19 rescue medications are provided in the table below. 


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Drug Class
Dictionary 
Level
Prohibited PREF 
Codes
Prohibited Ingredient, PREF, 
and/or ATC Decodes
Bamlanivimab and Etesevimab
PREF
15665101001
BAMLANIVIMAB;ETESEVIMAB
Bamlanivimab
PREF
15343501001
BAMLANIVIMAB
Bamlanivimab
PREF
15665101001
BAMLANIVIMAB;ETESEVIMAB
Casirivimab and Imdevimab
PREF
15585401001
CASIRIVIMAB;IMDEVIMAB
Cilgavimab and Tixagevimab
PREF
15616901001
CILGAVIMAB;TIXAGEVIMAB
Molnupiravir
PREF
15326101001
MOLNUPIRAVIR
Nirmatrelvir and Ritonavir
PREF
15892101001
NIRMATRELVIR;RITONAVIR
Remdesivir
PREF
14269001001
REMDESIVIR
Sotrovimab
PREF
15464401001
SOTROVIMAB
Bebtelovimab
PREF
16033001001
BEBTELOVIMAB
Ensitrelvir
PREF
16350701001
ENSITRELVIR
Ensitrelvir
PREF
16350702001
ENSITRELVIR FUMARIC ACID
ATC = anatomical therapeutic chemical; PREF = preferred 
Additional medication may be included during final review of Concomitant medications prior to 
data finalization.
3) Population, denominator, and numerator for efficacy endpoints summaries of proportion
Endpoint/Summary
Population /Denominator 
Numerator 
Proportion of participants with 
COVID-19 symptom alleviation
Proportion of participants with 
COVID-19 symptom resolution
Proportion of participants with 
COVID-19 related MAVs or all-cause 
death by Day 29
Proportion of participants with 
COVID-19 related hospitalization or 
all-cause death by Day 29
FAPS
Based on KM estimate, no 
explicit denominator used
Total number of events by 
selected visits
Note: Proportions from KM 
estimate differ from proportion 
calculated directly from 
number of event and 
participants at risk
Proportion of participants with moderate 
relapse of COVID-19 symptoms by 
Day 29
Participants in the FAPS who 
have achieved short symptom 
recovery by Day 29
Number of participants with 
moderate relapse of COVID-19 
symptoms by Day 29
Proportion of participants with relapse of 
COVID-19 symptoms by Day 29
Participants in the FAPS who 
have achieved short symptom 
recovery by Day 28
Number of participants with 
relapse of COVID-19 
symptoms by Day 29
Proportion of participants with symptoms 
at Days 60 and 90
Participants in the FAPS who 
completed Days 60 or 90 
COVID-19 questionnaire
Number of participants with 
any symptoms at Days 60 or 90


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Endpoint/Summary
Population /Denominator 
Numerator 
Proportion of participants with viral 
antigen rebound
Participants in the Antigen 
Analysis set who had antigen 
negativity at any postbaseline 
visit through Day 28
Number of participants with 
viral antigen rebound (antigen 
test positive after antigen 
negativity)
Proportion of participants with negative 
SARS-CoV-2 nasal swab viral load at 
Days 3, 5, 10, 15, 20, and 29
Participants in the Virology 
analysis set who had SARS-CoV-
2 nasal swab collected and 
nonmissing result of viral load 
reported at selected visits
Number of participants with 
negative SARS-CoV-2 nasal 
swab viral load
Proportion of participants with negative 
SARS-CoV-2 infectious viral titer at 
Days 3, 5, 10, 15, 20, and 29
Participants in the Virology 
analysis set who had nasal swab 
collected and nonmissing result 
of SARS-CoV-2 infectious viral 
titer reported at selected visits
Number of participants with 
negative SARS-CoV-2 
infectious viral titer
4) Use of rescue medication for relapse of COVID-19 symptoms and moderate relapse of 
COVID-19 symptoms by Day 29 
In addition to hospitalization or death, use of rescue medication is considered as an intercurrent 
event and handled as follows for symptom relapse:
If a participant takes rescue medication prior to the short recovery day, this participant is 
considered as not having short symptom recovery for 28 days. 
If a participant takes rescue medication after achieving short symptom recovery, this participant 
is considered to have symptom relapse and moderate symptom relapse on the day of taking 
rescue medication. 
5) Definition of Hospitalization
MAV type of Emergency room, non-ICU Hospitalization, ICU Hospitalization, and 
Hospitalization (unknown ward) could meet criteria for hospitalization if one of the following 
conditions is met: 
■
If the duration of the MAV is greater than 24 hours. 
■
If the duration is missing and end date of the MAV is 1 day after the start date.
Time to hospitalization is calculated as Start date of Hospitalization – First dose date + 1. 
6) SARS-CoV-2 positive at baseline
SARS-CoV-2 positive at baseline is defined as test result from central lab


