Clinical trial NCT05458102
Conditions: Human Immunodeficiency Virus Type 1 (HIV-1) Infection
Sponsor: Gilead Sciences
Start date: 2022-08-19; Completion date: 2023-05-01
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical study is to learn more about the impact of cobicistat (COBI) (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and strong cytochrome P450 enzyme \[CYP\]3A inhibitor), voriconazole (VOR) (strong CYP3A inhibitor), and rifabutin (RFB) (moderate CYP3A inducer) on the study drug, vesatolimod (VES), in people with HIV-1 on antiretroviral therapy (ART).

Detailed description:

Arms: arm 1: Participants will receive a single dose of vesatolimod (VES) 2 mg on Day 1 of Period 1. In Period 2, participants will receive cobicistat (COBI) 150 mg once daily on Days 1 to 5 along with a single dose of VES 2 mg on Day 2. In Period 3, participants will receive a loading dose of voriconazole (VOR) 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6, and a single dose of VES 2 mg in the morning on Day 3. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1. arm 2: Participants will receive a single dose of VES 6 mg on Day 1. In Period 2, participants will receive Rifabutin (RFB) 300 mg once daily on Days 1 to 9 along with a single dose of VES 6 mg on Day 6. There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1.
Interventions: intervention 1: Vesatolimod intervention 2: Cobicistat intervention 3: Voriconazole intervention 4: Rifabutin
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally intervention 4: Administered orally

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1, Open-label, Multicohort Study to Evaluate the Impact of 
Inhibitors and Inducers of Cytochrome P450 Enzyme (CYP)3A and/or 
P-glycoprotein (P-gp) on the Pharmacokinetics (PK) of Vesatolimod
(VES) in Virologically Suppressed Adults With HIV-1 on Antiretroviral
Therapy (ART)
Short Title:
Drug-Drug Interaction Study of Vesatolimod in Adults With HIV-1 
Who Have Very Low or Undetectable Virus Levels
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
122452
Not Applicable
NCT05458102
Indication:
Human immunodeficiency virus type 1 (HIV-1) infection
Protocol ID:
GS-US-382-1587
Contact Information:
The medical monitor name and contact information will be provided on 
the Key Study Team Contact List.
Protocol Version/Date:
Original:
25 March 2022
Amendment 1:
05 May 2022
Amendment 2:
28 June 2022
Amendment 3:
12 December 2022
This study will be conducted under United States Food and Drug Administration investigational new drug 
application regulations (21 Code of Federal Regulations Part 312).
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.
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................5
LIST OF IN-TEXT FIGURES........................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................................6
PROTOCOL SYNOPSIS................................................................................................................................................9
STUDY SCHEMA........................................................................................................................................................18
STUDY PROCEDURES TABLES ..............................................................................................................................19
1.
INTRODUCTION................................................................................................................................................28
1.1.
Background..............................................................................................................................................28
1.2.
Background on Study Interventions ........................................................................................................29
1.2.1.
Vesatolimod...........................................................................................................................29
1.2.2.
Cobicistat...............................................................................................................................31
1.2.3.
Voriconazole..........................................................................................................................31
1.2.4.
Rifabutin................................................................................................................................32
1.3.
Rationale for This Study..........................................................................................................................32
1.4.
Rationale for the Dose Selection of Study Drugs....................................................................................33
1.5.
Risk/Benefit Assessment for the Study ...................................................................................................34
1.6.
Compliance..............................................................................................................................................34
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................35
3.
STUDY DESIGN.................................................................................................................................................36
3.1.
Study Design ...........................................................................................................................................36
3.1.1.
Safety Review Team and Charter..........................................................................................36
3.2.
Duration of Dosing..................................................................................................................................36
3.3.
Protocol-Specific Discontinuation Criteria .............................................................................................37
3.3.1.
Criteria for Early Discontinuation of an Individual Cohort ..................................................38
3.3.2.
Loss to Follow-Up.................................................................................................................38
3.4.
Clinic Confinement .................................................................................................................................38
3.5.
Definitions for Time of Primary Endpoint and End of Study .................................................................39
3.5.1.
Primary Endpoint...................................................................................................................39
3.5.2.
End of Study..........................................................................................................................39
3.6.
Source Data .............................................................................................................................................39
4.
PARTICIPANT POPULATION..........................................................................................................................40
4.1.
Number of Participants and Participant Selection...................................................................................40
4.1.1.
Participant Replacement........................................................................................................40
4.2.
Inclusion Criteria.....................................................................................................................................40
4.3.
Exclusion Criteria....................................................................................................................................41
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................44
5.1.
Enrollment, Blinding, and Treatment Code Access ................................................................................44
5.1.1.
Enrollment .............................................................................................................................44
5.1.2.
Blinding .................................................................................................................................44
5.2.
Description and Handling of Vesatolimod..............................................................................................44
5.2.1.
Formulation ...........................................................................................................................44
5.2.2.
Packaging and Labeling ........................................................................................................44
5.2.3.
Storage and Handling ............................................................................................................45


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5.3.
Description and Handling of Commercially Available Drugs ................................................................45
5.4.
Dosage and Administration .....................................................................................................................45
5.5.
Fasting and Meals....................................................................................................................................46
5.6.
Dispensing, Accountability, and Disposal or Return of Study Drug ......................................................46
5.7.
Concomitant Medications and Other Protocol Restrictions ....................................................................46
5.7.1.
Concomitant Medications......................................................................................................46
5.7.2.
Other Protocol Restrictions ...................................................................................................50
6.
STUDY ASSESSMENTS....................................................................................................................................51
6.1.
Informed Consent ....................................................................................................................................51
6.2.
Participant Enrollment and Treatment Assignment ................................................................................52
6.3.
Instructions for Study Procedures ...........................................................................................................52
6.3.1.
Adverse Events......................................................................................................................52
6.3.2.
Screening Assessments..........................................................................................................52
6.3.3.
Admission Assessments ........................................................................................................53
6.3.4.
Check-in Assessments...........................................................................................................54
6.3.5.
Treatment Assessments .........................................................................................................54
6.3.6.
Pharmacokinetic Assessments...............................................................................................54
6.3.7.
Biomarker Testing.................................................................................................................55
6.4.
Safety Assessments .................................................................................................................................56
6.4.1.
Electrocardiogram Assessment .............................................................................................56
6.4.2.
Physical Examination ............................................................................................................57
6.4.3.
Vital Signs .............................................................................................................................57
6.4.4.
Body Mass Index...................................................................................................................57
6.4.5.
Clinical Laboratory Tests/Assessments.................................................................................57
6.4.6.
Creatinine Clearance .............................................................................................................58
6.4.7.
Concomitant Medications/Protocol Restrictions...................................................................59
6.5.
Posttreatment Assessments......................................................................................................................59
6.6.
Assessments for Early Discontinuation From Study Intervention or From the Study............................59
6.6.1.
Assessments for End of Study...............................................................................................59
6.7.
Sample Storage........................................................................................................................................59
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................60
7.1.
Definitions of Adverse Events and Serious Adverse Events...................................................................60
7.1.1.
Adverse Events......................................................................................................................60
7.1.2.
Serious Adverse Events.........................................................................................................60
7.1.3.
Study Drugs and Gilead Concomitant Therapy Special Situation Reports...........................61
7.2.
Assessment of Adverse Events and Serious Adverse Events..................................................................62
7.2.1.
Assessment of Causality for Study Drugs and Procedures ...................................................62
7.2.2.
Assessment of Severity..........................................................................................................62
7.3.
Investigator Reporting Requirements and Instructions ...........................................................................62
7.3.1.
Requirements for Collection Prior to Study Drug Initiation .................................................62
7.3.2.
Adverse Events......................................................................................................................63
7.3.3.
Serious Adverse Events.........................................................................................................63
7.3.4.
Study Drug Special Situations Reports .................................................................................63
7.3.5.
Concomitant Therapy Reports...............................................................................................63
7.4.
Reporting Process for Serious Adverse Events and Special Situations Reports.....................................64
7.4.1.
Serious Adverse Event Reporting Process ............................................................................64
7.4.2.
Special Situations Reporting Process ....................................................................................65
7.5.
Gilead Reporting Requirements ..............................................................................................................66
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events...........................................................................................................................66
7.7.
Toxicity Management..............................................................................................................................67
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7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event ..................................................68
7.7.2.
Grades 3 Laboratory Abnormality or Clinical Event ............................................................68
7.7.3.
Grades 4 Laboratory Abnormality or Clinical Event ............................................................68
8.
STATISTICAL CONSIDERATIONS.................................................................................................................69
8.1.
Analysis Objectives and Endpoints.........................................................................................................69
8.2.
Planned Analyses.....................................................................................................................................69
8.2.1.
Interim Analysis ....................................................................................................................69
8.2.2.
Final Analysis........................................................................................................................69
8.3.
Analysis Conventions..............................................................................................................................69
8.3.1.
Analysis Sets .........................................................................................................................69
8.3.2.
Data Handling Conventions ..................................................................................................70
8.4.
Demographic Data and Baseline Characteristics ....................................................................................70
8.5.
Safety Analysis........................................................................................................................................70
8.5.1.
Extent of Exposure ................................................................................................................70
8.5.2.
Adverse Events......................................................................................................................70
8.5.3.
Laboratory Evaluations .........................................................................................................71
8.5.4.
Other Safety Evaluations.......................................................................................................71
8.6.
Pharmacokinetic Analysis .......................................................................................................................71
8.7.
Biomarker Analysis.................................................................................................................................71
8.8.
Sample Size .............................................................................................................................................71
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 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.
Case Report Forms ................................................................................................................74
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.............................................................................................75
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 ...........................................................................................................76
10.
REFERENCES.....................................................................................................................................................77
11.
APPENDICES......................................................................................................................................................79
11.1.
Investigator Signature Page.....................................................................................................................80
11.2.
Pandemic Risk Assessment and Mitigation Plan ....................................................................................81
11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........84
11.4.
Management of Clinical and Laboratory Adverse Events ......................................................................88
11.5.
Gilead Toxicity Grading Scale for Severity of Adverse Events and Laboratory Abnormalities ............89


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LIST OF IN-TEXT TABLES
Table 1.
Study Procedures Table for Cohort 1, Periods 1 and 2 ...........................................................19
Table 2.
Study Procedures Table for Cohort 1, Period 3.......................................................................22
Table 3.
Study Procedures Table for Cohort 2, Periods 1 and 2 ...........................................................24
Table 4.
Summary of Vesatolimod Pharmacokinetic Parameters (Study GS-US-382-1450)...............30
Table 5.
Treatments to be Administered in Cohorts 1 and 2.................................................................45
Table 6.
Common Medications That Could Prolong QT Interval.........................................................48
Table 7.
Prohibited Medications............................................................................................................49
Table 8.
PK Sampling Time Points and Time Windows.......................................................................54
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ..........................................................................................................................18


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration of drug versus time curve of the drug
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
3TC
lamivudine
ABC
abacavir
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
APR
Antiretroviral Pregnancy Registry
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCinf
area under the concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/z)
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
BCRP
breast cancer resistance protein
BIC
bictegravir
BMI
body mass index
BSA
body surface area
bNAbs
broadly neutralizing antibodies
CD
clusters of differentiation
CFR
Code of Federal Regulations
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance
Clast
last observed quantifiable concentration of the drug
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
COBI
cobicistat
COVID-19
coronavirus disease 2019
CRF
case report form
CRS
cytokine release syndrome
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 enzyme
DNA
deoxyribonucleic acid
DOR
doravirine
DTG
dolutegravir
ECG
electrocardiogram


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eCRF
electronic case report form
EDC
electronic data capture
ET
early termination
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Gilead
Gilead Sciences/Gilead Sciences, Inc. 
GLSM
geometric least-squares mean
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IFN
interferon
IFN-α
interferon-alpha
IL
interleukin
IND
investigational new drug
IRB
institutional review board
ISG
interferon-stimulated gene
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger RNA
NRTI
nucleoside reverse transcriptase inhibitor
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PBPK
physiologically based pharmacokinetics
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
pDC
plasmacytoid dendritic cell
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetic(s)
PR (interval)
electrocardiographic interval occurring between the onset of the P wave and the QRS 
complex representing time for atrial and ventricular depolarization, respectively
PS
Patient Safety
PT
preferred term
PWH
people with HIV-1


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QRS
electrocardiographic deflection between the beginning of the Q wave and termination 
of the S wave, representing time for ventricular depolarization
QT (interval)
electrocardiographic interval between the beginning of the Q wave and termination of 
the T wave, representing the time for both ventricular depolarization and 
repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using the Fridericia formula
RAL
raltegravir
RFB
rifabutin
RMD
recommended maintenance dose
RNA
ribonucleic acid
SAE
serious adverse event
SOC
system organ class
SRT
safety review team
SSR
special situation report
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
Tlast
time (observed time point) of Clast
TLR7
toll-like receptor 7
Tmax
time (observed time point) of Cmax
ULN
upper limit of normal
UNAIDS
United Nations Programme on HIV/AIDS
US, USA
United States, United States of America
USPI
United States Prescribing Information
VES
vesatolimod
VOR
voriconazole
Vz/F
apparent volume of distribution of the drug


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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
Study Title: A Phase 1, Open-label, Multicohort Study to Evaluate the Impact of Inhibitors 
and Inducers of Cytochrome P450 Enzyme (CYP)3A and/or P-glycoprotein (P-gp) on the 
Phannacokinetics (PK) of Vesatolimod (VES) in Virologically Suppressed Adults With HIV-I 
on Antiretroviral Therapy (ART) 
Short Title: Drng-Drng Interaction Study of Vesatolimod in Adults With HIV-I Who Have 
Ve1y Low or Undetectable Vims Levels 
IND Number: 122452 
EudraCT Number: Not Applicable 
Clinical Trials.gov Identifier: NCT05458102 
Study Centers Planned: 
Multiple centers in the United States 
Objectives and Endpoints: 
Primary Objective(s) 
To evaluate the impact of the following dmgs on vesatolimod 
(VES) pharmacokinetics (PK) 
• 
Cobicistat (P-glycoprotein [P-gp ], breast cancer resistance 
protein [BCRP], and strong cytochrome P450 enzyme 
[CYP]3A inhibitor) 
• 
Voriconazole (strong CYP3A inhibitor) 
• 
Rifabutin (moderate CYP3A inducer) 
To evaluate the safety ofVES administered alone and in 
combination with inhibitors and inducers of metabolizing enzymes 
and transporters involved in VES disposition 
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P1imary Endpoint(s) 
Primary PK parameters throughout the study 
• 
VES AUC1as1, AUCu,r, Cmax 
Secondary PK parameters throughout the study 
• 
VES ¾AUC.,"P, Tmax, C1as1, T1as1, A.z, t112, CL/F, 
VJF 
Safety parameters 
• 
Incidence of treatment-emergent adverse events 
(TEAEs) and laborato,y abnonualities 
throughout the study 
I 
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Study Design: This is an open-label, multicohort Phase 1 study to evaluate the impact of 
inhibitors and inducers of CYP3A and/or P-gp on the PK and PD of VES in virologically 
suppressed adults with HIV-1 on antiretroviral therapy (ART). The overall study design is 
shown in Figure 1.
The study will be conducted in 2 cohorts:

Cohort 1: An open-label, single sequence cohort to evaluate the impact of cobicistat 
(COBI; P-gp, BCRP, and strong CYP3A inhibitor) and voriconazole (VOR; strong 
CYP3A inhibitor) on VES PK and PD

Cohort 2: An open-label, single sequence cohort to evaluate the impact of rifabutin 
(RFB; moderate CYP3A inducer) on VES PK and PD
A safety review team will assess relevant and available safety data for the first 3 participants in 
Cohort 1 who are dosed with COBI (up to and including Period 2 Day 3) before initiation of 
any additional participants in Cohort 1.
Number of Participants Planned: Approximately 45 enrolled: 25 in Cohort 1 and 20 in 
Cohort 2.
Target Population: Male and nonpregnant, nonlactating female, HIV-1 infected, virologically 
suppressed adults on ART
Duration of Dosing:
Cohort 1: VES will be administered as a single dose in Periods 1, 2, and 3; COBI will be 
administered for 5 days in Period 2; and VOR will be administered for 6 days in Period 3.
Cohort 2: VES will be administered as a single dose in Periods 1 and 2; and RFB will be 
administered for 9 days in Period 2.
Study Duration:
Cohort 1: Approximately 55 days (not including the 35-day screening window)
Cohort 2: Approximately 35 days (not including the 35-day screening window)
Diagnosis and Main Eligibility Criteria:
Eligible participants will be adults with HIV-1 assigned male at birth or nonpregnant, 
nonlactating participants assigned female at birth aged at least 18 years, on an ART regimen 
for at least 6 consecutive months, with no change in the ART regimen within 2 months prior to 
screening, and with documented plasma HIV-1 RNA levels less than 50 copies/mL at 
screening and for at least 6 months preceding the screening visit (using all available viral load 
measurements), and a CD4 T cell count of greater than or equal to 350 cells/μL. Participants’ 
ART will be consistent with the protocol requirements and participants will not receive 
prohibited medications from 14 days prior to study drug dosing through the follow-up visit. In 
addition, participants will be negative for chronic hepatitis B virus (HBV) infection (defined as 
positive hepatitis B surface antigen [HBsAg] and/or positive hepatitis B core antibody with 
positive reflex HBV DNA polymerase chain reaction [PCR] [Note: positive HBV core 


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antibody with negative reflex HBV DNA PCR results are acceptable]) and active hepatitis C 
virus (HCV) infection (defined as positive hepatitis C antibody and HCV RNA above lower 
limit of quantification [Note: positive anti-HCV antibody and negative HCV PCR results are 
acceptable]) and will be in good general health as determined by the investigator at the 
screening evaluation performed no more than 35 days prior to the scheduled first dose.
Study Procedures/Frequency:
Following completion of screening and admission assessments, eligible participants will 
receive the following treatments:

Cohort 1: 
— In Period 1, participants will receive a single dose of VES 2 mg on Day 1. 
— In Period 2, participants will receive COBI 150 mg once daily on Days 1 to 5; a 
single dose of VES 2 mg will be coadministered on Day 2. 
— In Period 3, participants will receive a loading dose of VOR 400 mg twice daily on 
Day 1, then VOR 200 mg twice daily on Days 2 to 6; a single dose of VES 2 mg will 
be coadministered in the morning on Day 3. 
There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and 
Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 
Day 5 and Period 3 Day 1. Participants should inform the site of any adverse event (AE) 
during the washout period.