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


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Appendix 3.
PATIENT REPORTED OUTCOMES
COVID-19 Symptom Questionnaire 
I.What was the severity of your stuffy or runny nose at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
2.What was the severity of your sore throat at its worst over the last 24 hom·s? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
3.What was the severity of your shortness of breath (difficulty breathing) at its worst over the 
last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
4.What was the severity of your cough at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
5.What was the severity of your low energy or tiredness at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
6.What was the severity of your muscle or body aches at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
7.What was the severity of your headache at its worst over the last 24 hours? 
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COVID-19 Symptom Questionnaire 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
8.What was the severity of your chills or shivering at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
9. What was the severity of your feeling hot or feverish at its worst over the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
10. What was the severity of your nausea (feeling like you wanted to throw up) at its worst over 
the last 24 hours? 
• 
None 
• 
Mild 
• 
Moderate 
• 
Severe 
11. How many times did you vomit (throw up) in the last 24 hom·s? 
• 
I did not vomit at all 
• 
1-2 times 
• 
3--4 times 
• 
5 or more times 
12. How many times did you have diarrhea (loose or watery stools) in the last 24 hours? 
• 
I did not have diarrhea at all 
• 
1-2 times 
• 
3--4 times 
• 
5 or more times 
13. Rate your sense of smell in the last 24 hours. 
• 
My sense of smell is THE SAME AS usual 
• 
My sense of smell is LESS THA usual 
• 
I have NO sense of smell 
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CO VID-19 Symptom Questionnaire 
14. Rate your sense of taste in the last 24 hours. 
• 
My sense of taste is THE SAME AS usual 
• 
My sense of taste is LESS THA usual 
• 
I have O sense of taste 
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Work Productivity and Activity Impairment Questionnaire 
plus Classroom Impairment Questions: 
COVID-19 Infection Specific V2.0 (WPAl+CIQ:COVID19 Infection) 
The following questions ask about the effect of your COVID-19 Infection on your ability 
to work, attend classes, and perform regular daily activities. Please fill in the blanks or 
circle a number, as indicated. 
1. Are you currently employed (working for pay)? 
NO 
YES 
If NO, check "NO" and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your COVID-19 Infection? Include hours you missed on 
sick days, times you went in late, left early, etc., because of your COVIO-19 
Infection. Do not include time you missed to participate in this study. 
HOURS 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
HOURS 
4. During the past seven days, how many hours did you actually work? 
__ HOU RS (If "0", skip to question 6.) 
WPAI+CIQ:COVID V2.0 English (US) 