Cohort 2: 
— In Period 1, participants will receive a single dose of VES 6 mg on Day 1. 
— In Period 2, participants will receive RFB 300 mg once daily on Days 1 to 9; a 
single dose of VES 6 mg will be coadministered on Day 6. 
There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and 
Period 2 Day 1. Participants should inform the site of any AE during the washout period.
— Note: Participants in Cohort 2 will be on a dolutegravir-based ART regimen
Vesatolimod is provided as 2 mg tablets, COBI is provided as 150 mg tablets, VOR is 
provided as 200 mg tablets, and RFB is provided as 150 mg capsules.
Clinic Confinement/Follow-Up
Following screening and admission assessments, eligible participants will be confined to the 
study center as follows:

Cohort 1
— In Period 1, participants will be confined beginning Day −1 until completion of 
assessments on Day 2
— In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 3
— In Period 3, participants will be confined beginning on Day −1 until completion of 
assessments on Day 4


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
Cohort 2

In Period 1, participants will be confined beginning on Day −1 until completion of 
assessments on Day 2

In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 7
Participants may remain confined for a longer duration within each treatment period if this is 
preferred by the principal investigator.
If a participant is experiencing signs and symptoms of cytokine release syndrome 
(CRS; see toxicity management below), the participant will remain confined (for CRS 
symptoms of Grade 1) or immediately be transferred to a hospital or emergency department 
(for CRS symptoms of ≥ Grade 2) until symptoms resolve.
Participants will return 10 ± 3 days after the last dose of VES for an in-clinic follow-up visit.
Study Drug Administration
All study treatments will be administered orally at approximately the same time relative to 
VES dosing in each period (± 1 hour) each day with 240 mL of water. All VES doses will be 
administered in the morning following an overnight fast (no food or drinks except water) for at 
least 8 hours. Participants will continue to fast until after collection of the 4-hour PK sample, 
relative to VES dosing. Additionally, participants will be restricted from water consumption 
from 2 hours before through 2 hours after VES dosing, except for the 240 mL given with the 
study drug. All COBI, VOR, and RFB doses will be administered on an empty stomach, 
defined as no food or drinks, except water, for at least 2 hours before and 2 hours after dosing.
Pharmacokinetic Assessments
Plasma PK:
Plasma samples for quantification of VES concentrations will be collected at the following 
time points relative to VES dosing in each period:

Predose (within 0.5 hours before dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 
72, and 96 hours postdose
Plasma concentrations of COBI, VOR, and RFB may be determined and PK parameters may 
be estimated.
Time windows allowed for PK samples to be collected are provided in Table 8.
Clinical staff should make every effort to ensure that the sampling time is as close as possible 
to the nominal time. The exact time and date of the blood draw must be recorded in the 
electronic data capture (EDC) system.
Biomarker Testing
Biomarker samples will be collected to assess the PD and safety following VES 
administration.
Serum samples for biomarker assessments will be collected at the following time points 
relative to VES dosing in each period:

Predose (within 0.5 hours before dosing) and 4, 8, 12, 24, 48, and 96 hours postdose


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The serum biomarkers to be evaluated may include (but not limited to): interferon-alpha 
(IFN-α), interleukin (IL)-1 receptor antagonist, interferon gamma inducible protein-10, 
interferon-inducible T cell alpha chemoattractant, interferon-gamma, IL-1 beta, IL-6, tumor 
necrosis factor alpha, and C-reactive protein.
Whole blood samples for ISG mRNA expression (including, but not limited to, MX1, ISG15, 
OAS1) will be collected at the following time points relative to VES dosing in each period:

Predose (within 0.5 hours before dosing) and 8, 12, 24, 48, 72, and 96 hours postdose
Whole blood for immune cell phenotyping will be collected at the following time points 
relative to VES dosing in each period:

Predose (within 0.5 hours before dosing) and 24, 72, and 96 hours postdose
Whole blood to evaluate VES TruCulture cytokine response will be collected for Cohort 2 at 
the following visit in Period 1:

On Day 1 (predose)
A time window of ± 10% will be allowed for biomarker samples collected through 8 hours 
postdose. Biomarker samples collected beyond 8 hours postdose will have a ± 30-minute 
window.
Clinical staff should make every effort to ensure that the sampling time is as close as possible 
to the nominal time. The exact time and date of the blood draw must be recorded in the EDC 
system.
Pharmacogenetic Assessments
A pharmacogenetics (PGx) sample will be collected on Day 1 Period 1 if applicable 
(preferably) or at any other time during the study for toll-like receptor 7 (TLR7) and BCRP 
(also known as the adenosine triphosphate-binding cassette transporter G2; gene symbol 
ABCG2) genotyping.
Cohort 1 (only): A PGx sample for CYP2C19 genotyping will be collected at screening as part 
of the inclusion/exclusion criteria.
Safety Assessments
Safety assessments will include a complete and symptom-driven physical examination, vital 
signs, height, weight, clinical laboratory tests, urine drug and alcohol assessments, 12-lead 
electrocardiogram (ECG), pregnancy testing, HBV and HCV testing, HIV-1 viral load test, 
CD4 cell count test, SARS-CoV-2 test, and assessment of AEs.
All safety assessments will be completed predose unless otherwise specified.

Complete physical examination: Screening, follow-up, and early termination (ET) visits, 
if applicable

Symptom-driven physical examination: every day during confinement, as needed, based on 
reported signs and symptoms


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
Vital signs (blood pressure, heart rate, oxygen saturation, and body temperature):

Cohort 1: Screening, Period 1 Day 1 predose (within 1 hour before VES dosing) and 2, 
4, 8, 12, and 24 hours postdose; Period 2 Day 2 predose (within 1 hour before VES 
dosing) and 2, 4, 8, 12, and 24 hours postdose; Period 3 Day 3 predose (within 1 hour 
before VES dosing) and 2, 4, 8, 12, and 24 hours postdose; at the follow-up visit, and at 
the ET visit, if applicable

Cohort 2: Screening, Period 1 Day 1 predose (within 1 hour before VES dosing) and 2, 
4, 8, 12, and 24 hours postdose; Period 2 Day 6 predose (within 1 hour before VES 
dosing) and 2, 4, 8, 12, and 24 hours postdose; at the follow-up visit, and at the ET 
visit, if applicable

Height: Screening

Weight: 

Cohort 1: Screening, Day −1 of each period, Period 1 Day 5, Period 2 Day 6, Period 3 
Day 7, at the follow-up visit, and at the ET visit, if applicable

Cohort 2: Screening, Day −1 of each period, Period 1 Day 5, Period 2 Day 10, at the 
follow-up visit, and at the ET visit, if applicable

Coagulation panel: Screening

Clinical laboratory tests (hematology, chemistry, calculated creatinine clearance, and 
urinalysis): 

Cohort 1: Screening, Day −1 of each period, Period 1 Day 5, Period 2 Day 6, Period 3 
Day 7, at the follow-up visit, and at the ET visit, if applicable

Cohort 2: Screening, Day −1 of each period, Period 1 Day 5, Period 2 Day 10, at the 
follow-up visit, and at the ET visit, if applicable

Urine drug and alcohol assessments: 

Cohort 1: Screening, Day −1 of each period, Period 1 Day 3, Period 2 Day 4, and 
Period 3 Day 5

Cohort 2: Screening, Day −1 of each period, Period 1 Day 3, and Period 2 Day 8
Note: On Day −1 (admission), 2 sets of safety laboratory results for hematology, chemistry, 
urinalysis, urine drug, and alcohol assessments will be collected upon study center 
admission. One will be sent to the central laboratory and the other will be sent to the site’s 
local laboratory to obtain results in time for enrollment on Day 1.
If a study center cannot perform a urine alcohol test or receive results from the local 
laboratory in time for enrollment on Day 1, then an alcohol breathalyzer test is acceptable. 

12-lead ECG: 

Cohort 1: Screening; Period 1 Days 1, 2, and 5; Period 2 Days 2, 3, and 6; Period 3 
Days 3, 4, and 7

Cohort 2: Screening, Period 1 Days 1, 2, and 5; and Period 2 Days 6, 7, and 10 


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Amendment 3
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
Serum or urine pregnancy test (participants assigned female at birth of childbearing 
potential only): Screening (serum), Day −1 of each period (serum or urine), at the follow-
up visit (urine), and at the ET visit (urine), if applicable. For Cohort 2 only, an at-home 
urine pregnancy test will be completed 10 days after the last dose of RFB. Participants will 
be contacted by telephone to report at-home pregnancy test results.
Note: Pregnancy test result is required prior to dosing. If Day −1 serum pregnancy test 
result is not available, a negative urine pregnancy test (performed locally) is required.

Follicle-stimulating hormone (participants assigned female at birth who are younger than 
54 years, not on hormonal contraception, and who have stopped menstruating for at least 
12 months but do not have documentation of ovarian hormonal failure): Screening

Hepatitis B virus, hepatitis C virus: Screening

HIV-1 viral load testing: 

Cohort 1: Screening, and Day −1 of Period 2 and Period 3

Cohort 2: Screening and Day −1 of Period 2

CD4 cell count: Screening

SARS-CoV-2: Day −1 of each period

Assessment of AEs and concomitant medications will continue throughout the study. All 
clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in protocol Appendix 11.4.
Protocol-Specific Discontinuation Criteria
Participant, cohort, and study-specific stopping criteria are detailed in Section 3.3.
Toxicity Management
After VES dosing, Grade 1 CRS, with influenza-like symptoms such as fever, fatigue, chills, 
myalgia, or headache without more severe manifestations such as changes in blood pressure or 
oxygen saturation, may be managed with supportive care (eg, paracetamol for myalgia or 
fever). If a participant experiences Grade 1 CRS, they will remain confined until symptoms 
resolve. For any Grade 2 or higher CRS, including hypotension and/or hypoxia, the participant 
will be immediately transferred to a hospital or emergency department for management in a 
monitored setting until symptoms resolve. Administration of steroids, intravenous fluid for 
hypotension, and supplemental oxygen for hypoxia should also be considered. If a participant 
experiences treatment-related Grade 2 or higher CRS, dosing in that participant must be 
discontinued.
Grading of Cytokine Release Syndrome
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Cytokine release 
syndrome
Fever with or without 
constitutional 
symptoms
Hypotension 
responding to fluids; 
hypoxia responding 
to < 40% O2
Hypotension 
managed with one 
pressor; hypoxia 
requiring ≥ 40% O2
Life-threatening 
consequences; urgent 
intervention indicated
National Cancer Institute Common Terminology Criteria for Adverse Events v5.0


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Amendment 3
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Test Product, Dose, and Mode of Administration:
Cohort 1
In Period 2, COBI 150 mg will be administered on an empty stomach once daily on the 
mornings of Days 1 to 5; a single dose of VES 2 mg will be coadministered in the fasted state 
on the morning of Day 2.
In Period 3, VOR 400 mg will be administered on an empty stomach twice daily on Day 1, 
then VOR 200 mg will be administered on an empty stomach twice daily Days 2 to 6; a 
single dose of VES 2 mg will be coadministered in the fasted state on the morning of Day 3.
Cohort 2
In Period 2, RFB 300 mg will be administered on an empty stomach once daily on the 
mornings of Days 1 to 9; a single dose of VES 6 mg will be coadministered in the fasted state 
on the morning of Day 6.
Reference Therapy, Dose, and Mode of Administration:
Cohort 1
In Period 1, a single dose of VES 2 mg will be administered in a fasted state on the morning of 
Day 1.
Cohort 2
In Period 1, a single dose of VES 6 mg will be administered in a fasted state on the morning of 
Day 1.
Statistical Methods: 
Pharmacokinetics:
Plasma concentrations and PK parameters will be listed and summarized for VES using 
descriptive statistics by treatment. 
For Cohorts 1 and 2, an analysis of variance using a mixed-effects model with treatment as a 
fixed effect and participant as a random effect will be fitted to the natural logarithmic 
transformation of PK parameters for each analyte. Two-sided 90% CIs will be calculated for 
the ratios of geometric least-squares means (GLSMs) between test and reference treatments 
being compared.
Biomarkers:
The absolute level of PD biomarkers (including serum cytokines, ISGs mRNA, and immune 
cell phenotype), their change from baseline, and fold change from baseline will be listed and 
summarized using descriptive statistics by treatment within each cohort.
The absolute and normalized levels of TruCulture cytokines, as well as their association with 
serum PD biomarkers will be evaluated.


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Final
Gilead Sciences, Inc.
Amendment 3
CONFIDENTIAL
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Safety:
The incidence of TEAEs and laboratory abnormalities will be summarized.
Select laboratory tests, vital signs, and ECG data will be summarized at scheduled visits and 
time points. All safety data will be provided in by-participant listings. 
Sample Size:
With 18 evaluable participants per cohort, the estimated 2-sided 90% CI of the GLSM ratio of 
test versus reference treatments with regards to AUCinf and Cmax will be within (0.50, 2.00) 
with at least 90% probability if the true GLSM ratio was 1.0. This is assuming a root mean 
square error of no more than 0.6 on a natural logarithm scale, which is supported by the 
previous Study GS-US-234-0101. With 35% and 10% overage for Cohorts 1 and 2, a total 
sample size of 25 participants and 20 participants will be required for Cohorts 1 and 2; 
respectively.


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Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
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STUDY SCHEMA
Figure 1.
Study Schema
ART = antiretroviral therapy; COBI = cobicistat; DTG = dolutegravir; RFB = rifabutin; SRT = safety review team; VES = vesatolimod; VOR = voriconazole
a
An SRT review of the available safety data after the first 3 participants who are dosed with COBI in Cohort 1 up to and including Period 2 Day 3 should occur before 
initiation of the rest of the cohort.
b
Prospective participants should be screened within 35 days prior to administration of the first dose of study drug.
c
Washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1.
d
Washout of period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1.
I Cohort 1a 
Screeningb 
I Cohort 2 I 
Screeningb 
(DTG-based ART) 
Period 1 
Period 2 
Dayl 
Dayl 
Day2 
Days 3 to 5 
VES 2 mg 
COBI 150 mg 
VES 2 mg+ 
COBI 150 mg 
COBI 150 mg 
Period 3 
Dayl 
Day2 
Day3 
Days 4 to 6 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
VOR 400 mg 
VOR400 mg 
VOR 200 mg 
VOR 200 mg 
VES 2 mg+ 
VOR 200 mg 
VOR 200 mg 
VOR 200 mg 
VOR 200 mg 
Period 1 
Period 2 
Dayl 
Days 1 to 5 
Day6 
Days 7to 9 
VES 6 mg 
RFB 300 mg 
VES 6 mg+ 
RFB 300 mg 
RFB 300 mg 


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Amendment 3
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STUDY PROCEDURES TABLES
Table 1.
Study Procedures Table for Cohort 1, Periods 1 and 2
Study Day
Period 1 (VES)
Period 2 (VES + COBI)
Study Procedure
Screeninga
−1b
1
2c
3
4
5
Wash outd
−1b
1
2
3c
4
5
6
Wash oute
Written informed 
consent
X
Eligibility criteria
X
Complete medical 
history
X
X
X
ART historyf
X
Complete physical 
examination
X
Symptom-driven 
physical examinationg
X
X
X
X
X
X
X
Demographics
X
Height 
X
Weight
X
X
X
X
X
Vital signsh
X
X
X
X
X
12-lead ECGi
X
X
X
X
X
X
X
HIV-1 viral load
X
X
CD4 cell count
X
HBV and HCV 
testingj
X
SARS-CoV-2k
X
X
Urine drug and 
alcohol screenu
X
X
X
X
X
Pregnancy test 
(women of 
childbearing 
potential)l
X
X
X


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Gilead Sciences, Inc. 
Amendment 3
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Study Day
Period 1 (VES)
Period 2 (VES + COBI)
Study Procedure
Screeninga
−1b
1
2c
3
4
5
Wash outd
−1b
1
2
3c
4
5
6
Wash oute
FSH (postmenopausal 
women)m
X
Blood chemistryu
X
X
X
X
X
Calculated CLcru
X
X
X
X
X
Coagulation panel
X
Hematologyu
X
X
X
X
X
Urinalysisu
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Enrollment
X
Confinementn
X
X
X
X
X
X
X
VES dosing
X
X
COBI dosing
X
X
X
X
X
Plasma VES and 
perpetrator PKo
X
X
X
X
X
X
X
X
X
X
Serum biomarkersp
X
X
X
X
X
X
X
X
Whole blood ISG 
mRNAq
X
X
X
X
X
X
X
X
X
X
PGx (TLR7 and 
BCRP)r
X
PGx CYP2C19s
X
Immune cell 
phenotypingt
X
X
X
X
X
X
X
X
AE = adverse event; ART = antiretroviral therapy; BCRP = breast cancer resistance protein; CD4 = clusters of differentiation 4; CLcr = creatinine clearance; COBI = cobicistat; 
CYP = cytochrome P450 enzyme; CRS = cytokine release syndrome; ECG = electrocardiogram; FSH = follicle-stimulating hormone; HBsAg = hepatitis B virus surface antigen; 
HBV = hepatitis B virus; HCV = hepatitis C virus; ISG = interferon-stimulated genes; mRNA = messenger RNA; PGx = pharmacogenetics; PK = pharmacokinetics; 
TLR7 = toll-like receptor 7; VES = vesatolimod 
a
Prospective participants should be screened within 35 days prior to administration of the first dose of study drug.
b
Admission to clinic.
c
Discharge from clinic.


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Amendment 3
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d
There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1. Participants should inform the site of any AE during the washout 
period.
e
There will be a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1 . Participants should inform the site of any AE during the washout 
period.
f
Collect ART history for at least the past 12 months.
g
Every day during confinement, as needed, based on reported signs and symptoms.
h
Vital signs include blood pressure, heart rate, oxygen saturation, and body temperature. Vital signs will be collected at predose (within 1 hour before VES dosing) and 2, 4, 8, 
12, and 24 hours after each dose of VES.
i
12-lead ECGs will be collected after the participant has rested for at least 5 minutes in the supine position. A 12-lead ECG will be collected 2 hours after each dose of VES.
j
HBV core antibody, HBsAg, and HCV antibody at screening.
k
COVID-19 testing in accordance with the local guidelines will be conducted and reviewed per site-specific policy at admission (Day −1) and as needed prior to the next 
scheduled test based upon symptoms. Termination of the cohort for any positive viral test result will be at the discretion of the sponsor and the investigator.
l
For participants assigned female at birth and of childbearing potential. Serum pregnancy test is required at screening. Serum or urine pregnancy test at Day −1 of each period 
is acceptable. Pregnancy test result is required prior to dosing. If Day −1 serum pregnancy test result is not available, a negative urine pregnancy test (performed locally) is 
required.
m
For participants assigned female at birth who are younger than 54 years, not on hormonal contraception, and who have stopped menstruating for at least 12 months but do not 
have documentation of ovarian hormonal failure.
n
In Period 1, participants will be confined beginning Day −1 until completion of assessments on Day 2. In Period 2, participants will be confined beginning on Day -1 until 
completion of assessments on Day 3. Participants may remain confined for a longer duration within each treatment period if this is preferred. If a participant is experiencing 
signs and symptoms of CRS, the participant will remain confined (for CRS symptoms of Grade 1) or immediately be transferred to a hospital or emergency department 
(for CRS symptoms of ≥ Grade 2) until symptoms resolve.
o
VES and perpetrator PK samples will be collected at predose (within 0.5 hours before dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after each 
dose of VES. Time windows allowed for PK samples to be collected are provided in Table 8.
p
Serum biomarker samples will be collected at predose (within 0.5 hours before dosing) and 4, 8, 12, 24, 48, and 96 hours after each dose of VES. A time window of ± 10% 
will be allowed for biomarker samples collected through 8 hours postdose. Biomarker samples collected beyond 8 hours postdose will have a ± 30 minute window.
q
Whole blood samples for ISG mRNA expression and transcriptional profile will be collected predose (within 0.5 hours before dosing) and 8, 12, 24, 48, 72, and 96 hours 
postdose relative to VES. A time window of ± 10% will be allowed for whole blood samples collected at 8 hours postdose. Whole blood samples collected beyond 8 hours 
postdose will have a ± 30-minute window.
r
A PGx sample will be collected on Day 1 (preferably) or at any other time during the study.
s
Results must be reviewed prior to enrollment.
t
Whole blood sample for immune cell phenotyping will be collected predose (within 0.5 hours before dosing), and 24, 72, and 96 hours postdose relative to VES. Whole blood 
samples collected postdose will have a ± 30-minute window.
u
On Day −1 (admission), 2 sets of safety laboratory results for hematology, chemistry, urinalysis, urine drug, and alcohol assessments will be collected upon study center 
admission. One will be sent to the central laboratory and the other will be sent to the site’s local laboratory to obtain results in time for enrollment on Day 1. If a study center 
cannot perform a urine alcohol test or receive results from the local laboratory in time for enrollment on Day 1, then an alcohol breathalyzer test is acceptable. 
All clinical and clinically significant laboratory toxicities will be managed according to uniform guidelines detailed in protocol Appendix 11.4.


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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Table 2.
Study Procedures Table for Cohort 1, Period 3
Study Day
Period 3 (VES + VOR)
Study Procedure
−1a
1
2
3
4b
5
6
7
Follow-upc/ETd
Complete physical examination
X
Symptom-driven physical examinatione
X
X
X
X
X
Weight
X
X
X
Vital signsf
X
X
X
12-lead ECGg
X
X
X
HIV-1 viral load
X
SARS-CoV-2h
X
Urine drug and alcohol screenq
X
X
Pregnancy test (women of childbearing 
potential)i
X
X
Blood chemistryq
X
X
X
Calculated CLcrq
X
X
X
Hematologyq
X
X
X
Urinalysisq
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Confinementj
X
X
X
X
X
VES dosingk
X
VOR dosingl
X
X
X
X
X
X
Plasma VES and perpetrator PKm
X
X
X
X
X
Serum biomarkersn
X
X
X
X
Whole blood ISG mRNAo
X
X
X
X
X
Immune cell phenotypingp
X
X
X
X
CLcr = creatinine clearance; CRS = cytokine release syndrome; ECG = electrocardiogram; ET = early termination; ISG = interferon-stimulated genes; mRNA = messenger RNA; 
PK = pharmacokinetics; VES = vesatolimod; VOR = voriconazole


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Amendment 3
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a
Admission to clinic.
b
Discharge from clinic.
c
Participants will return for an in-clinic follow-up visit 10 (± 3) days after the last dose of VES.
d
Assessments will be performed within 72 hours of ET from the study, if possible.
e
Every day during confinement, as needed, based on reported signs and symptoms. 
f
Vital signs include blood pressure, heart rate, oxygen saturation, and body temperature. Vital signs will be collected at predose (within 1 hour before VES dosing) and 2, 4, 8, 
12, and 24 hours after the VES dose in Period 3.
g
12-lead ECGs will be collected after the participant has rested for at least 5 minutes in the supine position. A 12-lead ECG will be collected 2 hours after the VES dose in 
Period 3.
h
COVID-19 testing in accordance with the local guidelines will be conducted and reviewed per site-specific policy at admission (Day −1) and as needed based upon symptoms. 
Termination of the cohort for any positive viral test result will be at the discretion of the sponsor and the investigator.
i
For participants assigned female at birth and of childbearing potential. Serum pregnancy test is required at screening. Serum or urine pregnancy test at Day −1 of each period 
is acceptable. Pregnancy test result is required prior to dosing. If Day −1 serum pregnancy test result is not available, a negative urine pregnancy test (performed locally) is 
required. Urine pregnancy testing is repeated at the follow-up visit and ET visit, if applicable.
j
In Period 3, participants will be confined beginning on Day −1 until completion of assessments on Day 4. Participants may remain confined for a longer duration if this is 
preferred. If a participant is experiencing signs and symptoms of CRS, the participant will remain confined (for CRS symptoms of Grade 1) or immediately be transferred to a 
hospital or emergency department (for CRS symptoms of ≥ Grade 2) until symptoms resolve.
k
VES will be dosed in the morning.
l
VOR will be dosed twice daily.
m
VES and perpetrator PK samples will be collected at predose (within 0.5 hours before dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after 
administration of VES. Time windows allowed for PK samples to be collected are provided in Table 8.
n
Serum biomarker samples will be collected at predose (within 0.5 hours before dosing) and 4, 8, 12, 24, 48, and 96 hours after administration of VES. A time window of 
± 10% will be allowed for biomarker samples collected through 8 hours postdose. Biomarker samples collected beyond 8 hours postdose will have a ± 30-minute window.
o
Whole blood samples for ISG mRNA expression and transcriptional profile will be collected predose (within 0.5 hours before dosing) and 8, 12, 24, 48, 72, and 96 hours 
postdose relative to VES. A time window of ± 10% will be allowed for whole blood samples collected at 8 hours postdose. Whole blood samples collected beyond 8 hours 
postdose will have a ± 30 minute window.
p
Whole blood sample for immune cell phenotyping will be collected predose (within 0.5 hours before dosing), and 24, 72, and 96 hours postdose relative to VES. Whole blood 
samples collected postdose will have a ± 30-minute window.
q
On Day −1 (admission), 2 sets of safety laboratory results for hematology, chemistry, urinalysis, urine drug, and alcohol assessments will be collected upon study center 
admission. One will be sent to the central laboratory and the other will be sent to the site’s local laboratory to obtain results in time for enrollment on Day 1. If a study center 
cannot perform a urine alcohol test or receive results from the local laboratory in time for enrollment on Day 1, then an alcohol breathalyzer test is acceptable. 
All clinical and clinically significant laboratory toxicities will be managed according to uniform guidelines detailed in protocol Appendix 11.4.