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5. During the past seven days, how much did your COVID-19 Infection affect your 
productivity while you were working? 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual. If your COVIO-19 Infection affected your work only a little, choose 
a low number. Choose a high number if your COVIO-19 Infection affected your work 
a great deal. 
Consider only how much your COVID-19 Infection affected productivity while you were 
working. 
My COVID-19 
My COVID-19 
Infection had 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Infection 
no effect on my 
completely 
work 
prevented me 
from working 
6. Do you currently attend classes in an academic setting (middle school, high school, 
college, graduate school, additional course work, etc.)? __ NO __ YES 
If NO, check "NO" and skip to question 10. 
7. During the past seven days, how many hours did you miss from class or school 
because of problems associated with your COVID-19 Infection? Do not include time 
you missed to participate in this study. 
HOURS 
8. During the past seven days, how many hours did you actually attend class or 
school? 
__ HOURS (If "0", skip to question 10.) 
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9. During the past seven days, how much did your COVID-19 Infection affect your 
productivity while in school or attending classes in an academic setting? 
Think about days your attention span was limited, you had trouble with 
comprehension or days in which you could not take tests as effectively as usual. If 
your COVID-19 Infection affected your productivity at school or in class only a little, 
choose a low number. Choose a high number if your COVID-19 Infection affected 
your productivity at school or in class a great deal. 
Consider only how much your COVID-19 Infection affected productivity while in 
school or attending classes. 
My COVID-19 
My COVID-19 
------------------
Infection had 
O 
1 
2 
3 
4 
5 
6 
7 
8 
no effect on 
my class work 
9 
1 O Infection 
completely 
prevented me 
from doing my 
class work 
10. During the past seven days, how much did your COVID-19 Infection affect your 
ability to do your regular daily activities, other than work at a job or attending 
classes? 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc. Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like. If your COVID-19 infection affected your activities only a 
little, choose a low number. Choose a high number if your COVID-19 Infection 
affected your activities a great deal. 
Consider only how much your COVID-19 Infection affected your ability to do your 
regular daily activities, other than work at a job or attending classes. 
My COVID-19 
My COVID-19 
Infection had 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Infection 
no effect on 
completely 
my daily 
prevented me 
activities 
from doing my 
daily activities 
Adapted from: Reilly MC, Tanner A, Meltzer EO: Work, classroom and activity impairment instruments: validation 
studies in allergic rhinitis. Clin Drug Invest 1996; 11 (5):278-288. 
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PROMIS®-29 Profile v2.1 
Please respond to each question or statement by marking one box per row. 
'Without 
With a 
With 
With 
Phvsical Function 
any 
little 
some 
much 
Unable 
difficulty 
difficulU: 
difficulU: 
difficulty 
to do 
PFA11 
Are you able to do chores such as 
vacuuming or yard work? ....... 
4 
PFA21 
Are you able to go up and down stairs 
at a nomrnl pace? .... ..................... ........... 
4 
PFA23 
Are you able to go for a walk of at least 
15 minutes? ............. ..................... ......... 
4 
PFA53 
Are you able to run errands and shop? 
4 
Anxietv 
In the past 7 days ... 
Never 
R,u-ely 
Sometimes 
Often 
Always 
EDANX01 
I felt fearfuL ............... •••• •••••• •••••••••• •••••• •• 
4 
I found it hard to focus on anything 
EDANX40 
other than my anxiety .. 
4 
............................ 
EDANX41 
My worries overwhelmed me .................. 
4 
EDANX53 
I felt uneasy ................. •••• •••••• •••••••••• ••••• ••• 
2 
4 
Depression 
In the past 7 days ... 
Never 
Rarely 
Sometimes 
Often 
Always 
EDDEP04 
I felt worthless ............. •••• •••••• •••••••••• •••••• •• 
2 
4 
EDDEP06 
I felt helpless ................ •••• •••••• •••••••••• ••••• ••• 
4 
EDDEP29 
I felt depressed .... ......... •••• •••••• •••••••••••••••• •• 
4 
EDDEP41 
I felt hopeless ................... ...................... 
4 
Fatigue 
During the past 7 days .. . 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
Hl7 
I feel fatigued 
···················•· 
2 
4 
I have trouble starting things because I 
AN3 
am tired ......... 
2 
4 
07 Febrnmy 2018 
© 2008-2022 PROMIS Health Organization (PHO) 
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PROMIS®-29 Profile v2.1 
Fatigue 
In the past 7 days ... 
ot at all 
A little bit 
Somewhat 
Quite a bit 
Ve1·y much 
FATEXP41 
How run-down did you feel on 
average? ............................. .. ..... 
2 
3 
4 
FATEXP40 
How fatigued were you on 
average? 
.............. 
2 
3 
4 
Slee12 Disturbance 
In the past 7 days ... 
Very poor 
Poor 
Fair 
Good 
Very ~oocl 
Sleep109 
My sleep quality was .. ... .. ..... ..... .. 
4 
3 
2 
In the past 7 days ... 
Not at all 
A little bit 
Somewhat 
2uite a bit 
Ve1·y much 
Sleep11 6 
My sleep was refreshing. 
4 
3 
2 
Sleep20 
I had a problem with my sleep ..... 
2 
3 
4 
Sleep44 
I had difficulty falling asleep ....... 
2 
3 
4 
5 
Abilitv to Partici12ate in Social 
Roles and Activities 
Never 
Rarely 
Sometimes 
Usually 
Always 
I have trouble doing all of my 
regular leisure activities with 
SRPPER11_CaPS 
others .... ..................................... 
4 
3 
2 
I have trouble doing all of the 
family activities that I want to 
SRPPER18_CaPS 
do ............ .............................. ........ 
4 
3 
2 
I have trouble doing all of my 
usual work (include work at 
SRPPER23_CaPS 
home) .. 
4 
3 
2 
... ........... . .. ............ ....... 
I have trouble doing all of the 
activities with friends that I 
SRPPER46_CaPS 
want to do .................. 
4 
3 
2 
..... ..... ...... .. 
Pain Interference 
In the past 7 days ... 
Not at all 
A little bit 
Somewhat 
2uite a bit 
Ve1·y much 
PAININ9 
How much did pain interfere 
with your day to day activities? 
2 
3 
4 
PAININ22 
How much did pain interfere 
with work around the home? .... 
2 
3 
4 
PAINI N31 
How much did pain interfere 
with your ability to participate 
in social activities? ............... .... 
2 
3 
4 
07 Febrnmy 201 8 
© 2008-2022 PROMIS Health Organization (PHO) 
Page 2 of3 


GS-5245
GS-US-611-6549
Statistical Analysis Plan – Primary Analysis and Final Analysis
Version 1.0
11 January 2024
GILEAD CONFIDENTIAL INFORMATION
Page 71 of 71
PAININ34 
Global07 
PROMIS®-29 Profile v2.1 
Pain Interference 
In the past 7 days ... 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
How much did pain interfere 
with your household chores? 
2 
3 
4 
Pain Intensitv 
In the past 7 days ... 
How would you rate your pain 
on average?... . . . . . . . . ... . ... . . . . . . . . ... . ... . 
o 
4 
6 
s 
9 
10 
07 Febrnary 201 8 
No 
pain 
2008-2022 PROMIS Health Organization (PHO) 
Page 3 of3 
Worst pain 
ilnaginable 


GS-US-611-6459-Primary and Final Analysis-SAP v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
12-Jan-2024
15:40:32
Global Development
Lead (GDL) eSigned
13-Jan-2024
02:39:17
PPD
PPD