Vesatolimod
Protocol GS-US-382-1587
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Table 3.
Study Procedures Table for Cohort 2, Periods 1 and 2
Study Day
Period 1 (VES)
Period 2 (VES + RFB)
Study 
Procedure
Screeninga
−1b
1
2c
3
4
5
Wash 
outd
−1b
1
2
3
4
5
6
7c
8
9
10
Follow-upe/ETf
Telephone 
contactg
Written 
informed 
consent
X
Eligibility 
criteria
X
Complete 
medical history
X
X
X
ART historyh
X
Complete 
physical 
examination
X
X
Symptom-driven 
physical 
examinationi
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Height 
X
Weight
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
X
X
X
HIV-1 viral load
X
X
CD4 cell count
X
HBV and HCV 
testingl
X
SARS-CoV-2m
X
X
Urine drug and 
alcohol screenn
X
X
X
X
X
Pregnancy test 
(women of 
childbearing 
potential)o
X
X
X
X
X


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Study Day
Period 1 (VES)
Period 2 (VES + RFB)
Study 
Procedure
Screeninga
−1b
1
2c
3
4
5
Wash 
outd
−1b
1
2
3
4
5
6
7c
8
9
10
Follow-upe/ETf
Telephone 
contactg
FSH 
(postmenopausal 
women)p
X
Blood 
chemistryn
X
X
X
X
X
X
Calculated CLcrn
X
X
X
X
X
X
Coagulation 
panel
X
Hematologyn
X
X
X
X
X
X
Urinalysisn
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Enrollment
X
Confinemento
X
X
X
X
X
X
X
X
X
X
X
VES dosing
X
X
RFB dosing
X
X
X
X
X
X
X
X
X
Plasma VES and 
perpetrator PKr
X
X
X
X
X
X
X
X
X
X
Serum 
biomarkerss
X
X
X
X
X
X
X
X
Whole blood 
ISG mRNAt
X
X
X
X
X
X
X
X
X
X
PGx (TLR7 and 
BCRP)u
X
Immune cell 
phenotypingv
X
X
X
X
X
X
X
X
TruCulture 
cytokine 
responsew
X


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ART = antiretroviral therapy; BCRP = breast cancer resistance protein; CD4 = clusters of differentiation 4; CLcr = creatinine clearance; CRS = cytokine release syndrome; 
ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; HBsAg = hepatitis B virus surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; ISG = interferon-stimulated genes; mRNA = messenger RNA; PGx = pharmacogenetics; PK = pharmacokinetics; RFB = rifabutin; TLR7 = toll-like receptor 7; 
VES = vesatolimod
a
Prospective participants should be screened within 35 days prior to administration of the first dose of study drug.
b
Admission to clinic.
c
Discharge from clinic.
d
There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1. Participants should inform the site of any AE during the washout 
period.
e
Participants will return for an in-clinic follow-up visit 10 (± 3) days after the last dose of VES.
f
Assessments will be performed within 72 hours of ET from the study, if possible.
g
For participants assigned female at birth of childbearing potential, an at-home urine pregnancy test will be completed 10 days after the last dose of RFB. Participants will be 
contacted by telephone to report at-home pregnancy test results.
h
Collect ART history for at least the past 12 months.
i
Every day during confinement, as needed, based on reported signs and symptoms. 
j
Vital signs include blood pressure, heart rate, oxygen saturation, and body temperature. Vital signs will be collected at predose (within 1 hour before VES dosing) and 2, 4, 8, 
12, and 24 hours after each dose of VES.
k
12-lead ECGs will be collected after the participant has rested for at least 5 minutes in the supine position. A 12-lead ECG will be collected 2 hours after each dose of VES.
l
HBV core antibody, HBsAg, and HCV antibody at screening.
m
COVID-19 testing in accordance with the local guidelines will be conducted and reviewed per site-specific policy at admission (Day −1) and as needed prior to the next 
scheduled test based upon symptoms. Termination of the cohort for any positive viral test result will be at the discretion of the sponsor and the investigator.
n
On Day −1 (admission), 2 sets of safety laboratory results for hematology, chemistry, urinalysis, urine drug, and alcohol assessments will be collected upon study center 
admission. One will be sent to the central laboratory and the other will be sent to the site’s local laboratory to obtain results in time for enrollment on Day 1. If a study center 
cannot perform a urine alcohol test or receive results from the local laboratory in time for enrollment on Day 1, then an alcohol breathalyzer test is acceptable. 
o
For participants assigned female at birth and of childbearing potential. Serum pregnancy test is required at screening. Serum or urine pregnancy test at Day −1 of each period 
is acceptable. Pregnancy test result is required prior to dosing. If Day −1 serum pregnancy test result is not available, a negative urine pregnancy test (performed locally) is 
required. Urine pregnancy testing is repeated at the follow-up visit and ET visit, if applicable. 
p
For participants assigned female at birth who are younger than 54 years, not on hormonal contraception, and who have stopped menstruating for at least 12 months but do not 
have documentation of ovarian hormonal failure.
q
In Period 1, participants will be confined beginning Day −1 until completion of assessments on Day 2. In Period 2, participants will be confined beginning on Day -1 until 
completion of assessments on Day 7. Participants may remain confined for a longer duration within each treatment period if this is preferred. If a participant is experiencing 
signs and symptoms of CRS, the participant will remain confined (for CRS symptoms of Grade 1) or immediately be transferred to a hospital or emergency department 
(for CRS symptoms of ≥ Grade 2) until symptoms resolve.
r
VES and perpetrator PK samples will be collected at predose (within 0.5 hours before dosing) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 96 hours after each 
dose of VES. Time windows allowed for PK samples to be collected are provided in Table 8.
s
Serum biomarker samples will be collected at predose (within 0.5 hours before dosing) and 4, 8, 12, 24, 48, and 96 hours after each dose of VES. A time window of ± 10% 
will be allowed for biomarker samples collected through 8 hours postdose. Biomarker samples collected beyond 8 hours postdose will have a ± 30-minute window.
t
Whole blood samples for ISG mRNA expression and transcriptional profile will be collected predose (within 0.5 hours before dosing) and 8, 12, 24, 48, 72, and 96 hours 
postdose relative to VES. A time window of ± 10% will be allowed for whole blood samples collected at 8 hours postdose. Whole blood samples collected beyond 8 hours 
postdose will have a ± 30-minute window.
u
A PGx sample will be collected on Day 1 (preferably) or at any other time during the study.
v
Whole blood sample for immune cell phenotyping will be collected predose (within 0.5 hours before dosing), and 24, 72, and 96 hours postdose relative to VES. Whole blood 
samples collected postdose will have a ± 30 minute window.


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w
Whole blood sample for TruCulture cytokine response will be collected on Period 1 Day 1 (predose).
All clinical and clinically significant laboratory toxicities will be managed according to uniform guidelines detailed in protocol Appendix 11.4.


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus type-1 (HIV-1) infection is a life-threatening and serious 
disease that is of major public health interest around the world. A 2021 report by the 
Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that 79.3 million people 
have been infected with HIV since the start of the epidemic, contributing to 36.3 million deaths 
from AIDS-related illnesses {Joint United Nations Programme on HIV/AIDS (UNAIDS) 2021}. 
Untreated infection leads to deterioration in immune function and death. Although antiretroviral 
therapy (ART) has been associated with a dramatic decrease in AIDS-related morbidity and 
mortality {Mocroft 1998, Palella 1998, Sterne 2005}, there is still an urgent medical need to 
develop new therapies and approaches to eradicate HIV. Current therapy is associated with 
challenges with tolerability, long-term adherence and safety, drug-drug interactions, and 
expense. Persistent HIV infection may also be associated with psychosocial stigma. Despite the 
availability of chronic treatment, morbidity and mortality due to HIV infection remain high due 
to the persistence of a latent HIV reservoir, which may contribute to ongoing 
inflammation-driven disease. Persistent viral reservoirs fuel rebound viremia when treatment 
ceases. Thus, the discovery and development of therapeutic interventions that can eradicate or 
control HIV reservoirs, leading to long-term ART-free remission or HIV cure, is a major 
priority.
The innate immune response modulates the production of type I interferons 
(IFNs; eg, interferon-alpha [IFN-α]) and promotes the cross-priming of cytotoxic T lymphocytes, 
resulting in an efficient immune response {Iwasaki 2010, Knolle 2012}. A key innate immune 
effector cell is the plasmacytoid dendritic cell (pDC) that expresses toll-like receptor 7 (TLR7). 
Following TLR7 stimulation, pDCs produce type I IFNs, resulting in increased transcription of 
interferon-stimulated genes (ISG), many of which have antiviral activity {Sadler 2008}. TLR7 
stimulation also activates pDCs, monocytes, natural killer cells, and CD4 and CD8 T cells 
{Riddler 2020, SenGupta 2021, Tel 2013}. Finally, TLR7 is expressed by B lymphocytes, and 
TLR7 activation results in polyclonal expansion and differentiation towards 
immunoglobulin-producing plasma cells, providing a humoral component to the adaptive 
immune response {Bekeredjian-Ding 2005}.
During HIV-1 infection, levels of IFN-α and ISG messenger RNA (mRNA) increase, which is 
consistent with TLR7 stimulation; B cell and CD8 T-cell responses to virus are also detected in 
most individuals with HIV-1. However, in most cases, these immune responses are not sufficient 
to control the infection without ART. Activation of TLR7 can generate a variety of effects and 
enhance innate and adaptive immunity that may provide a novel treatment paradigm for people 
with HIV-1 infection.
Vesatolimod (VES) is a TLR7 agonist currently in clinical development for the treatment and 
remission of HIV-1 infection. Vesatolimod has been shown to induce ISG mRNA expression and 
production of cytokines and chemokines, and to induce activation of CD4 and CD8 T 
lymphocytes in HIV-1-infected individuals (virologically suppressed on ART). The ability of 


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VES to increase the cytotoxic activity of HIV-specific T lymphocytes and activate phagocytic 
cells, improving antibody-dependent cell-mediated cytotoxicity in vitro, suggests that its 
immunomodulatory effect could enhance the antiviral activity of HIV-1 broadly neutralizing 
antibodies (bNAbs). In fact, in rhesus macaque studies, sequential regimens including TLR7 
agonists and either therapeutic vaccination or bNAbs have led to simian-human 
immunodeficiency virus ART-free viral control {Borducchi 2016, Borducchi 2018}. Similar 
results have now been demonstrated in a chronically-infected nonhuman primate model 
{Mercado 2020}.
Vesatolimod is a substrate of cytochrome P450 enzyme (CYP)3A, P-glycoprotein (P-gp), and 
breast cancer resistance protein (BCRP). This study will evaluate the impact of cobicistat (COBI) 
(P-gp, BCRP, and strong CYP3A inhibitor), voriconazole (VOR) (strong CYP3A inhibitor), and 
rifabutin (RFB) (moderate CYP3A inducer) on the pharmacokinetics (PK) and 
pharmacodynamics (PD) of VES as well as the safety in virologically suppressed adults with 
HIV-1 on ART to inform future studies of VES.
1.2.
Background on Study Interventions
1.2.1.
Vesatolimod
1.2.1.1.
General Information
Vesatolimod is an orally administered TLR7 agonist in development for the treatment and 
remission of HIV infection. Data in vitro have shown that VES is a potent and selective TLR7 
receptor agonist with greater than 30-fold selectivity for TLR7 (32-fold based on half-maximal 
effective concentration and 81-fold based on minimum effective concentration) over TLR8, with 
no detectable stimulation of other human toll-like receptors at concentrations up to 100 μM.
For further information on VES, refer to the investigator’s brochure (IB), including information 
on the following:

Nonclinical PK and in vitro metabolism

Nonclinical pharmacology and toxicology

Clinical experience
1.2.1.2.
Nonclinical Pharmacokinetics and Drug Interaction Potential
High systemic clearance of VES was observed in the mouse, rat, dog, and monkey. Plasma 
protein binding in human plasma is 81.5%. Metabolism is the main route of elimination for VES, 
and CYP3A is the enzyme predominantly responsible for VES metabolism. When tested in 
human hepatic microsomes, ketoconazole (a CYP3A-selective inhibitor) had the largest effect on 
the metabolism of VES (90% inhibition). Based on in vitro assays, VES is also a substrate of 
P-gp and BCRP. Therefore, VES concentrations may be altered in the presence of concomitant 
medications that inhibit or induce these drug metabolizing enzymes and transporters. 


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Vesatolimod is not a perpetrator of drug interactions; based on in vitro studies, VES is not 
predicted to be a clinically relevant inhibitor of the transporters P-gp, BCRP, organic anion 
transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, 
organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion 1, bile salt export 
pump, multidrug resistance-associated protein, or the drug metabolizing enzymes CYP1A2, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and was not an inducer of the 
acetylcholine receptor or the constitutive androstane receptor.
1.2.1.3.
Clinical Studies of Vesatolimod in People With HIV-1
Safety data from 2 Phase 1b Studies GS-US-382-1450 and GS-US-382-3961 suggest that VES is 
generally well tolerated in people with HIV-1 (PWH) on ART who received multiple doses up to 
12 mg each. The most common drug-related treatment-emergent adverse events (TEAEs) were 
flu-like symptoms such as pyrexia, chills, headache, myalgia, and fatigue. The majority of 
adverse events (AEs) were Grade 1 or 2. Few serious adverse events (SAEs) or Grade 3 to 4 AEs 
were observed. Grade 3 events included gastritis viral, gout, arthralgia, and sciatica (all observed 
in 1 participant) and lower abdominal pain. Serious adverse events included chronic gastritis 
(1 participant) and diverticulitis (1 participant, concurrent with the lower abdominal pain Grade 3 
AE mentioned above).
Pharmacokinetic assessments for VES showed that AUClast, AUCinf, and Cmax increased across 
the dose range of 1 to 12 mg in PWH (Table 4). Across doses, median Tmax was 1.0 to 3.0 hours 
and t1/2 was 9 to 19 hours. As no accumulation of VES is anticipated based on the observed 
half-life, the PK parameters observed after the first dose are representative of chronic exposure 
following every other week dosing.
Table 4.
Summary of Vesatolimod Pharmacokinetic Parameters
(Study GS-US-382-1450)
VES Dose
PK 
Parameter
1 mg
2 mg
4 mg
6 mg
8 mg
10 mg
12 mg
AUCinf
(h*pg/mL)
4573.9
(78.5)
9938.7 
(40.2)
27,402.1 
(69.6)
44,078.1 
(76.0)
50,971.5 
(88.6)
62,872.1 
(78.0)
101,112.8 
(49.3)
AUClast
(h*pg/mL)
2757.8
(70.1)
7736.5 
(55.5)
21,774.9 
(80.0)
38,196.1 
(73.7)
44,930.4 
(82.0)
57,341.9 
(77.1)
94,339.6 
(49.8)
Cmax 
(pg/mL)
461.0
(72.5)
972.8
(38.9)
1990.3
(62.1)
3088.3
(66.3)
6680.0 
(120.4)
5833.3
(71.7)
11,988.3 
(71.5)
Tmax (h)
1.50 
(1.00, 4.00)
1.75 
(0.50, 4.00)
1.00 
(1.00, 2.00)
2.00 
(1.00, 4.00)
1.00 
(1.00, 2.00)
2.01
(2.00, 3.97)
3.00 
(2.00, 4.00)
t1/2 (h)
9.29 
(7.98, 12.15)
14.65 
(8.37, 20.15)
19.21 
(14.14, 24.04)
17.37 
(16.25, 18.41)
12.03 
(10.86, 15.30)
14.44 
(13.36, 15.19)
13.47
(12.38, 15.78)
Data are presented as mean (%CV), except for Tmax and t1/2, which are presented as median (Q1, Q3).


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1.2.2.
Cobicistat
Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or 
darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the 
treatment of HIV-1 infection in adults. Cobicistat is also coformulated with ARTs, such as 
elvitegravir + nucleoside reverse transcriptase inhibitors (NRTIs). The recommended dosage of 
COBI in adults is 150 mg orally once daily.
In adults the most common adverse reactions (Grades 2 to 4) and reported in more than 2% of 
participants in the COBI group (N = 344) were jaundice (6%), rash (5%), ocular icterus (4%), 
nausea, diarrhea, and headache (2% each). The proportion of participants who discontinued 
study drug due to AEs, regardless of severity, was 11% in the COBI group.
Cobicistat causes increases in serum creatinine and decreases in estimated creatinine clearance 
due to inhibition of tubular secretion without affecting actual renal glomerular function. The 
most common Grade 3 or 4 laboratory abnormality (incidence ≥ 10%) in the COBI group was 
increased total bilirubin (> 2.5  upper limit of normal [ULN]; 73%).
For further information on COBI, refer to the United States (US) prescribing information for 
Tybost (COBI) {TYBOST 2021}.
1.2.3.
Voriconazole
Voriconazole is a synthetic broad-spectrum antifungal agent for use in the treatment of systemic 
fungal infections such as invasive aspergillosis, candidemia, disseminated candidiasis in skin, 
oral thrush, and serious infections caused by Scedosporium apiospermum and Fusarium species. 
The recommended oral maintenance dose in adults is 200 mg every 12 hours. In adults 
(N = 1655), the most common adverse reactions (incidence ≥ 2%) in clinical studies were visual 
disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), 
headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), and hallucinations 
(2.4%). The adverse reactions which most often led to discontinuation of VOR were elevated 
liver function tests, rash, and visual disturbances.
Voriconazole is a strong inhibitor of CYP3A and also inhibits CYP2C19 and CYP2C9; it’s 
major metabolite also inhibits the metabolic activity of CYP450 enzymes and therefore, there is 
potential for VOR and its major metabolite to increase the systemic exposure of other drugs 
metabolized by these CYP450 enzymes.
For further information on VOR, refer to the US prescribing information for VFEND (VOR) 
{VFEND® 2021}.


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1.2.4.
Rifabutin
Rifabutin is a rifamycin antimycobacterial agent indicated for the prevention of disseminated 
Mycobacterium avium complex disease in people with advanced HIV infection. The 
recommended dose in adults is 300 mg once daily. In adults (N = 566), the most common AEs 
(incidence ≥ 2%) in clinical studies were discolored urine (30%), rash (11%), leucopenia (10%), 
nausea (6%), abdominal pain (4%), diarrhea, dyspepsia, eructation, headache, nausea and 
vomiting, and taste perversion (3% each), and anorexia, fever, flatulence, and myalgia 
(2% each). Primary reasons for discontinuation of rifabutin in clinical studies were rash (4%), 
gastrointestinal intolerance (3%), and neutropenia (2%).
Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs 
metabolized by those enzymes.
For further information on RFB, refer to the US prescribing information for Mycobutin (RFB) 
{MYCOBUTIN® 2021}.
1.3.
Rationale for This Study
Vesatolimod is a substrate of P-gp, BCRP, and CYP3A. Vesatolimod exposure is expected to 
increase when coadministered with P-gp, BCRP, and/or CYP3A inhibitors and to decrease when 
coadministered with inducers. Therefore, this study will evaluate the impact of 3 perpetrator 
drugs on the PK of VES.
Cohort 1 - Period 2: Cobicistat (COBI)

Cobicistat is a common component of ART and is a P-gp, BCRP, and strong CYP3A 
inhibitor and expected to be a worst-case perpetrator for inhibition
Cohort 1 - Period 3: Voriconazole (VOR)

Voriconazole is a strong CYP3A inhibitor that does not inhibit P-gp or BCRP
Cohort 2 – Period 2: Rifabutin (RFB)

Rifabutin is a moderate CYP3A inducer
Comparing results of Cohort 1 and Cohort 2 may provide information regarding the relative 
importance of transporters and drug metabolizing enzymes for VES disposition. All cohorts will 
be evaluated in an open-label design, which is appropriate because the primary endpoint is an 
objective measure of VES PK.
The open-label, single sequence study design of Cohorts 1 and 2 allows for the within-participant 
comparison of VES PK when administered alone and in combination with the perpetrator of drug 
interaction. The within-participant design minimizes the impact of factors other than the 
interacting drug on VES PK.


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Cohort 1: The ART regimens permitted in Cohort 1 (bictegravir [BIC], dolutegravir [DTG], 
raltegravir [RAL], or doravirine [DOR] + NRTIs) were selected because these ARTs are not 
expected to impact VES PK and because the impact of COBI and VOR on the ART 
concentrations are not expected to be clinically meaningful based on drug interaction data in the 
prescribing information for these medications. Because VOR has been associated with QT 
prolongation, other drugs with the potential for QT prolongation (such as rilpivirine) are not 
permitted in Cohort 1.
Cohort 2: The ART regimens permitted in Cohort 2 (DTG/abacavir [ABC]/lamivudine [3TC], 
DTG/3TC, or DTG + NRTIs) were selected because these ARTs are not expected to impact VES 
PK and because the impact of RFB on these ART concentrations are not expected to be clinically 
meaningful based on drug interaction data in the prescribing information for these medications. 
1.4.
Rationale for the Dose Selection of Study Drugs
Cohort 1: Increases in VES exposure are expected when VES is coadministered with strong 
CYP3A inhibitors in Period 2 (COBI) and Period 3 (VOR). Based on physiologically based 
pharmacokinetic (PBPK) modeling, a VES dose of 2 mg, in combination with COBI or VOR, is 
predicted to achieve VES AUC in the range of those achieved with a therapeutic dose of VES 
(6 to 8 mg) in the absence of an inhibitor. The Cmax value for the 2 mg dose of VES in 
combination with COBI or VOR is predicted to be below Cmax for single 6 mg and 8 mg doses of 
VES in the absence of an inhibitor. Therefore, a dose of VES 2 mg has been selected for 
Cohort 1. As COBI (which also inhibits P-gp) will be dosed before VOR in Cohort 1 and inhibits 
CYP3A in a similar mechanism and magnitude to VOR, the sentinel group of participants 
evaluating the COBI + VES combination will mitigate the risk of overexposure to VES when 
dosed with VOR.
Cobicistat will be administered at the approved dose of 150 mg once daily, for the treatment of 
HIV-1 infection in adults starting on the day prior to VES administration and continuing through 
the duration of PK sampling. Based on literature and PBPK modeling, this COBI regimen is 
expected to provide near maximal inhibition of CYP3A {Mathias 2010}.
Voriconazole will be administered as a loading dose of 400 mg twice daily, then as 200 mg twice 
daily which are the approved loading and maintenance doses for adults weighing 40 kg or more. 
Voriconazole dosing will start 2 days prior to VES administration and continue through the 
duration of PK sampling. Based on literature and PBPK modeling, this VOR regimen is expected 
to provide near maximal inhibition of CYP3A {Katzenmaier 2011}.
Cohort 2: A therapeutic dose of VES 6 mg has been selected to allow accurate assessment of PK 
changes with an inducer, which is expected to decrease VES concentrations.
Rifabutin will be administered at the approved dose in adults of 300 mg once daily starting 
5 days prior to VES administration and continuing through to 3 days after. 


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1.5.
Risk/Benefit Assessment for the Study
Potential risks of a participant’s study involvement include unknown AEs, general risks 
associated with frequent clinic visits and laboratory blood draws. Based on the current available 
clinical data, potential risks associated with VES include transient influenza-like symptoms, such 
as chills, pyrexia, aches, and headache and cytokine release syndrome (CRS). In completed and 
ongoing studies of VES, the majority of the influenza-like symptoms have been mild (302 of 
387 flu-like AEs, 78.0%) and transient. One healthy volunteer who received 1 dose of VES 8 mg 
coadministered with elipovimab (an HIV-1 bNAb) 250 mg experienced a Grade 3 SAE) of CRS 
that was considered related to VES, leading to treatment and observation in the hospital followed 
by full recovery. The other 3 healthy volunteers receiving this regimen did not experience SAEs. 
At the 12 mg dose level of VES in healthy volunteers (Study GS-US-243-0101), nongraded 
nonclinically significant decreases in platelet counts were observed in some participants, which 
resolved within 2 days without intervention. Treatment-emergent platelet decreases have not 
been observed at doses up to 12 mg in PWH in Study GS-US-382-1450 or in 
Study GS-US-382-3961. Safety laboratory values, including complete blood count and chemistry 
panels, will be regularly monitored throughout the study.
Strategies to mitigate these risks include close monitoring of participants’ clinical status, 
laboratory values, and AEs. Parameters for discontinuation of the study drug due to AEs will be 
well defined and closely followed.
There is no direct benefit to participants in this study; however, data from this study will support 
the development of VES.
An infectious disease pandemic may pose additional risks to study drug availability, study visit 
schedule, and adherence to protocol-specified safety monitoring or laboratory assessments. Refer 
to Appendix 11.2 for further details on the risks and risk mitigation strategy.
1.6.
Compliance
This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.


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2_ 
OBJECTIVES AND ENDPOINTS 
Primary Objective(s) 
To evaluate the impact of the following drugs on VES PK 
• 
Cobicistat (P-gp, BCRP, and strong CYP3A inhibitor) 
• 
Voriconazole (strong CYP3A inhibitor) 
• 
Rifabutin (moderate CYP3A inducer) 
To evaluate the safety ofVES administered alone and in 
combination with inhibitors and inducers of metabolizing 
enzymes and transpo1ters involved in VES disposition 
---
CONFIDENTIAL 
Page 35 
Primary Endpoint(s) 
Prima1y PK parameters throughout the study 
• 
VES AUC1as1, AUCinf, Cmax 
Secondary PK parameters throughout the study 
• 
VES %AUCexp, Tmax, C1as1, Ttast, 'A,,, t112, 
CL/F, V/F 
Safety parameters 
• 
Incidence ofTEAEs and laboratory 
abno1malities throughout the study 
I 
I 
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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes an open-label, multicohort Phase 1 study to evaluate the impact of 
inhibitors and inducers of CYP3A and/or P-gp on the PK and PD of VES in virologically 
suppressed adults with HIV-1 on ART. Approximately 45 participants will be enrolled. An 
overview of the study design is described below and shown in Figure 1.
The study will be conducted in 2 cohorts:

Cohort 1: An open-label, single sequence cohort to evaluate the impact of COBI (P-gp, 
BCRP, and strong CYP3A inhibitor) and VOR (strong CYP3A inhibitor) on VES PK and PD

Cohort 2: An open-label, single sequence cohort to evaluate the impact of RFB (moderate 
CYP3A inducer) on VES PK and PD
3.1.1.
Safety Review Team and Charter
A safety review team (SRT) will be established to assess relevant and available safety data for 
the first 3 participants in Cohort 1 who are dosed with COBI (up to and including Period 2 
Day 3) to decide to continue or halt enrollment of additional participants in Cohort 1.
An SRT charter defining the team membership, meeting conduct, and decision-making process 
will be agreed upon by all team members before the first meeting. The data reviewed at the team 
meetings will be defined in the charter. The quality control checks performed on the data 
reviewed will also be described in the charter.
Source data verification may not be performed before SRT meetings. Alternative data quality 
control checks that are performed on data are described in the SRT charter (or similar document).
3.2.
Duration of Dosing 
Duration of dosing for each cohort is as follows:

Cohort 1: VES will be administered as a single dose in Periods 1, 2, and 3; COBI will be 
administered for 5 days in Period 2; and VOR will be administered for 6 days in Period 3. 
There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and 
Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 
and Period 3 Day 1.

Cohort 2: VES will be administered as a single dose in Periods 1 and 2; and RFB will be 
administered for 9 days in Period 2. There will be a washout period of 7 to 14 days between 
treatments in Period 1 Day 1 and Period 2 Day 1.


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3.3.
Protocol-Specific Discontinuation Criteria 
Conduct of the study will be governed by participant withdrawal criteria and study-specific 
stopping criteria.
Study drug and/or study procedures may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

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 
to not be in the participant’s best interest

Participant request to discontinue for any reason

Participant noncompliance

Pregnancy during the study; refer to Appendix 11.3

Discontinuation of the study at the request of Gilead Sciences (Gilead), a regulatory agency, 
or an institutional review board (IRB) 

Participant receives study drug(s) and experiences 1 or more AEs or laboratory abnormalities 
as follows:

Grade 2 or higher CRS, judged by the investigator as at least possibly related to study 
drug, OR
Grade 3 or higher TEAE (including new finding of splenomegaly, mucosal petechiae or 
purpura on physical examination) judged by the investigator as at least possibly related to 
study drug, OR
Grade 3 or higher confirmed laboratory abnormality (including a confirmed significant 
drop in platelets to < 50  109/L and/or confirmed drop of 50% from baseline), unless 
there is a clear and obvious physiologic explanation for the events (eg, blood in urine 
occurring in a menstruating female, creatine kinase [CK] elevation after strenuous 
exercise, or triglyceride elevation that is nonfasting) judged by the investigators as at 
least possibly related to study drug, OR
A persistent (≥ 72 hours) Grade 2 or higher pyrexia considered related to study drug by 
the investigator, OR
Any SAE considered at least possibly related to study drug


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3.3.1.
Criteria for Early Discontinuation of an Individual Cohort
Study drug dosing of a cohort will be suspended when:

2 or more participants in a cohort experience a treatment-emergent, drug-related Grade 3 or 
higher clinical AE with the same medically similar preferred term (with the exception of 
headache or nausea)

2 or more participants in a cohort experience treatment-emergent, drug-related SAEs with the 
same medically similar preferred terms

2 or more participants in a cohort experience confirmed treatment-emergent, drug-related 
Grade 3 or higher clinically significant laboratory abnormality (with the exception of 
clinically insignificant Grade 3 or 4 cholesterol, triglyceride, glucose, CK elevations, 
or bilirubin abnormalities)

The number and/or severity of AEs justifies discontinuation of the study

The sponsor unilaterally requests it
If 2 or more participants in any cohort experience the same or similar SAE, Grade 3 or 4 TEAE 
or confirmed laboratory abnormality, unless there is a clear and obvious physiologic explanation 
for the events (eg, blood in urine due to menses, CK elevation after strenuous exercise, 
nonfasting triglyceride elevations), a review of all safety data generated in participants dosed to 
date will be initiated.
Decisions to reinitiate the cohort will be made in consultation with the sponsor and pending a 
safety review. In the event of a participant death, safety reports will be submitted to the 
appropriate regulatory authority for review and approval prior to reinitiating the cohort.
3.3.2.
Loss to Follow-Up
Should the participant fail to return to the study site for a scheduled protocol-specified visit, the 
site will need to make multiple attempts by a combination of telephone calls and certified letters 
to contact the participant. The site must document all attempts to contact the participant. If a 
participant does not respond within 1 month after the missed protocol-specific visit, the 
participant will be considered lost to follow-up and no additional contact will be required.
3.4.
Clinic Confinement
Following screening and admission assessments, eligible participants will be confined to the 
study site as follows:

Cohort 1: 
— In Period 1, participants will be confined beginning Day −1 until completion of assessments 
on Day 2. 
— In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 3. 
— In Period 3, participants will be confined beginning on Day −1 until completion of 
assessments on Day 4. 


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
Cohort 2: 
— In Period 1, participants will be confined beginning on Day −1 until completion of 
assessments on Day 2. 
— In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 7.
Participants may remain confined for a longer duration within each treatment period if this is 
preferred by the principal investigator (PI).
If a participant is experiencing signs and symptoms of CRS (see toxicity management 
Section 7.7), the participant will remain confined (for CRS symptoms of Grade 1) or 
immediately be transferred to a hospital or emergency department (for CRS symptoms of 
≥ Grade 2) until symptoms resolve.
Participants will return 10 ± 3 days after the last dose of VES for an in-clinic follow-up visit.
3.5.
Definitions for Time of Primary Endpoint and End of Study
3.5.1.
Primary Endpoint
The date for the last participant last visit for the primary endpoint is the date of the last visit to 
perform assessments for the primary analysis.
3.5.2.
End of Study
The end of this study will be the last participant’s last observation (or visit).
3.6.
Source Data
The source data for this study will be obtained from local laboratory and/or specialty laboratory 
(for PK and PD data).


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection
Approximately 45 unique participants will be enrolled in the study. The study population will 
include male and nonpregnant, nonlactating female, virologically suppressed adults with HIV-1 
on ART. 
4.1.1.
Participant Replacement
If necessary, replacement participants may be enrolled after discussion and approval from Gilead 
if participants do not complete all intensive PK procedures or the participant is considered 
nonevaluable. Replacement participants will not be enrolled for participants who discontinue the 
study due to study drug-related AEs.
4.2.
Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Have the ability to understand and sign a written informed consent form (ICF), which must 
be obtained prior to initiation of study procedures
2) Males or nonpregnant, nonlactating females with HIV-1 aged at least 18 years
3) Be either a non-smoker/non-nicotine product user, or a smoker/nicotine product user who 
does not intend to change their pattern of use during the study
4) On an ART regimen for at least 6 consecutive months, with no change in the ART regimen 
within 2 months prior to screening. Permitted ART regimens are as follows:
Cohort 1: A regimen of (BIC, DTG, RAL, or DOR) plus NRTIs. Examples of acceptable 
regimens include BIC/emtricitabine/tenofovir, DTG/ABC/3TC, DTG/3TC, DTG + 
emtricitabine/tenofovir, or DOR/3TC/tenofovir
Cohort 2: A DTG-based regimen is required (DTG/ABC/3TC), (DTG/3TC), or (DTG + 
NRTIs)
5) Plasma HIV-1 RNA levels less than 50 copies/mL at screening.
6) Documented plasma HIV-1 RNA < 50 copies/mL for at least 6 months prior to the screening 
visit:
a) Using all available viral load determinations for at least 6 consecutive months prior to the 
screening visit, HIV-1 RNA viral load must be below the limit of detection 
(50 copies/mL). 
b) A single isolated blip (defined as plasma HIV-1 RNA higher than the limit of 
quantification but < 200 copies/mL followed by a subsequent value below the limit of 
quantification) is allowed in the 6 months prior to screening.


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7) Have normal hematologic function with an absolute neutrophil count greater than or equal 
to 1.5 × 109/L, platelets greater than or equal to 150 × 109/L; hemoglobin greater than or 
equal to 10.5 g/dL for females and greater than or equal to 11.5 g/dL for males
8) CD4 T cell count greater than or equal to 350 cells/μL
9) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 
2.5  ULN and total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin and 
creatinine less than or equal to 1.25  ULN
10) Have a calculated creatinine clearance (CLcr) of at least 60 mL/min (using the 
Cockcroft-Gault method {Cockcroft 1976}) based on serum creatinine and actual body 
weight as measured at screening and upon admission:
Assigned male at birth:
(140 – Age [years])  (Weight [kg])  CLcr (mL/min)
72  (Serum Creatinine [mg/dL])
Assigned female at birth:
(140 – Age [years])  (Weight [kg])  0.85  CLcr (mL/min)
72  (Serum Creatinine [mg/dL])
11) Participants assigned female at birth and of childbearing potential and males at birth who 
engage in heterosexual intercourse must agree to use protocol-specified method(s) of 
contraception as described in Appendix 11.3 
12) Must be willing and able to comply with all study requirements and available to complete the 
study schedule of assessments
13) In the judgment of the investigator, be in good general health, based on review of the results 
from a screening visit (to include physical examination, measurement of vital signs, resting 
12-lead electrocardiogram [ECG], and routine clinical laboratory testing), performed no more 
than 35 days prior to first study drug administration
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria will not be enrolled in this study:
1) Have received any study drug within 30 days prior to study dosing
2) Participation in any other clinical study (including observation studies) without prior 
approval from the sponsor is prohibited while participating in this study
3) Have current alcohol or substance abuse judged by the investigator to potentially interfere 
with participant compliance or participant safety, or a positive drug or alcohol test at 
screening or baseline
4) Evidence of chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface 
antigen [HBsAg] and/or positive HBV core antibody with positive reflex HBV DNA 
polymerase chain reaction [PCR]). Note: positive HBV core antibody with negative reflex 
HBV DNA PCR results are acceptable.


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5) Evidence of active hepatitis C virus (HCV) infection (defined as positive hepatitis C antibody 
and HCV RNA above lower limit of quantitation). Note: positive anti-HCV antibody and 
negative HCV PCR results are acceptable.
6) Have poor venous access that limits phlebotomy
7) Acute febrile illness within 35 days prior to Day 1
8) Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic 
agents within 3 months prior to screening or is expected to receive these agents during the 
study (eg, corticosteroids, immunoglobulins, other immune- or cytokine-based therapies)
9) Received any vaccine or immunomodulatory medication within 4 weeks prior to screening. 
Elective vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study 
will require prior approval from the sponsor
a) COVID-19 vaccinations are allowed, with the requirement that they should not be 
administered within 7 ± 2 days of receiving VES
10) Have a history of any of the following:
Significant serious skin disease, such as but not limited to rash, food allergy, eczema, 
psoriasis, or urticaria
Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients 
(see Section 5)
Autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, inflammatory, bowel 
disease, sarcoidosis, moderate or severe psoriasis)
Significant cardiac disease (including history of myocardial infarction based on ECG 
and/or clinical history, any history of ventricular tachycardia, congestive heart failure, 
or dilated cardiomyopathy with left ventricular ejection fraction ≤ 40%); or a family 
history of long QT syndrome, or unexplained death in an otherwise healthy individual 
between the ages of 1 and 30 years
Syncope, palpitations, or unexplained dizziness
Implanted defibrillator or pacemaker
Liver disease, including Gilbert syndrome
Severe peptic ulcer disease requiring prolonged (≥ 6 months) medical treatment
Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or 
intestinal surgery). A history of cholecystectomy is not exclusionary


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11) Have any serious or active medical or psychiatric illness (including depression) that, in the 
opinion of the investigator, would interfere with participant treatment, assessment, or 
compliance with the protocol. This would include renal, cardiac, hematological, hepatic, 
pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, 
gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders other than HIV-1 infection, active infection, or malignancy that 
are clinically significant or requiring treatment
12) Requirement for ongoing therapy with or use (within 14 days prior to study drug 
administration) of any prohibited medications listed in Section 5.7.1
13) For Cohort 1, participant with CYP2C19 genotype of CYP2C19*2/*2, CYP2C19*2/*3, 
or CYP2C19*3/*3
14) Have any of the following ECG abnormalities at screening: QRS more than 
120 milliseconds; heart rate less than 45 beats per minute; second or third degree heart block; 
prolongation of QTcF interval (eg, a prolongation of the QTcF interval of greater than 
450 milliseconds for males and more than 470 milliseconds for females); or PR interval more 
than 200 milliseconds


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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Enrollment, Blinding, and Treatment Code Access
5.1.1.
Enrollment
At screening, study participants will be assigned a screening number at the time of consent and 
they will be assigned to Cohort 1 or 2. Once eligibility has been confirmed following completion 
of the admission study procedures, participants will be enrolled and assigned a unique participant 
number using an interactive response technology. 
All screening and admission (Day −1) tests and procedures must be completed and reviewed by 
the investigator prior to the administration of the first dose of study drug on Day 1. It is the 
responsibility of the investigator to ensure that the participant is eligible for the study prior to 
enrollment. Once a participant number has been assigned to a participant, it will not be 
reassigned to another participant. If necessary, replacement participants may be enrolled after 
discussion and approval from the sponsor. A new unique participant number will be assigned to 
the replacement participant.
5.1.2.
Blinding 
Blinding to treatment assignments or data will not be performed in this study.
5.2.
Description and Handling of Vesatolimod 
5.2.1.
Formulation
Vesatolimod 2 mg strength tablets are round, biconvex, plain-faced, white, and film-coated. 
Vesatolimod tablets contain the following inactive ingredients: lactose anhydrous, 
microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, and titanium dioxide.
5.2.2.
Packaging and Labeling
Vesatolimod tablets are packaged in white, high-density polyethylene bottles. Each bottle 
contains 3 tablets of 2 mg strength, silica gel desiccant, and polyester packing material. Each 
bottle is capped with a child-resistant polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
Study drugs to be distributed to US centers will be labeled to meet applicable requirements of the 
US Food and Drug Adminstration (FDA) and/or other local regulations.


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5.2.3.
Storage and Handling
Vesatolimod tablets should be stored at controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are 
specified on the label. Bottles are to be kept tightly closed.
Until dispensed to the participants, the study drug should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure proper product identification, the drug 
products should be stored in the containers in which they are supplied. 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 the study drug.
If the 3 tablets in a bottle are not administered at the same time, the tablets in an opened bottle 
are consumed first before opening a new bottle to minimize exposure to moisture. The cap of an 
opened bottle should be closed during storage.
5.3.
Description and Handling of Commercially Available Drugs
Commercial products of COBI, VOR, and RFB will be used for the study. Cobicistat will be 
provided as 150 mg tablets, VOR will be provided as 200 mg tablets, and RFB will be provided 
as 150 mg capsules. Further information regarding storage and handling are available in the 
prescribing information for these commercial products.
5.4.
Dosage and Administration 
Following completion of screening and admission assessments, eligible participants will receive 
treatments orally according to the cohort to which they are assigned as outlined in Table 5.
Table 5.
Treatments to be Administered in Cohorts 1 and 2
Cohort
Period 1
Period 2
Period 3
1
VES 2 mg on Day 1
COBI 150 mg once daily on Days 1 to 
5 and a single dose of VES 2 mg on 
Day 2 within 1 hour after COBI 
dosing
VOR 400 mg twice daily on Day 1, 
then VOR 200 mg twice daily on 
Days 2 to 6, and a single dose of 
VES 2 mg on Day 3 within 1 hour 
after the morning VOR dose
2
VES 6 mg on Day 1
RFB 300 mg once daily on Days 1 to 
9 and a single dose of VES 6 mg on 
Day 6 within 1 hour after RFB dosing
NA
COBI = cobicistat; NA = not applicable; RFB = rifabutin; VES = vesatolimod; VOR = voriconazole
Vesatolimod tablets are 2 mg each.


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5.5.
Fasting and Meals
All study treatments will be administered orally at approximately the same time each day relative 
to VES dosing in each period (± 1 hour) with 240 mL of water. All VES doses will be 
administered in the morning following an overnight fast (no food or drinks except water) for at 
least 8 hours. Participants will continue to fast until after collection of the 4-hour PK sample, 
relative to VES dosing. Additionally, participants will be restricted from water consumption 
from 2 hours before through 2 hours after VES dosing, except for the 240 mL given with the 
study drug. All COBI, VOR, and RFB doses will be administered on an empty stomach, defined 
as no food or drinks, except water, for at least 2 hours before and 2 hours after dosing.
5.6.
Dispensing, Accountability, and Disposal or Return of Study Drug
The investigator (or designee, eg, study site pharmacist) will acknowledge receipt of the study 
drugs (after reviewing the shipment’s content and condition) from Gilead (or designee). The 
investigator (or designee) will maintain an accurate inventory of all study drugs. Each dose of the 
study drugs administered at the study site will be administered by qualified study site staff. The 
dose of study drugs administered to participants in the clinic under the supervision of staff will 
be accurately recorded on the Study Drug Accountability form provided by Gilead (or on 
equivalent documentation maintained by the study site), which indicates the date and quantity of 
each dosage formulation dispensed to individual participants.
Gilead recommends that used and unused study drugs should be destroyed at the site. If the site 
has an appropriate standard operating procedure for study drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused study drugs 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 study drugs are 
destroyed on 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 drug. Upon study completion, copies of 
the study drug accountability records must be filed at the site. Another copy will be returned to 
Gilead. 
If the site does not have an appropriate procedural document 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.
5.7.
Concomitant Medications and Other Protocol Restrictions
5.7.1.
Concomitant Medications 
5.7.1.1.
Permitted Medications
This section describes permitted medications for use during the study. If participants are taking 
other medications, they must be reviewed with the sponsor prior to enrollment. In addition, 
if medications, other than the stated permitted medications, are needed during the study, they 
should be reviewed with the sponsor as soon as possible.


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5.7.1.1.1.
ART
See Inclusion Criteria (Section 4.2).
5.7.1.1.2.
Contraception
See Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive 
Requirements (Appendix 11.3).
5.7.1.1.3.
Other Permitted Medications
Vitamins, acetaminophen (paracetamol), aspirin, ibuprofen, antacids, famotidine, nizatidine, 
dexlansoprazole, lansoprazole, pantoprazole, rabeprazole, and short-term use of topical steroid 
(eg, hydrocortisone) and antihistamine (eg, diphenhydramine) creams are allowed during the 
study period.
Participants assigned female at birth taking hormonal contraception (oral or implant) may 
continue to use these medications during the study but must not rely solely on these methods for 
contraception (see Appendix 11.3 for additional details on contraception requirements).
There are no substantial safety data regarding the concomitant administration of the COVID-19 
vaccines and VES. Participants are allowed to receive the COVID‑19 vaccine, and study visits 
should continue as planned if vaccination occurs while the participant is on the study. A 
COVID-19 vaccination should not be administered within 7 ± 2 days of receiving VES. 
5.7.1.2.
Prohibited Medications
If participants are taking medications, other than the stated permitted medications 
(Section 5.7.1.1), they should be reviewed with the sponsor prior to enrollment. In addition, if a 
participant requires a new medication, other than the stated permitted medications, they should 
be reviewed with the sponsor as soon as possible.
The following types of medications and herbal supplements are prohibited from within 14 days 
prior to enrollment and through the follow-up visit.

Medications that could increase VES exposure through inhibition of CYP3A, P-gp, or BCRP.

Medications that could decrease VES exposure through induction of CYP3A, P-gp, or 
BCRP.

Medications that prolong the QT interval (applicable to Cohort 1 Period 3, see Table 6). 
Opioids (excluding methadone) are permitted after discussion with and approval from the 
Gilead medical monitor.

Any and all illegal or illicit drug use, including use of prescription drugs outside the care of 
the prescribing physician.

Recreational or medical cannabinoids or derivatives.


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Table 6.
Common Medications That Could Prolong QT Interval
Antibiotics
Antifungals
Antivirals
Antianginals
Antihistaminics
Antipsychotics
Quinolones
Azoles
Lopinavir
Ranolazine
Fexofenadine
Aripiprazole
Macrolides
Nelfinavir
Ivabradine
Astemizole
Chlorpromazine
Telavancin
Saquinavir
Diphenhydramine
Haloperidol
Metronidazole
Amantadine
Droperidol
Pentamidine
Atazanavir
Olanzapine
Risperidone
Thioridazine
Antidepressants
Antiemetics
Analgesics
CNS Stimulant
Antineoplastic 
Agents
Sedatives
Amitriptyline
Metoclopramide
Methadone
Dexamphetamine
Arsenic trioxide
Dexmedetomidine
Amoxapine
Domperidone
Amphetamine
Bosutinib
Chloral hydrate
Citalopram
Dolasetron
Methylphenidate
Dasatinib
Doxepin
Ondansetron
Dabrafenib
Escitalopram
Granisetron
Eribulin
Imipramine
Nilotinib
Nortriptyline
CNS = central nervous system
Immunomodulators are prohibited from 28 days prior to screening through the follow-up visit.
Systemic steroids, immunosuppressant therapies, or chemotherapeutic agents are prohibited from 
3 months prior to screening through the follow-up visit.
Prohibited medications are provided in Table 7. Participants who are taking any medications not 
specifically included as either permitted medications (Section 5.7.1.1) or prohibited medications 
(Table 7) should have their medications reviewed by the sponsor prior to enrollment. 
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Table 7.
Prohibited Medications
Drug Class
Agent(s) Disallowed
Acetyl-coenzyme A acetyltransferase inhibitor
Avasimibe
Angiotensin-converting enzyme inhibitor
Captopril
Analeptic
Modafinil, lomitapide
Angiotensin II inhibitor
Telmisartan
Anti-androgens
Apalutamide, enzalutamide
Anti-anginal
Ranolazine
Anti-arrhythmics
Amiodarone, dronedarone, quinidine
Antibiotics
Azithromycin, clarithromycin, erythromycin, nafcillin, 
telithromycin
Anticonvulsants
Carbamazepine, phenytoin, phenobarbital, 
oxcarbazepine, cenobamate
Antidepressants
Fluvoxamine, nefazodone, venlafaxine, ziprasidone, 
paroxetine
Antidiabetic
Pioglitazone
Antiepileptic
Divalproex
Antiemetics
Aprepitant, casopitant
Antifungals
Caspofungin, ketoconazole, itraconazole, voriconazole, 
posaconazole, fluconazole, clotrimazole
Antimigraine
Rimegepant
Antimycobacterials
Rifampin, rifapentine 
Beta-blockers
Carvedilol, talinolol
Calcium channel blockers
Amlodipine, diltiazem, felodipine mibefradil, 
nicardipine, nifedipine, nitrendipine, verapamil
Diuretic
Conivaptan
Endothelin receptor antagonist
Bosentan
Gonadotropin-releasing hormone receptor antagonist
Elagolix
Herbal/natural supplements
St John’s wort, echinacea, gingko, milk thistle, Chinese 
herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Histamine-2 receptor antagonists
Cimetidine, ranitidine
3-hydroxy-3-methylglutaryl-coenzyme A reductase 
inhibitor 
Atorvastatin
Immunosuppressants
Cyclosporine, rapamycin, sirolimus, tacrolimus
Proton pump inhibitors
Esomeprazole, omeprazole
Systemic corticosteroids
All agents, including dexamethasone
Systemic chemotherapeutic (antineoplastic) agents
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5.7.2.
Other Protocol Restrictions

Participants will be required to refrain from the consumption of beverages containing alcohol 
products 72 hours prior to the first dose of study drug and during the course of the study 
through the follow-up visit

Participants who are smokers/nicotine product users will be required to not change their 
pattern of use throughout the course of the study

Participants will be required to refrain from consumption of grapefruit juice, grapefruits, and 
Seville orange juice 72 hours prior to the first dose of study drug and during the course of the 
study through the end of study drug administration period

While confined at the study site, tea, coffee, chocolate, and other foods and beverages 
containing caffeine and other methyl xanthines will be prohibited on each dosing day. At all 
other times, caffeine-containing beverages and food may be served or withheld in accordance 
with normal practice at the site. Caffeine-containing beverages and food will not be restricted 
while participants are outside of the clinic

Participants will be encouraged to avoid strenuous or prolonged exercise, as well as saunas, 
steam baths, and sunbathing or other prolonged ultraviolet exposure (eg, in a tanning salon) 
from the screening evaluation until completion of the follow-up visit, as these activities are 
known to affect certain clinical laboratory test parameters (eg, CK) and will provide false 
indicators of a potentially treatment-related toxicity
Upon every admission to the clinic, each participant will be questioned as to their compliance 
with the above protocol restrictions. If a participant is unable to comply with any of the 
restrictions described above, the participant’s continued participation in the study will be 
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6_ 
STUDY ASSESSMENTS 
Final 
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The study procedures to be conducted for each paiticipant emolled in the study are presented in 
tabulai· f01m in Table 1 through Table 3 and detailed below. 
Any deviation from protocol procedures should be noted in the paiticipant's clinical chart and 
appropriate electronic case repo1t fonns (eCRFs). In addition, the sponsor should be promptly 
notified of any protocol deviations. 
The study site will not initiate dosing until the following have all been met: 
• 
The IRB or other applicable regulato1y agencies have reviewed and approved the study and 
the info1med consent document 
• 
All requested regulato1y documents have been submitted to and approved by Gilead 
• 
A master services agreement and/or study agreement is executed 
• 
The study initiation meeting has been conducted by Gilead ( or designee) 
The initiation meeting will include but is not limited to a review of the protocol, the IB, study 
drng(s), and investigator responsibilities. 
Documentation of the personally signed and dated ICF for each participant, using the 
study-specific, !RB-approved ICF, is required before initiating the screening process. 
6.1. 
Informed Consent 
Written info1med consent must be obtained from each paiticipant before initiation of any 
screening procedure. After a paiticipant has provided info1med consent, the investigator and 
other study personnel will dete1mine if the paiticipant is eligible for paiticipation in the study 
(Section 6.3.2). 
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6.2.
Participant Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
study enrollment, 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.
Once the ICF has been obtained, all screening and admission tests and assessments have been 
assessed, and study eligibility has been confirmed, participants will be enrolled to receive study 
drug on Day 1.
Participants will receive the study treatments as described in Section 5.4.
6.3.
Instructions for Study Procedures
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 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 (including washout periods [Participants should inform 
the site of any AE during the washout period]). Evaluation of AEs will occur at the visits shown 
in Table 1 through Table 3. See Section 7 for additional details.
6.3.2.
Screening Assessments
Screening laboratory assessments may be repeated once within 35 days prior to administration of 
study drug for exclusionary laboratory values if, in the PI’s opinion, 1 of the following are met: 
there is reason to believe the retest value will be within accepted parameters, if the initial value 
was deemed to be inaccurate or inconsistent with the participant’s previous result(s), if the initial 
value was generated in error (eg, mishandled sample), or there is another relevant extenuating 
circumstance. In any instance, the site should obtain approval from Gilead prior to repeating the 
laboratory assessment.
A sufficient number of participants will be screened to identify the planned number of 
participants for enrollment.
Participants should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the screening visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection the next morning.
The screening assessment will include a review of the inclusion/exclusion criteria and 
completion of all screening procedures as outlined in Table 1 and Table 3 and described in the 
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Eligible participants meeting all of the inclusion criteria and none of the exclusion criteria will be 
instructed on all protocol requirements, including the restrictions on concomitant medication 
usage and other substances as well as consumption of food or beverages containing alcohol, 
caffeine, or xanthine. Participants will be asked to arrive at the study site on Day −1 for 
admission assessments.
6.3.3.
Admission Assessments
6.3.3.1.
Admission
Participants should be instructed to fast (no food or drink, except water), starting from midnight 
(00:00) or earlier, as appropriate, on the evening prior to the admission visit to ensure an 
approximate 8-hour fast prior to the fasted blood sample collection.
Participants meeting all eligibility criteria following the screening evaluation will return to the 
site for admission assessments on Day −1. The admission evaluations and/or procedures are 
outlined in Table 1 and Table 3.
Note: On Day −1 (admission), 2 sets of safety laboratory results for hematology, chemistry, 
urinalysis, urine drug, and alcohol assessments will be collected upon study center admission. 
One will be sent to the central laboratory and the other will be sent to the site’s local laboratory 
to obtain results in time for enrollment on Day 1.
If a study center cannot perform a urine alcohol test or receive results from the local laboratory 
in time for enrollment on Day 1, then an alcohol breathalyzer test is acceptable. 
Prior to dosing on Day 1, the results of the clinical and laboratory evaluations (as described in 
Table 1 and Table 3) must be reviewed by the investigator to confirm the continued eligibility of 
each participant to participate in the study. At the time of enrollment, participants will be 
assigned a participant number as described in Section 5.1.1. Participants will remain confined to 
the study clinic for the duration as described in Section 6.3.3.2 and Table 1 through Table 3.
6.3.3.2.
Clinic Confinement
6.3.3.2.1.
Cohort 1 (With or Without COBI or VOR)
In Period 1, participants will be confined beginning Day −1 until completion of assessments on 
Day 2. In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 3. In Period 3, participants will be confined beginning on Day −1 until 
completion of assessments on Day 4.
6.3.3.2.2.
Cohort 2 (With or Without RFB)
In Period 1, participants will be confined beginning on Day −1 until completion of assessments 
on Day 2. In Period 2, participants will be confined beginning on Day −1 until completion of 
assessments on Day 7.


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6.3.4.
Check-in Assessments
Following completion of screening and Day −1 assessments, eligible participants will be 
assigned a participant number and receive study treatments as described in Section 5.4.
6.3.5.
Treatment Assessments
Study procedures and assessments are outlined in Table 1 through Table 3.
6.3.6.
Pharmacokinetic Assessments
6.3.6.1.
Plasma PK Collection
Plasma concentrations of VES will be determined and PK parameters estimated. Plasma 
concentration of COBI, VOR, and RFB may be determined and PK parameters may be 
estimated.
Intensive PK sampling time points and time windows allowed are shown in Table 8.
Table 8.
PK Sampling Time Points and Time Windows
Day
Nominal Hour (Min)
Time Window
0.25 (15 min)
± 3 min
0.5 (30 min)
± 5 min
1 (60 min)
± 10 min
1.5
± 10 min
2
± 10 min
2.5
± 10 min
3
± 10 min
4
± 10 min
6
± 30 min
8
± 30 min
1
12
± 30 min
2
24
± 30 min
3
48
± 30 min
4
72
± 30 min
5
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± 30 min


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Clinical staff should make every effort to ensure that the sampling time is as close as possible to 
the nominal time. The exact time and date of the blood draw must be recorded in the electronic 
data capture (EDC) system.
6.3.6.2.
Blood Collection for Pharmacogenetic Assessments
A blood specimen will be collected for the extraction of DNA to test for polymorphisms of genes 
that could regulate or be involved in the disposition or effects of VES, including TLR7 and 
BCRP (also known as the adenosine triphosphate-binding cassette transporter G2; gene symbol 
ABCG2). The pharmacogenetics sample should be collected on Day 1 in Period 1, before 
administration of the first dose of study drug, but may be collected at any time during the study, 
if necessary.
For Cohort 1, a sample for CYP2C19 genotyping will be collected during screening as part of the 
inclusion/exclusion criteria.
6.3.7.
Biomarker Testing
6.3.7.1.
Biomarker Samples to Address the Study Objectives 
The following biological specimens will be collected from all participants who have provided 
consent to participate in this study and may be used to evaluate the association of systemic 
and/or tissue-based biomarkers with study drug response (including efficacy and/or AEs) and 
dosage selection, and to better understand the biological pathways, biology of HIV or related 
diseases and/or the validation of a companion diagnostic for HIV cure. Because biomarker 
science is a rapidly evolving area of investigation, and AEs in particular are difficult to predict, 
it may not be possible to specify prospectively all tests that may be done on the specimens 
provided. The specific analyses will include but may not be limited to the biomarkers and assays 
listed below. The testing outlined below is based upon the current state of scientific knowledge. 
It may be modified during or after the end of study to remove tests no longer indicated and/or to 
add new tests based upon new state of the art knowledge.
The following samples will be collected relative to dosing at the time points specified in Table 1 
through Table 3:

Serum biomarkers for PD and safety assessments, which may include (but not limited to): 
IFN-α, interleukin (IL)-1 receptor antagonist, interferon gamma inducible protein-10, 
interferon-inducible T cell alpha chemoattractant, interferon-gamma, IL-1 beta, IL-6, tumor 
necrosis factor alpha, and C-reactive protein

Whole blood for ISG mRNA expression (including, but not limited to, MX1, ISG15, OAS1)

Whole blood for immune cell phenotyping

Whole blood for TruCulture cytokine response


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Clinical staff should make eve1y effo1i to ensure that the sampling time is as close as possible to 
the nominal time. The exact time and date of the blood draw must be recorded in the EDC 
system. 
Samples collected for biomarker assessments will be destroyed no later than 15 years after the 
end of study or per countiy requirements (Section 9.1.4). 
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and/or diagnostic assays and establish the 
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6.4. 
Safety Assessments 
Safety will be evaluated throughout the study. All safety assessments will be completed predose 
unless othe1wise specified as in the schedule of assessments in Table 1 through Table 3. 
6.4.1. 
Electrocardiogram Assessment 
Paiiicipants should rest quietly in the supine position for a minimum of 5 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
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There should be no environmental distractions (including TV, radio, video games, and 
conversation) while the participants are resting prior to and during the recordings. 
Electrocardiograms will be recorded using the site’s standard ECG equipment. All ECGs will be 
obtained using instruments that analyze data using the same algorithms and produce the same 
data for interpretation. Electrode placement will be performed according to the method of 
Wilson, Goldberger, and Einthoven with a check to confirm that the aVR lead is not inverted.
The investigator or other qualified individuals at the study site will review ECGs to assess for 
changes in ECG intervals and morphology as compared with pretreatment ECGs. The ECG 
interval measurements output by the machine will be used for bedside safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP.
6.4.2.
Physical Examination
Physical examinations conducted throughout the study will be a complete physical examination 
or a symptom-driven physical examination, as outlined in Table 1 through Table 3. The complete 
physical examination conducted at screening will also include the following assessments:

Review medical history, including history of allergies, prior and current use of nicotine or 
nicotine-containing products, alcohol and illegal drug use, and prior (within 30 days) and 
current medication use
6.4.3.
Vital Signs
Vital sign measurements include blood pressure, heart rate, oxygen saturation, and body 
temperature and should be taken once participants have been seated or in the supine position. 
Participant position for measurement should be kept consistent throughout the study. Refer to 
Table 1 through Table 3 for vital signs collection time points.
6.4.4.
Body Mass Index
Height and weight will be collected at screening for calculation of body mass index (BMI).
6.4.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Table 1 through Table 3.


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6.4.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: Hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell 
count with differential (absolute and percentage), including lymphocytes, monocytes, 
neutrophils, eosinophils, basophils, and mean corpuscular volume 

Coagulation panel (screening only): prothrombin time, partial thromboplastin time, and 
international normalized ratio 

Chemistry (fasting): alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, 
total protein, albumin, lactic acid dehydrogenase, CK, bicarbonate, blood urea nitrogen, 
calcium, chloride, creatinine (see Section 6.4.6), glucose, phosphorus, magnesium, 
potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in participants 
with total amylase greater than 1.5 × ULN)

Serum pregnancy test (participants assigned female at birth of childbearing potential only) 

Follicle-stimulating hormone testing (screening only): participants assigned female at birth 
who are younger than 54 years, not on hormonal contraception, and who have stopped 
menstruating for at least 12 months but do not have documentation of ovarian hormonal 
failure

HIV-1 viral load at screening and on Day −1 of Period 2 and Period 3 in Cohort 1, and 
screening and Day −1 of Period 2 in Cohort 2

HBV and HCV testing (screening only) 
6.4.5.2.
Urine Samples
Urine samples will be collected for urinalysis and alcohol and drug screen assessments, which 
include alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, marijuana, 
3,4-methlenediozymethamphetamine, methadone, opiates, phencyclidine, and propoxyphene.
6.4.6.
Creatinine Clearance
Serum creatinine and weight will be collected at screening and upon admission to calculate CLcr 
for inclusion criteria. Weight collected at admission will be used to calculate CLcr from Day 5 
until the end of study in each cohort. Serum creatinine to calculate CLcr will be collected at later 
time points as outlined in Table 1 through Table 3.


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6.4.7. 
Concomitant Medications/Protocol Restrictions 
Final 
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Review of concomitant medications, and review of protocol restrictions will occur at the times 
shown in Table 1 through Table 3. See Sections 4.3 and 5.7.1 for more info1mation about 
concomitant medications. 
6.5. 
Posttreatment Assessments 
All participants will return 10 days± 3 days after last dose ofVES for an in-clinic follow-up 
visit. For participants assigned female at bi1ih of childbearing potential in Coho1i 2 only, an at-
home urine pregnancy test will be completed 10 days after the last dose of RFB . Paiiicipants 
will be contacted by telephone to repo1i at-home pregnancy test results. Study procedures and 
assessments are outlined in Table 2 and Table 3. 
6.6. 
Assessments for Early Discontinuation From Study Intervention or From the 
Study 
If a paiticipant discontinues study treatment dosing (see Sections 3.3), for example as a result of 
an AE, eve1y attempt should be made to keep the paiticipant and continue to perfo1m procedures 
for stabilization per the investigator. Evaluations indicating abnormal results believed to be 
possibly or probably related to study dmg at the eai·ly tennination (ET) visit should be repeated 
weekly or as often as deemed appropriate by the investigator until the abno1mality resolves, 
returns to baseline visit levels, or is othe1w ise explained. 
6.6.1. 
Assessments for End of Study 
A paiiicipant who completes the study will have an end of study visit for assessments and 
procedures specified in Table 2 and Table 3. If the participant withdraws consent from the study, 
the ET evaluations and/or procedures outlined in Table 2 and Table 3 should be perfo1med 
within 72 hours of pennanently discontinuing the study. 
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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 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, and 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 (see 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 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)

Inpatient 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 a 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 Therapy Special Situation Reports
Special situations 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, patient, 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/device interaction.
Unexpected benefit is defined as an unintended therapeutic effect where the results are judged to 
be desirable and beneficial. 


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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 Gilead Grading Scale for Severity of Adverse 
Events and Laboratory Abnormalities, Antiviral Toxicity Grading Scale, Version 01 April 2015 
(Appendix 11.5). For each episode, the highest grade attained should be reported as defined in 
the Antiviral Toxicity Grading Scale (Appendix 11.5). The Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 grading scale will be used to grade CRS AEs.
7.3.
Investigator Reporting Requirements and Instructions 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation
After informed consent, but prior to initiation of study medication, the following types of events 
must be reported on the applicable forms: all SAEs (paper case report forms [CRFs]) and any 
AEs related to protocol-mandated procedures (eCRFs).


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7.3.2.
Adverse Events
Following initiation of study treatment, all AEs, regardless of cause or relationship, throughout 
the duration of the study, including the protocol-required posttreatment follow-up period, must 
be reported to the CRF database as instructed. Following initiation of study treatment, collect all 
AEs, regardless of cause or relationship, until 30 days after follow-up and report the AEs on the 
CRF as instructed.
All AEs and clinically significant laboratory abnormalities should be followed up 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 occurs after the participant first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the posttreatment follow-up visit, must be reported on the applicable CRFs and 
to Gilead Patient Safety (PS) as instructed below in this section. This also includes any SAEs 
resulting from protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur throughout the duration of the study including the 
protocol-defined follow-up period, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if an 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 the study drug, the 
investigator should promptly document and report the event to Gilead PS.
Instructions for reporting SAEs are described in Section 7.4.1.
7.3.4.
Study Drug Special Situations 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 PS (Section 7.4.2). 
Adverse events and SAEs resulting from SSRs must be reported in accordance to the AE and 
SAE reporting guidance (Section 7.3).
7.3.5.
Concomitant Therapy Reports
7.3.5.1.
Gilead Concomitant Therapy Special Situations Report
Special situations reports involving a Gilead concomitant therapy (not considered study drug), 
that occurs after the participant first consents to participate in the study (ie, signing the informed 
consent) and throughout the duration of the study, including the posttreatment follow-up visit, 
must be reported to Gilead PS utilizing the paper SSR (Section 7.4.2.2).


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7.3.5.2.
Non-Gilead Concomitant Therapy 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 due to a non-Gilead concomitant 
medication, the AE should be reported on the AE form. 
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 report form. 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 Situations 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.
Paper Serious Adverse Event Reporting Process 
All SAEs will be recorded on the SAE report form and transmitted by emailing or faxing the 
report form within 24 hours of the investigator’s knowledge of the event to the attention of 
Gilead PS from ICF signature throughout the duration of the study, including the 
protocol-required posttreatment follow-up period. Additionally, the SAE must be captured on the 
applicable CRF.
Gilead PS
Email:
 
or
Fax: PPD
PPD


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7.4.2.
Special Situations Reporting Process 
7.4.2.1.
Paper Special Situations Reporting Process for Study Drug 
All SSRs will be recorded on the SSR form and transmitted by emailing or faxing the report 
form within 24 hours of the investigator’s knowledge of the event to the attention of Gilead PS 
from study drug initiation throughout the duration of the study, including the protocol-required 
posttreatment follow-up period.
Gilead PS
Email: 
 
or
Fax: 
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 PS 
utilizing the paper SSR form to:
Gilead PS
Email: 
 
or
Fax: 
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 due to a non-Gilead concomitant 
medication, must be reported as an AE.
7.4.2.3.
Pregnancy Reporting Process
The investigator should report pregnancies identified after initiation of study drug and 
throughout the study, including the protocol-required posttreatment follow-up period 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 PS using the pregnancy report form within 24 hours of becoming aware of the pregnancy. 
Contact details for transmitting the pregnancy report form are as follows:
Gilead PS
Email: 
 
or
Fax: 
The pregnancy itself is not considered an AE, nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
PPD
PPD
PPD
PPD
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All other premature terminations of pregnancy (eg, a spontaneous abortion, an induced 
therapeutic abortion due to 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 poststudy must 
be reported to the Gilead PS.
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 PS 
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 PS. Gilead 
PS contact information is as follows: email: 
and fax: 
. 
Refer to Appendix 11.3 for Pregnancy Precautions, Definition for Childbearing Potential, and 
Contraceptive Requirements.
7.5.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable FDA CFR, the 
European Union (EU) Clinical Trials Directive (2001/20/EC)/EU Regulation 536/2014 and 
relevant updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, which may be in the form of 
line-listings, serious adverse drug reactions, or suspected unexpected serious adverse reactions 
(SUSARs). In accordance with the European Union Clinical Trials Directive (2001/20/EC)/EU 
Regulation 536/2014, Gilead or a specified designee will notify worldwide regulatory agencies 
of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB of SUSAR reports as soon as is 
practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not to be recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, urinalysis) that require 
medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, X-rays, vital signs) that are associated with 
signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is 
part of a syndrome, record the syndrome or diagnosis (eg, anemia) not the laboratory result 
(ie, decreased hemoglobin).
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Severity should be recorded and graded according to the Gilead Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities, Antiviral Toxicity Grading Scale, Version 01, 
April 2015, and the CTCAE v5.0 grading scale for CRS (Appendix 11.5 and Section 7.7, 
respectively) Toxicity Grading Scales (Section 7.2.2). For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.7.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 11.5, and as outlined below.
Cytokine Release Syndrome
After VES dosing, Grade 1 CRS, with influenza-like symptoms such as fever, fatigue, chills, 
myalgia, or headache without more severe manifestations such as changes in blood pressure or 
oxygen saturation, may be managed with supportive care (eg, paracetamol for myalgia or fever). 
If a participant experiences Grade 1 CRS, they will remain confined until symptoms resolve. For 
any Grade 2 or higher CRS, including hypotension and/or hypoxia, the participant will be 
immediately transferred to a hospital or emergency department for management in a monitored 
setting until symptoms resolve. Administration of steroids, intravenous fluid for hypotension, 
and supplemental oxygen for hypoxia should also be considered. If a participant experiences 
treatment-related Grade 2 or higher CRS, dosing in that participant must be discontinued.
Grading of Cytokine Release Syndrome
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Cytokine release 
syndrome
Fever with or 
without 
constitutional 
symptoms
Hypotension 
responding to 
fluids; hypoxia 
responding to 
< 40% O2
Hypotension 
managed with one 
pressor; hypoxia 
requiring ≥ 40% O2
Life-threatening 
consequences; urgent 
intervention indicated
National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
Other Laboratory Abnormalities and Clinical Events

Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing as soon as possible, and preferably within 3 calendar days after receipt of the original 
test results. The study drug may be continued without dose interruption for a clinically 
insignificant Grade 3 and 4 laboratory abnormality (eg, CK elevation after strenuous 
exercise, triglyceride elevation that is nonfasting or that can be medically managed). 
Recurrence of laboratory abnormalities considered unrelated to the study drug may not 
require permanent discontinuation

Grade 3 or 4 clinical events if considered unrelated to the study drug may not require dose 
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The Gilead medical monitor should be consulted prior to study drug discontinuation when 
medically feasible.
7.7.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue study drug at the discretion of the investigator (with the exception of Grade 2 CRS 
where dosing must be discontinued as detailed in Section 7.7)
7.7.2.
Grades 3 Laboratory Abnormality or Clinical Event

For a Grade 3 clinically significant laboratory abnormality or clinical event, the study drug 
may be continued if the event is considered to be unrelated to the study drug

For a Grade 3 clinically significant laboratory abnormality or clinical event confirmed by 
repeat testing, that is considered to be related to the study drug, then the study drug should be 
permanently discontinued and the participant managed according to local practice. 
Recurrence of laboratory abnormalities considered unrelated to the study drug may not 
require permanent discontinuation
7.7.3.
Grades 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant laboratory abnormality confirmed by 
repeat testing considered to be related to the study drug, study drug should be permanently 
discontinued and the participant 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
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor, and the appropriate course of action will be discussed and decided. 
Whether or not considered treatment related, all participants experiencing AEs must be 
monitored periodically until symptoms subside, any abnormal laboratory values have resolved or 
returned to baseline levels or they are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the Gilead medical monitor.


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8.
STATISTICAL CONSIDERATIONS
Details of the statistical methods will be provided in the statistical analysis plan, including any 
deviations from the original statistical analyses planned.
8.1.
Analysis Objectives and Endpoints
Objectives and endpoints are listed in Section 2.
8.2.
Planned Analyses
8.2.1.
Interim Analysis 
Prior to the final analysis, interim analyses may be conducted after each cohort has completed 
the study. 
8.2.2.
Final Analysis
The 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.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all participants enrolled into the study after screening. 
This is the primary analysis set for safety listings.
8.3.1.2.
Safety Analysis Set
The Safety Analysis Set will include all enrolled participants who received at least 1 dose of 
study drug. Participants who received treatment other than that to which they were assigned will 
be analyzed according to the treatment received.
8.3.1.3.
Pharmacokinetics Analysis Set
The PK Analysis Set will include all enrolled participants who received at least 1 dose of VES 
and had at least 1 nonmissing PK concentration datum reported by PK laboratory for each 
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8.3.1.4.
Biomarker Analysis Set
The Biomarker Analysis Set will include all enrolled participants who received at least 1 dose of 
study drug and have at least 1 blood sample collected for biomarker evaluation after 
administration of study drug.
8.3.2.
Data Handling Conventions
The rule for handling PK concentration values below the limit of quantitation will described in 
the statistical analysis plan.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit 
minus or plus 1 significant digit, respectively (eg, if the result of a continuous laboratory test is 
less than 20, a value of 19 will be assigned; if the result of a continuous laboratory test is less 
than 20.0, a value of 19.9 will be assigned).
Missing data can have an impact upon the interpretation of the study data. As this study is of 
short duration, it is anticipated that missing data will be minimal. In general, values for missing 
data will not be imputed. However, a missing pretreatment laboratory result would be treated as 
normal (ie, no toxicity grade) for the laboratory abnormality summary.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized and descriptive statistics will be 
provided. 
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include a summary of weight and BMI.
8.5.
Safety Analysis
All safety data collected on or after the date that study drug was first administered up to the study 
completion will be summarized by treatment (according to the study drug received) using the 
Safety Analysis Set. 
8.5.1.
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 listed.
8.5.2.
Adverse Events
Clinical and laboratory AEs will be coded using the current version of the MedDRA. System 
organ class (SOC), high-level group term, high-level term, preferred term (PT), and lower-level 
term will be attached to the clinical database.


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Adverse event data will be listed by participant. Treatment-emergent AEs, serious TEAEs, and 
TEAEs leading to discontinuation of treatment will be summarized by treatment, SOC, and PT 
using the current version of MedDRA. 
8.5.3.
Laboratory Evaluations
Listings of individual participant laboratory results will be provided. Laboratory results and 
changes from predose values for selected laboratory tests will be summarized by cohort at 
scheduled visits. The incidence of treatment-emergent graded laboratory abnormalities will be 
summarized by treatment.
8.5.4.
Other Safety Evaluations
Vital signs and ECG data will be summarized by cohort over time.
8.6.
Pharmacokinetic Analysis
Plasma concentrations and PK parameters will be listed and summarized for each analyte using 
descriptive statistics by treatment, as applicable. 
In addition, for Cohorts 1 and 2, an analysis of variance using a mixed-effects model with 
treatment as a fixed effect and participant as a random effect will be fitted to the natural 
logarithmic transformation of PK parameters (AUClast, AUCinf, and Cmax) for each analyte. 
Two-sided 90% CIs will be calculated for the ratios of geometric least-squares means (GLSMs) 
between test and reference treatments being compared. 
8.7.
Biomarker Analysis
The absolute level of PD biomarkers (including serum cytokines, ISGs mRNA, and immune cell 
phenotype), their change from baseline, and fold change from baseline will be listed and 
summarized using descriptive statistics by treatment within each cohort.
The absolute and normalized levels of TruCulture cytokines, as well as their association with 
serum PD biomarkers will be evaluated.
8.8.
Sample Size
With 18 evaluable participants per cohort, the estimated 2-sided 90% CI of the GLSM ratio of 
test versus reference treatments with regards to AUCinf and Cmax will be within (0.50, 2.00) with 
at least 90% probability if the true GLSM ratio was 1.0. This is assuming a root mean square 
error of no more than 0.6 on a natural logarithm scale, which is supported by the previous 
Study GS-US-234-0101. With 35% and 10% overage for Cohorts 1 and 2, a total sample size of 
25 participants and 20 participants will be required for Cohorts 1 and 2, respectively.


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9_ 
9.1. 
9.1.1. 
RESPONSIBILITIES 
Investigator Responsibilities 
Good Clinical Practice 
Final 
Amendment3 
The investigator will ensure that this study is conducted in accordance with International Council 
for Haim onisation (ICH) E6(R2) 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 an angements with the sponsor or proprietaiy interests in the study diug. This 
documentation must be provided prior to the investigator's (and any subinvestigator's) 
paiiicipation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in repo1iable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last paiiicipant completes the protocol-defined 
activities. 
9.1.3. 
Institutional Review Board 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 pa1iicipant (such as 
adve1iisements, paiiicipant infonnation sheets, or descriptions of the study used to obtain 
info1med consent) to an IRB. The investigator will not begin any study paiiicipant activities until 
approval from the IRB 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 for any modifications made to the protocol or any accompanying material to be provided 
to the paiiicipant after initial IRB approval, with the exception of those necessaiy to reduce 
immediate risk to study paiiicipants. 
9.1.4. 
Informed Consent 
The investigator is responsible for obtaining written infonned consent from each individual 
paiiicipating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazai·ds of the study before unde1iaking any study-related procedures. The investigator 
must use the most cunent !RB-approved ICF for documenting written infonned consent. Each 
ICF will be appropriately signed and dated by the paiiicipant, the person conducting the consent 
discussion, and also by an impaiiial witness if required by the IRB or local requirements. 
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Confidentiality 
Final 
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The investigator must ensure that paiiicipants' anonymity will be strictly maintained and that 
their identities ai·e protected from unauthorized paiiies. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of bi1ih) will be recorded on any fo1m 
or biological sample submitted to Gilead, IRB, or the laborato1y . Laborato1y specimens must be 
labeled in such a way as to protect paiiicipant identity while allowing the results to be recorded 
to the proper paiticipant. Refer to specific laborato1y instructions. NOTE: The investigator must 
keep a screening log with details for all paiiicipants screened and emolled in the study. 
Paiiicipant data will be processed in accordance with all applicable regulations. 
The investigator agrees that all info1mation received from Gilead, including but not limited to the 
IB, this protocol, CRFs, study dmg info1m ation, and any other study info1m ation, remain the sole 
and exclusive prope1iy of Gilead during the conduct of the study and thereafter. This info1mation 
is not to be disclosed to any third paiiy ( 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 fmther agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the investigational site to any third paiiy or othe1wise 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) paiiicipant clinical source documents. 
The investigator's study file will contain the protocol/amendments, CRFs, IRB, and 
governmental approval with con espondence, ICF, diu g records, staff cmTiculum vitae and 
authorization fo1ms, and other appropriate documents and conespondence. 
The required source data should include sequential notes containing at least the following 
info1mation for each paiiicipant: 
• 
Paiiicipant identification (name, date of bi1i h, gender) 
• 
Documentation that paiiicipant meets eligibility criteria, ie, histo1y , physical exainination, 
and confnm ation of diagnosis (to suppo1t inclusion and exclusion criteria) 
• 
Documentation of the reason(s) a consented paiiicipant is not emolled 
• 
Paiiicipation in study (including study number) 
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
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 dates (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 (including start and end dates, dose if relevant, and 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, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, for 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study 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.
9.1.7.
Case Report Forms 
An eCRF casebook will be completed by an authorized study personnel member whose training 
for this function is completed in the 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 nonelectronic data capture 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 CRF 
Completion Guidelines provided by the sponsor. Subsequent to data entry, a study monitor may 
perform source data verification. System-generated or manual queries will be issued in the EDC 
system as data discrepancies are identified by the study monitor or Gilead personnel who 
routinely review the data for completeness, correctness, and consistency. The site investigator, 


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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 PI 
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, 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 
in accordance with local requirements and receive documented IRB approval before 
modifications may be implemented.
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 (ICH 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 after the global end of study (as defined in Section 3.5.2).
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.


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9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at investigator's 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 accuracy of the data recorded in the CRFs. The study monitor is responsible 
for routine review of the CRFs 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, on-site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead study monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Gilead reserves the right to terminate the study at any time, and the investigator has the right to 
terminate the study at his or her site. Should this be necessary, both parties will arrange 
discontinuation procedures and notify the participants, appropriate regulatory authority(ies), and 
IRB. 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
Bekeredjian-Ding IB, Wagner M, Hornung V, Giese T, Schnurr M, Endres S, et al. Plasmacytoid 
dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol 
2005;174 (7):4043-50.
Borducchi EN, Cabral C, Stephenson KE, Liu J, Abbink P, Ng'ang'a D, et al. Ad26/MVA 
Therapeutic Vaccination with TLR7 Stimulation in SIV-Infected Rhesus 
Monkeys. Nature 2016;540 (7632):284-7.
Borducchi EN, Liu J, Nkolola JP, Cadena AM, Yu WH, Fischinger S, et al. Antibody and TLR7 
Agonist Delay Viral Rebound in SHIV-Infected Monkeys [Author Manuscript]. 
Nature 2018;563 (7731):360-4.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. 
Science 2010;327 (5963):291-5.
Joint United Nations Programme on HIV/AIDS (UNAIDS). Fact Sheet - World AIDS Day 2021 
- Global HIV Statistics.  2021.
Katzenmaier S, Markert C, Riedel KD, Burhenne J, Haefeli WE, Mikus G. Determining the time 
course of CYP3A inhibition by potent reversible and irreversible CYP3A 
inhibitors using A limited sampling strategy. Clin Pharmacol Ther 2011;90 
(5):666-73.
Knolle PA. The liver's imprint on CD8(+) T cell priming. J Hepatol 2012;57 (4):718-9.
Mathias AA, German P, Murray BP, Wei L, Jain A, West S, et al. Pharmacokinetics and 
pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-
HIV activity. Clin Pharmacol Ther 2010;87 (3):322-9.
Mercado N, Chandrashekar A, Borducchi E, Nkolola J, Geleziunas R, Carr B, et al. PGT121 and 
Vesatolimod in Chronically Treated Shiv-Infected Rhesus Monkeys [Poster]. 
Conference on Retroviruses and Opportunistic Infections (CROI); 2020 March 
08-11; Boston, Massachusetts. 
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of 
mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. 
Lancet 1998;352 (9142):1725-30.


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MYCOBUTIN®, Pharmacia & Upjohn Company LLC. MYCOBUTIN® (Rifabutin) Capsules 
for oral administration. U.S. Prescribing Information. New York, NY. Revised 
September. 2021.
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining 
Morbidity and Mortality Among Patients With Advanced Human 
Immunodeficiency Virus Infection. N Eng J Med 1998;338 (13):853-60.
Riddler SA, Para M, Benson CA, Mills A, Ramgopal M, DeJesus E, et al. Vesatolimod, a Toll-
like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed 
Adults Living With Human Immunodeficiency Virus–1. Clin Infect Dis 2020.
Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nature reviews 2008;8 (7):559-
68.
SenGupta D, Brinson C, DeJesus E, Mills A, Shalit P, Guo S, et al. The TLR7 agonist 
vesatolimod induced a modest delay in viral rebound in HIV controllers after 
cessation of antiretroviral therapy. Science translational medicine 2021;13 (599).
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.
Tel J, Sittig SP, Blom RA, Cruz LJ, Schreibelt G, Figdor CG, et al. Targeting uptake receptors 
on human plasmacytoid dendritic cells triggers antigen cross-presentation and 
robust type I IFN secretion. J Immunol 2013;191 (10):5005-12.
TYBOST, Gilead Sciences Inc. TYBOST® (cobicistat) tablets, for oral use. U.S. Prescribing 
Information. Foster City, CA. Revised September.  2021.
VFEND®, Pfizer. VFEND® (voriconazole), tablets for oral use, for oral suspension and for 
injection, for intravenous use. U.S. Prescribing Information. New York. Revised 
October.  2021.


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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
USA
STUDY ACKNOWLEDGEMENT
A Phase 1, Open-label, Multicohort Study to Evaluate the Impact of Inhibitors and Inducers of 
Cytochrome P450 Enzyme (CYP)3A and/or P-glycoprotein (P-gp) on the Pharmacokinetics (PK) 
of Vesatolimod (VES) in Virologically Suppressed Adults With HIV-1 on Antiretroviral 
Therapy (ART) 
Amendment 3
12 December 2022
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
[See appended electronic signature]
Medical Monitor
Signature
[See appended electronic signature]
Date
INVESTIGATOR STATEMENT
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study.
Principal Investigator Name (Printed)
Signature
Date
Site Number
PPD
-
- - -


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11.2.
Pandemic Risk Assessment and Mitigation Plan
During an ongoing pandemic, potential risks associated with participants being unable to attend 
study visits have been identified for this study. 
These risks can be summarized as follows:
1) Study drug supplies to participants and sites:
a) Shipments of study drug could be delayed because of transportation issues. Without study 
drugs, the participant would not be able to continue receiving the study drug as planned 
per protocol.
Mitigation plan: The sites study drug inventory should be closely monitored. Site staff 
should notify the sponsor or delegate if they foresee shortage in study drug inventory or 
if there is any interruption in local shipping service. The sponsor will continue to monitor 
inventory at the study drug depot and investigational sites. Manual shipments will be 
triggered as necessary.
2) Participant safety monitoring and follow-up:
a) Participants may be unable or unwilling to come to the investigational site for their 
scheduled study visits as required per protocol.
Mitigation plan: For participants who may be unable or unwilling to visit the 
investigational site for their scheduled study visits as required per protocol, the PI 
or qualified delegate will conduct a virtual study visit, via phone or video conferencing, 
to assess the participant within target visit window date whenever possible. During the 
remote study visit, the following information at minimum will be reviewed: 
i)
Confirm if participant has experienced any adverse events (AEs)/serious adverse 
events (SAEs)/special situations (including pregnancy) and follow-up on any 
unresolved AE/SAEs.
ii) Review 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 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 participant to maintain current dosing and to keep all dispensed 
study drug kits for return at the next on-site visit.


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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 visit per protocol. Any changes in the party conducting laboratory assessments 
for the study due to 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 ICF 
version.
Mitigation plan: The site staff will follow their approved consent process and remain in 
compliance with local IRB and national laws and regulations. Remote consent will be 
allowed if has been approved by the local IRB. The consent process will be documented 
and confirmed by normal consent procedure at the earliest opportunity.
3) Protocol and monitoring compliance:
d) Protocol deviations may occur in case scheduled visits cannot occur 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 due to the pandemic must be reported in the eCRF and described 
in the clinical study report (CSR). Any virtual study visits that are conducted in lieu of 
clinic visits due to the pandemic will be documented as a protocol deviation related to the 
pandemic.
e) Study monitors may be unable to carry out source data review or source data verification 
(SDV), or study drug accountability or assess protocol and Good Clinical Practice 
compliance. This may lead to delays in SDV, 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 SDV may be arranged if allowed. The 
study monitor is to reference the Study Monitoring Plan for guidance on how to conduct 
a remote 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.


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4) Missing data and data integrity:
f)
There may be an increased amount of missing data due to 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 
(ie, 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 VES in study participants will remain unchanged. 


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11.3.
Pregnancy Precautions, Definition of Childbearing Potential, and 
Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a participant assigned female at birth is considered of childbearing 
potential following the initiation of puberty (Tanner stage 2) until becoming postmenopausal 
unless the participant is permanently sterile or has medically documented ovarian failure.
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.
For the purpose of this study, permanent sterilization includes hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy in a participant assigned female at birth of any age.
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 
medical documentation.
2) Contraception Requirements for Female Participants Assigned Female at Birth and of 
Childbearing Potential
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Vesatolimod
The overall potential for genetic toxicity of VES is considered to be low. In developmental 
toxicity studies in mice and rabbits, dose-developmental findings were observed in the rabbit 
only at doses that caused maternal toxicity (see VES investigator’s brochure [IB], Sections 3.3.5 
and 6.1.1.1.2). Such findings included increased incidence of early and late fetal resorptions, 
reduced fetal weights, and increased incidence of soft tissue/skeletal alterations (malformations 
and variations) at 15 and 30 mg/kg doses. Given these findings in nonclinical studies, VES has 
shown the potential for embryofetal developmental effects.
There are no clinical data regarding the use of VES in pregnant women. The effects of VES on 
an unborn child are unknown. A clinical pharmacokinetic (PK) study evaluating the drug 
interaction potential of VES has not been conducted; however, based on the non-overlapping 
metabolic pathways for VES and oral contraceptives, no clinically relevant drug interactions are 
expected upon coadministration of these agents. Please refer to the latest version of the VES IB 
for additional information.


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Cobicistat 
Cobicistat (COBI) use during pregnancy has been evaluated in a limited number of individuals as 
reported by the Antiretroviral Pregnancy Registry (APR), and available data show no significant 
difference in the rate of overall birth defects for COBI compared with the background rate for 
major defects of 2.7% in a United States (US) reference population of the Metropolitan Atlanta 
Congenital Defects Program. The rate of miscarriage is not reported in the APR. The estimated 
background rate of miscarriage in clinically recognized pregnancies in the US general population 
is 15% to 20%. In animal reproduction studies in rats and rabbits, no evidence of fetal harm was 
observed with oral administration of COBI during organogenesis at doses that produced 
exposures up to 1.4 and 3.3 times, respectively, the maximal recommended human dose of 
150 mg. 
No data are available to make recommendations on the use of COBI with hormonal 
contraceptives. 
Please refer to the latest version of the COBI United States Prescribing Information (USPI) for 
further human and animal data in pregnancy, and additional information.
Voriconazole
Voriconazole (VOR) can cause fetal harm when administered to a pregnant woman. There are no 
available data on the use of VOR in pregnant women. In animal reproduction studies, oral VOR 
was associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and 
hydronephrosis/hydroureter were observed in rat pups exposed to VOR during organogenesis at 
and above 10 mg/kg (0.3 times the recommended maintenance dose (RMD) of 200 mg every 
12 hours based on body surface area [BSA] comparisons). In rabbits, embryomortality, reduced 
fetal weight and increased incidence of skeletal variations, cervical ribs, and extrasternal 
ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg 
(6 times the RMD based on BSA comparisons) during organogenesis. Rats exposed to VOR 
from implantation to weaning experienced increased gestational length and dystocia, which were 
associated with increased perinatal pup mortality at the 10 mg/kg dose. 
The coadministration of VOR with an oral contraceptive, ethinylestradiol/norethindrone, results 
in an interaction between these 2 drugs, but is unlikely to reduce the contraceptive effect. 
Please refer to the latest version of the VOR USPI for further animal data in pregnancy and 
additional information.
Rifabutin
There are no adequate and well-controlled studies in pregnant women. Reproduction studies 
have been carried out in rats and rabbits given rifabutin (RFB) using dose levels up to 200 mg/kg 
(about 6 to 13 times the recommended human daily dose based on BSA comparisons). No 
teratogenicity was observed in either species. In rats, given 200 mg/kg/day, (about 6 times the 
recommended human daily dose based on BSA comparisons), there was a decrease in fetal 
viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily 
dose based on BSA comparisons), RFB caused an increase in fetal skeletal variants. In rabbits, at 
80 mg/kg/day (about 5 times the recommended human daily dose based on BSA comparisons), 
RFB caused maternotoxicity and increase in fetal skeletal anomalies. 


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Rifabutin may decrease the serum concentration of hormonal contraceptives 
(ie, ethinylestradiol/norethindrone). Patients should be advised to use additional or alternative 
methods of contraception. 
Please refer to the latest version of the RFB USPI for additional information.
b. Contraception Requirements for Female Participants 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 also not rely on a hormone-containing contraceptive as a form of birth control during the 
study. They must have a negative serum pregnancy test at screening and a negative pregnancy 
test at the admission (Day −1) visit before enrollment. Pregnancy tests will be performed at 
monthly intervals thereafter until the end of contraception requirement. 
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 10 days after the 
last dose of study drug.
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: 

Nonhormonal intrauterine device (IUD) 

Bilateral tubal occlusion (upon medical assessment of surgical success)

Vasectomy in the partner assigned male at birth (upon medical assessment of surgical 
success)
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 from screening through the duration of study treatment and 
until the end of contraception requirement (ie, 10 days after the last dose of study drug).
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 condoms during treatment and until 
10 days after last dose of study drug. If the partner assigned female at birth and of childbearing 
potential is not pregnant, additional contraception recommendations should also be considered.


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Participants assigned male at birth must also refrain from sperm donation/in vitro fertilization 
during treatment and until the end of contraception requirement.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), hormone-containing 
contraceptive only, 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 during the study, or if they become pregnant 
within 10 days after the last dose of study drug. Study drug must be discontinued immediately. 
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study to 10 days after the last study drug dose must also report the 
information to the investigator. Instructions for reporting pregnancy and pregnancy outcome are 
outlined in Section 7.4.2.3.


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11.4.
Management of Clinical and Laboratory Adverse Events
Grade 1 
Grade 2 
Grade 3 
Continue study drug dosing at the 
discretion of the investigator 
Repeat lab to confirm toxicity 
grade 
If confirmed, and possibly or probably related to study drug(s): 
If confirmed and 
unrelated to study 
drug(s), dosing may 
continue at the 
discretion of the 
investigator. 
1. Withhold study drug(s) until~ Grade 2 
2. Restart all study drug(s) at full dose upon discussion with the 
Gilead Medical Monitor 
If Grade 3 or 4 recurrence is 
confirmed and possibly or 
probably related to study drug(s), 
discontinue all study drug(s) 
permanently, and manage the 
subject according to local practice. 
If Grade 3 or 4 recurrence is 
confirmed and unrelated to 
study drug(s), continue all 
investigational medicinal 
product(s) at the same dose at 
the discretion of the 
investigator. 
Grade 4 
If confirmed, and 
possibly or probably 
related to study 
drug(s), discontinue 
study(s) dosing 
permanently, and 
manage subject 
according to local 
practice. Subject 
should be followed as 
clinically indicated 
until the laboratory 
abnormality returns to 
baseline, or is 
otherwise explained. 


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11.5.
Gilead Toxicity Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale, Version 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric  57 Days
8.5 to 10.0 g/dL
85 to 100 g/L
7.5 to  8.5 g/dL
75 to  85 g/L
6.5 to  7.5 g/dL
65 to  75 g/L
 6.5 g/dL
 65 g/L
HIV NEGATIVE
Adult and Pediatric  57 days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from baseline
2.5 to  3.5 g/dL
25 to  35 g/L
9.0 to  10.0 g/dL
90 to  100 g/L
OR
Any decrease from baseline
3.5 to  4.5 g/dL
35 to  45 g/L
7.0 to  9.0 g/dL
70 to  90 g/L
OR
Any decrease from baseline
 4.5 g/dL
 45 g/L
 7.0 g/dL
 70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR 
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to  8.5 g/dL
70 to  85 g/L
6.0 to  7.0 g/dL
60 to < 70 g/L
 6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR 
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to  9.5 g/dL
80 to  95 g/L
7.0 to  8.0 g/dL
70 to  80 g/L
 7.0 g/dL
 70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR 
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to  12.0 g/dL
100 to  120 g/L
9.0 to  10.0 g/dL
90 to  100 g/L
 9.0 g/dL
 90 g/L
1.00 to 1.30  109/L
0.75 to  1.00  109/L
0.50 to  0.75  109/L
 0.50  109/L
Absolute Neutrophil Count
Adult and Pediatric,
≥ 7 Monthsa 
1.00 to 1.30 GI/L
0.75 to  1.00 GI/L
0.50 to  0.75 GI/L
 0.50 GI/L
Absolute CD4 Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to  300/mm3
200 to  300/μL
100 to  200/mm3
100 to  200/μL
 100/mm3
 100/μL


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
 13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to  600/mm3
0.50 to  0.60 GI/L
350 to  500/mm3
0.35 to  0.50 GI/L
 350/mm3
 0.35 GI/L
Platelets
100 to < 125  109/L
100 to  125 GI/L
50 to  100  109/L
50 to  100 GI/L
25 to  50  109/L
25 to  50 GI/L
 25  109/L
 25 GI/L
2000/mm3 to 2500/mm3
1500 to  2000/mm3
1000 to  1500/mm3
 1000/mm3
White Blood Cells 
2.00 GI/L to 2.50 GI/L
1.50 to  2.00 GI/L
1.00 to  1.50 GI/L
 1.00 GI/L
100 to 200 mg/dL
75 to  100 mg/dL
50 to  75 mg/dL
 50 mg/dL
Hypofibrinogenemia
1.00 to 2.00 g/L
0.75 to  1.00 g/L
0.50 to  0.75 g/L
 0.50 g/L
 ULN to 600 mg/dL
 600 mg/dL
—
—
Hyperfibrinogenemia
 ULN to 6.0 g/L
 6.0 g/L
—
—
20 to 40 μg/mL
 40 to 50 μg/mL
 50 to 60 μg/mL
 60 μg/mL
Fibrin Split Product 
20 to 40 mg/L
 40 to 50 mg/L
 50 to 60 mg/L
 60 mg/L
Prothrombin Time 
 1.00 to 1.25  ULN
 1.25 to 1.50  ULN
 1.50 to 3.00  ULN
 3.00  ULN
International Normalized Ratio 
of Prothrombin Time
1.1 to 1.5  ULN
> 1.5 to 2.0  ULN
> 2.0 to 3.0  ULN
> 3.0  ULN
Activated Partial 
Thromboplastin Time
 1.00 to 1.66  ULN
 1.66 to 2.33  ULN
 2.33 to 3.00  ULN
 3.00  ULN
Methemoglobin
5.0% to 10.0%
 10.0% to 15.0%
 15.0% to 20.0%
 20.0%
ULN = upper limit of normal
a
An overlap between the Grade 1 scale and the laboratory’s normal range for absolute neutrophils may result for pediatric participants. Please follow the Gilead convention of 
grading any result within the lower limit of normal and ULN.


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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12 December 2022
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
130 to < LLN mEq/L
125 to  130 mEq/L
121 to  125 mEq/L
 121 mEq/L
Hyponatremia
130 to < LLN mmol/L
125 to  130 mmol/L
121 to  125 mmol/L
 121 mmol/L
> ULN to 150 mEq/L
 150 to 154 mEq/L
 154 to 159 mEq/L
 159 mEq/L
Hypernatremia
> ULN to 150 mmol/L
 150 to 154 mmol/L
 154 to 159 mmol/L
 159 mmol/L
3.0 to < LLN mEq/L
2.5 to  3.0 mEq/L
2.0 to  2.5 mEq/L
 2.0 mEq/L
Hypokalemia
Adult and Pediatric
 1 Year
3.0 to < LLN mmol/L
2.5 to  3.0 mmol/L
2.0 to  2.5 mmol/L
 2.0 mmol/L
Infant < 1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to  3.0 mEq/L
2.5 to < 3.0 mmol/L
2.0 to  2.5 mEq/L
2.0 to < 2.5 mmol/L
 2.0 mEq/L
< 2.0 mmol/L
Hyperkalemia
Adult and Pediatric
 1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
 6.0 to 6.5 mEq/L
 6.0 to 6.5 mmol/L
 6.5 to 7.0 mEq/L
 6.5 to 7.0 mmol/L
 7.0 mEq/L
 7.0 mmol/L
Infant < 1 Year
> ULN to 6.0 mEq/L
> ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
 6.5 to 7.0 mEq/L
 6.5 to 7.0 mmol/L
 7.0 mEq/L
 7.0 mmol/L
Hypoglycemia
Adult and Pediatric
 1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to  55 mg/dL
2.20 to  3.03 mmol/L
30 to  40 mg/dL
1.64 to  2.20 mmol/L
 30 mg/dL
 1.64 mmol/L
Infant  1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to  50 mg/dL
2.2 to  2.8 mmol/L
30 to  40 mg/dL
1.7 to  2.2 mmol/L
 30 mg/dL
 1.7 mmol/L
116 to 160 mg/dL
 160 to 250 mg/dL
 250 to 500 mg/dL
 500 mg/dL
Hyperglycemia (nonfasting)
6.42 to 8.91 mmol/L
 8.91 to 13.90 mmol/L
 13.90 to 27.79 mmol/L
 27.79 mmol/L
Hyperglycemia (fasting)
110 to 125 mg/dL
6.08 to 6.96 mmol/L
> 125 to 250 mg/dL
> 6.96 to 13.90 mmol/L
> 250 to 500 mg/dL
> 13.90 to 27.79 mmol/L
> 500 mg/dL
> 27.79 mmol/L


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 92
12 December 2022
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia
(corrected for albumin if 
appropriatea)
Adult and Pediatric
≥ 2 Years
7.8 to < LLN mg/dL
1.94 to < LLN mmol/L
7.0 to  7.8 mg/dL
1.74 to  1.94 mmol/L
6.1 to  7.0 mg/dL
1.51 to  1.74 mmol/L
 6.1 mg/dL
 1.51 mmol/L
Pediatric ≥ 7 Days to 2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to < 7.8 mg/dL
1.74 to < 1.94 mmol/L
6.1 to < 7.0 mg/dL
1.51 to < 1.74 mmol/L
< 6.1 mg/dL
< 1.51 mmol/L
Infant  7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to  6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to  6.0 mg/dL
1.36 to < 1.49 mmol/L
 5.5 mg/dL
< 1.36 mmol/L
> ULN to 11.5 mg/dL
 11.5 to 12.5 mg/dL
 12.5 to 13.5 mg/dL
 13.5 mg/dL
Hypercalcemia (corrected for 
albumin if appropriatea)
Adult and Pediatric  7 Days
> ULN to 2.88 mmol/L
 2.88 to 3.13 mmol/L
 3.13 to 3.38 mmol/L
 3.38 mmol/L
Infant  7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
 12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
 12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
 13.5 mg/dL
> 3.38 mmol/L
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to  2.5 mg/dL
 2.0 mg/dL
Hypocalcemia (ionized)
0.74 mmol/L to LLN
0.62 to  0.74 mmol/L
0.49 to  0.62 mmol/L
 0.49 mmol/L
ULN to 6.0 mg/dL
 6.0 to 6.5 mg/dL
 6.5 to 7.0 mg/dL
 7.0 mg/dL
Hypercalcemia (ionized)
ULN to 1.50 mmol/L
 1.50 to 1.63 mmol/L
 1.63 to 1.75 mmol/L
 1.75 mmol/L
1.40 to < LLN mg/dL
1.2 to < LLN mEq/L
1.04 to  1.40 mg/dL
0.9 to  1.2 mEq/L
0.67 to  1.04 mg/dL
0.6 to  0.9 mEq/L
 0.67 mg/dL
 0.6 mEq/L
Hypomagnesemia
0.58 to < LLN mmol/L
0.43 to  0.58 mmol/L
0.28 to  0.43 mmol/L
 0.28 mmol/L


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 93
12 December 2022
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
 14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to  2.0 mg/dL
0.47 to  0.63 mmol/L
1.0 to  1.5 mg/dL
0.31 to  0.47 mmol/L
 1.0 mg/dL
 0.31 mmol/L
Pediatric 1–14 Years 
3.0 to < LLN mg/dL
0.96 to < LLN mmol/L
2.5 to  3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to  2.5 mg/dL
0.47 to < 0.80 mmol/L
 1.5 mg/dL
< 0.47 mmol/L
Pediatric  1 Year
3.5 to < LLN mg/dL
1.12 to < LLN mmol/L
2.5 to  3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to  2.5 mg/dL
0.47 to < 0.80 mmol/L
 1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia
Adult and Pediatric > 14 Days
 1.0 to 1.5  ULN
 1.5 to 2.5  ULN
 2.5 to 5.0  ULN
 5.0  ULN
Infant  14 Days
(nonhemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
 25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
 30.0 mg/dL
> 513 μmol/L
Infant  14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
 25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
> ULN to 10.0 mg/dL
 10.0 to 12.0 mg/dL
 12.0 to 15.0 mg/dL
 15.0 mg/dL
Hyperuricemia
> ULN to 597 μmol/L
 597 to 716 μmol/L
 716 to 895 μmol/L
 895 μmol/L
1.5 mg/dL to LLN
87 μmol/L to LLN
to  1.5 mg/dL
57 to  87 μmol/L
0.5 to  1.0 mg/dL
27 to  57 μmol/L
 0.5 mg/dL
 27 μmol/L
Hypouricemia
Adult and Pediatric
≥ 1 Year
Infant < 1 Year
N/A
mg/dL to < LLN
57 μmol/L to < LLN
0.5 to  1.0 mg/dL
27 to  57 μmol/L
 0.5 mg/dL
 27 μmol/L
Creatinineb
 1.50 to 2.00 mg/dL
 133 to 177 μmol/L
 2.00 to 3.00 mg/dL
 177 to 265 μmol/L
 3.00 to 6.00 mg/dL
 265 to 530 μmol/L
 6.00 mg/dL
 530 μmol/L


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 94
12 December 2022
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
16.0 mEq/L to  LLN
11.0 to  16.0 mEq/L
8.0 to  11.0 mEq/L
 8.0 mEq/L
Bicarbonate
Adult and Pediatric
≥ 4 Years
16.0 mmol/L to  LLN
11.0 to  16.0 mmol/L
8.0 to  11.0 mmol/L
 8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/L to < LLN
8.0 to  11.0 mEq/L
 8.0 mEq/L
11.0 mmol/L to < LLN
8.0 to  11.0 mmol/L
 8.0 mmol/L
Triglycerides
(fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
 750 to 1200 mg/dL
 8.47 to 13.55 mmol/L
 1200 mg/dL
 13.55 mmol/L
130 to 160 mg/dL
> 160 to 190 mg/dL
> 190 mg/dL
NA
Low-Density Lipoprotein 
(fasting)
Adult
3.35 to 4.15 mmol/L
> 4.15 to 4.92 mmol/L
> 4.92 mmol/L
110 to 130 mg/dL
> 130 to 190 mg/dL
> 190 mg/dL
NA
Low-Density Lipoprotein 
(fasting)
Pediatric > 2 to < 18 Years
2.84 to 3.37 mmol/L
> 3.37 to 4.92 mmol/L
> 4.92 mmol/L
200 to 239 mg/dL
 239 to 300 mg/dL
 300 mg/dL
NA
Hypercholesterolemia
(fasting)
5.16 to 6.19 mmol/L
 6.19 to 7.77 mmol/L
 7.77 mmol/L
Pediatric  18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
 199 to 300 mg/dL
 5.15 to 7.77 mmol/L
 300 mg/dL
 7.77 mmol/L
NA
Creatine Kinase
3.0 to  6.0  ULN
6.0 to  10.0  ULN
10.0 to  20.0  ULN
 20.0  ULN
LLN = lower limit of normal; ULN = upper limit of normal
a
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
b
An overlap between the Grade 1 scale and the laboratory’s normal range for creatinine may result for male participants > 70 years. Please follow the Gilead convention of 
grading any result within the lower limit of normal (LLN) and upper limit of normal (ULN).


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 95
12 December 2022
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
ALT (SGPT) 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
GGT
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
Alkaline Phosphatase 
1.25 to 2.50  ULN
 2.50 to 5.00  ULN
 5.00 to 10.00  ULN
 10.00  ULN
Total Amylase
 1.0 to 1.5  ULN
 1.5 to 2.0  ULN
 2.0 to 5.0  ULN
 5.0  ULN
Pancreatic Amylase
 1.0 to 1.5  ULN
 1.5 to 2.0  ULN
 2.0 to 5.0  ULN
 5.0  ULN
Lipase 
 1.0 to 1.5  ULN
 1.5 to 3.0  ULN
 3.0 to 5.0  ULN
 5.0  ULN
-
2.0 g/dL to LLN
20 g/L to LLN
 2.0 g/dL
 20 g/L
NA
Albumin
Pediatric < 16 Years
Adult and Pediatric
≥ 16 Years
3.0 g/dL to LLN
30 g/L to LLN
2.0 to  3.0 g/dL
20 to  30 g/L
 2.0 g/dL
 20 g/L
NA
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; LLN = lower limit of normal; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 96
12 December 2022
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (dipstick)
1
2
3-4+
NA
Hematuria (quantitative)
See Note below
Females
> ULN to 10 RBC/HPF
 10 to 75 RBC/HPF
> 75 RBC/HPF
NA
Males
6 to 10 RBC/HPF
 10 to 75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (dipstick)
1
2–3
4
NA
Proteinuria, 24-Hour Collection
Adult and Pediatric
 10 Years
200 to 999 mg/24 h
> 999 to 1999 mg/24 h
> 1999 to 3500 mg/24 h
 3500 mg/24 h
Pediatric  3 Months to < 10 Years
201 to 499 mg/m2/24 h
> 499 to 799 mg/m2/24 h
> 799 to 1000 mg/m2/24 h
 1000 mg/m2/24 h
Glycosuria (dipstick)
1+
2-3
4
NA
RBC/HPF = red blood cells per high power field
Notes:

Toxicity grades for quantitative and dipstick hematuria will be assigned by Covance laboratory; however, for other laboratories, toxicity grades will only be assigned to 
dipstick hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the lower limit of normal and upper limit of normal should be assigned Grade 0.

If the severity of a clinical adverse event (AE) could fall under either 1 of 2 grades (eg, the severity of an AE could be either Grade 2 or Grade 3), select the higher of the 
2 grades for the AE.


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 97
12 December 2022
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(by ECG or physical examination)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND 
Non-urgent medical 
intervention indicated
Symptomatic, 
non-life-threatening AND 
Non-urgent medical 
intervention indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing consistent 
with ischemia
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND Transfusion 
of  2 units packed RBCs (for 
children  10 cc/kg) indicated
Life-threatening 
hypotension OR 
Transfusion of  2 units 
packed RBCs indicated 
(for children  10 cc/kg) 
indicated
Hypertension (with repeat testing at same 
visit)
140 to 159 mm Hg systolic
OR
90 to 99 mm Hg diastolic
 159 to 179 mm Hg systolic
OR
 99 to 109 mm Hg diastolic
 179 mm Hg systolic
OR
 109 mm Hg diastolic
Life-threatening 
consequences
(eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric  17 Years (with repeat testing at 
same visit)
NA
91st to 94th percentile 
adjusted for age, height, and 
gender (systolic and/or 
diastolic)
≥ 95th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic)
Life-threatening 
consequences
(eg, malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency 
room visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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12 December 2022
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with 
non-life-threatening physiologic 
consequences OR Effusion with 
nonurgent intervention indicated
Life-threatening 
consequences 
(eg, tamponade) OR 
Urgent intervention 
indicated
Prolonged PR Interval
PR interval
0.21 to 0.25 sec
PR interval
 0.25 sec
Type II second degree AV 
block OR Ventricular pause 
 3.0 sec
Complete AV block
Pediatric  16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I second degree AV 
block
Type II second degree AV 
block
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval  0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
 0.50 sec OR Increase in 
interval  0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade 
de pointes or other 
associated serious 
ventricular dysrhythmia
Pediatric  16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec
Asymptomatic, QTc interval 
0.465 to 0.479 sec
Asymptomatic, QTc interval 
 0.480 sec
Life-threatening 
consequences, eg, Torsade 
de pointes or other 
associated serious 
ventricular dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)
Deep vein thrombosis AND 
Intervention indicated 
(eg, anticoagulation, lysis filter, 
invasive procedure)
Embolic event 
(eg, pulmonary embolism, 
life-threatening thrombus)
Vasovagal Episode (associated with a 
procedure of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular Dysfunction (congestive heart 
failure [CHF])
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms OR 
Worsening symptomatic CHF
Life-threatening CHF
AV = atrioventricular; ECG = electrocardiogram; ER = emergency room; IV = intravenous; RBC = red blood cell


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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12 December 2022
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70% to 80%
FEV1 or peak flow 50% to 69%
FEV1 or peak flow 25% to 49%
Cyanosis OR FEV1 or peak flow 
 25% OR Intubation
Dyspnea or Respiratory Distress
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities
Dyspnea on exertion causing 
greater than minimal 
interference with usual social & 
functional activities
Dyspnea at rest causing inability 
to perform usual social & 
functional activities
Respiratory failure with 
ventilatory support indicated
Pediatric  14 Years
Wheezing OR minimal increase 
in respiratory rate for age
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90% to 95%
Dyspnea at rest causing inability 
to perform usual social & 
functional activities OR Pulse 
oximetry  90%
Respiratory failure with 
ventilatory support indicated
FEV1 = forced expiratory volume in the first second of expiration
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable on 
exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention indicated
Disabling visual loss in affected 
eye(s)
Visual Changes (from baseline)
Visual changes causing no or 
minimal interference with usual 
social & functional activities
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities
Visual changes causing inability 
to perform usual social & 
functional activities
Disabling visual loss in affected 
eye(s)


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Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 100
12 December 2022
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Alopecia
Thinning detectable by study 
participant or caregiver (for 
disabled adults)
Thinning or patchy hair loss 
detectable by health care 
provider
Complete hair loss
NA
Cutaneous Reaction – Rash
Localized macular rash
Diffuse macular, maculopapular, 
or morbilliform rash OR Target 
lesions
Diffuse macular, maculopapular, 
or morbilliform rash with 
vesicles or limited number of 
bullae OR Superficial 
ulcerations of mucous 
membrane limited to one site
Extensive or generalized bullous 
lesions OR Stevens-Johnson 
syndrome OR Ulceration of 
mucous membrane involving 2 
or more distinct mucosal sites 
OR Toxic epidermal necrolysis
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis
(itching – no skin lesions)
(See also Injection Site 
Reactions: Pruritis associated 
with injection)
Itching causing no or minimal 
interference with usual social & 
functional activities
Itching causing greater than 
minimal interference with usual 
social & functional activities
Itching causing inability to 
perform usual social & 
functional activities
NA


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Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight loss
Loss of appetite associated 
with significant weight loss
Life-threatening consequences 
OR Aggressive intervention 
indicated [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated (eg, 
diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation)
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea
Adult and Pediatric  1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of  3 stools over 
baseline/24 hours
Persistent episodes of 
unformed to watery stools OR 
Increase of 4 to 6 stools over 
baseline per 24 hours
Bloody diarrhea OR Increase 
of  7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric  1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 102
12 December 2022
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis
(clinical examination)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea
Transient ( 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 
 48 hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis 
(functional- symptomatic)
Also see Mucositis/Stomatitis for 
Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated
Symptoms causing inability to 
perform usual 
social/functional activities OR 
Operative intervention 
indicated
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)
ER = emergency room; IV = intravenous


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 103
12 December 2022
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-Behavior 
or in Mood (eg, agitation, anxiety, 
depression, mania, psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities
Alteration causing greater 
than minimal interference 
with usual social & functional 
activities
Alteration causing inability to 
perform usual social & 
functional activities
Behavior potentially harmful to self 
or others (eg, suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing inability to 
perform basic self-care functions
Altered Mental Status
For Dementia, see Cognitive and 
Behavioral/Attentional Disturbance 
(including dementia and Attention 
Deficit Disorder)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities
Disabling ataxia causing inability to 
perform basic self-care functions
Cognitive and 
Behavioral/Attentional Disturbance 
(including dementia and Attention 
Deficit Disorder)
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care functions 
OR Institutionalization indicated
Central Nervous System Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident (stroke) 
with neurological deficit
Developmental delay
Pediatric  16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Developmental regression, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 104
12 December 2022
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care functions 
OR Hospitalization indicated (other 
than ER visit) OR Headache with 
significant impairment of alertness 
or other neurologic function
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-care 
functions
Neuromuscular Weakness
(including myopathy & neuropathy)
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no 
or minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation
Neurosensory Alteration (including 
paresthesia and painful neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or 
minimal interference with 
usual social & functional 
activities
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & functional 
activities
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care functions
Seizure: (new onset)
NA
1 seizure
2–4 seizures
Seizures of any kind that are 
prolonged, repetitive (eg, status 
epilepticus), or difficult to control 
(eg, refractory epilepsy)
Seizure: (preexisting)
For Worsening of Existing Epilepsy 
the Grades Should Be Based on an 
Increase from Previous Level of 
Control to Any of These Levels
NA
Increased frequency of 
preexisting seizures 
(nonrepetitive) without 
change in seizure character 
OR infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality 
(eg, severity or focality)
Seizures of any kind that are 
prolonged, repetitive (eg, status 
epilepticus), or difficult to control 
(eg, refractory epilepsy)


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 105
12 December 2022
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure
– Pediatric  18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting
5 to 20 minutes with
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting
> 20 minutes
Seizure, generalized onset with or 
without secondary generalization, 
requiring intubation and sedation
Syncope (not associated with a 
procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing inability 
to perform basic self-care functions
ER = emergency room


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 106
12 December 2022
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
See also Arthritis
Joint pain causing no or minimal 
interference with usual social & 
functional activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability to 
perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual social & 
functional activities
Stiffness or joint swelling 
causing greater than minimal 
interference with usual social & 
functional activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0
BMD t-score or z-score
 –2.5
Pathological fracture (including 
loss of vertebral height)
Pathologic fracture causing 
life-threatening consequences
Pediatric  21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture (including 
loss of vertebral height)
Pathologic fracture causing 
life-threatening consequences
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with usual 
social & functional activities
Muscle pain causing greater 
than minimal interference with 
usual social & functional 
activities
Muscle pain causing inability to 
perform usual social & 
functional activities
Disabling muscle pain causing 
inability to perform basic 
self-care functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND No 
operative intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic 
self-care functions
BMD = bone mineral density


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 107
12 December 2022
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening bronchospasm 
OR laryngeal edema
Chills
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7 C to 38.6 C
99.8 F to 101.5 F
38.7 C to 39.3 C
101.6 F to 102.8 F
39.4 C to 40.5 C
102.9 F to 104.9 F
 40.5 C
 104.9 F
Pain- Indicate Body Site
See also Injection Site Pain, 
Headache, Arthralgia, and 
Myalgia
Pain causing no or minimal 
interference with usual social & 
functional activities
Pain causing greater than 
minimal interference with usual 
social & functional activities
Pain causing inability to perform 
usual social & functional 
activities
Disabling pain causing inability 
to perform basic self-care 
functions OR Hospitalization 
(other than ER visit) indicated
Unintentional Weight Loss
NA
5% to 9% loss in body weight 
from baseline
10% to 19% loss in body weight 
from baseline
 20% loss in body weight from 
baseline OR Aggressive 
intervention indicated (eg, tube 
feeding or total parenteral 
nutrition)
ER = emergency room


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 108
12 December 2022
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain without 
touching)
Or Tenderness (pain when area 
is touched) 
Pain/tenderness causing no or 
minimal limitation of use of 
limb
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social & 
functional activities
Pain/tenderness causing inability 
to perform usual social & 
functional activities
Pain/tenderness causing inability 
to perform basic self-care 
function OR Hospitalization 
(other than ER visit) indicated 
for management of 
pain/tenderness
Injection Site Reaction 
(localized)
Adult and Pediatric 
 15 Years
Erythema OR Induration
of 5  5 cm to 9  9 cm (or 25-
81 cm2)
Erythema OR Induration OR 
Edema  9 cm any diameter (or 
 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pediatric  15 Years
Erythema OR Induration OR 
Edema present but  2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (eg, upper 
arm/thigh)
Erythema OR Induration OR 
Edema involving  50% surface 
area of the extremity segment 
(eg, upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection site 
AND Relieved spontaneously or 
with  48 h treatment
Itching beyond the injection site 
but not generalized OR Itching 
localized to injection site 
requiring  48 h treatment
Generalized itching causing 
inability to perform usual social 
& functional activities
NA
ER = emergency room


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 109
12 December 2022
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back of 
neck, breasts, abdomen)
Detectable by study participant 
or caregiver (for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to 
initiate medication OR 
Modification of current meds to 
regain glucose control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, hyperosmolar 
non-ketotic coma)
Gynecomastia
Detectable by study participant 
or caregiver (for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
suppression therapy indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification
Life-threatening consequences
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
replacement therapy indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss from 
the face, extremities, buttocks)
Detectable by study participant 
or caregiver (for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


Vesatolimod
Protocol GS-US-382-1587
Final
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 110
12 December 2022
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with 
life-threatening hypotension OR 
Operative intervention indicated
Urinary Tract obstruction 
(eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other than HIV 
infection)
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social & 
functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Operative intervention (other 
than simple incision and 
drainage) indicated
Life-threatening consequences
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


protocol GS-US-382-1587 amd-3
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
PPD
PPD

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N
St u d y Title:
A P hase 1, O pe n-la bel, M ultic o h ort St u d y t o E val uate t he 
I m pact of I n hi bit ors a n d I n d ucers of C yt oc hr o me P 4 5 0 
E nz y me ( C Y P) 3 A a n d/ or P- gl yc o pr otei n ( P- g p) o n t he 
P har mac o ki netics ( P K) of Vesat oli m o d ( V E S) i n 
Vir ol o gicall y S u p presse d A d ults Wit h HI V- 1 o n 
A ntiretr o viral T hera p y ( A R T)
St u d y P h ase:
1
N a me of Test Dr u g:      
Vesat oli m o d
St u d y N u m ber:
G S- U S- 3 8 2- 1 5 8 7
Pr ot oc ol Versi o n ( D ate):   
A me n d me nt 3 ( 1 2 Dece m ber 2 0 2 2)
A n al ysis T y pe:
Fi nal A nal ysis 
A n al ysis Pl a n Versi o n:      
1. 0 
A n al ysis Pl a n D ate:      
1 9 Ja n uar y 2 0 2 4
A n al ysis Pl a n A ut h or(s):
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
P P D
[r) GI L  E  A  U 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2
1 9 Ja n uar y 2 0 2 4
T A B L E O F C O N T E N T S
S T A TI S TI C A L A N A L Y SI S P L A N............................................................................................................................... 1
T A B L E O F C O N T E N T S................................................................................................................................................ 2
LI S O F I N- T E X T T A B L E S............................................................................................................................................ 3
LI S T O F I N- T E X T FI G U R E S........................................................................................................................................ 3
LI S T O F A B B R E VI A TI O N S......................................................................................................................................... 4
P H A R M A C O KI N E TI C A B B R E VI A TI O N S................................................................................................................. 5
1.  
I N T R O D U C TI O N.................................................................................................................................................. 6
1. 1.    
St u d y O bjecti ves a n d E n d p oi nts................................................................................................................ 6
1. 2.    
St u d y Desi g n ............................................................................................................................................. 6
1. 3.    
Sa m ple Size a n d P o wer........................................................................................................................... 1 1
2.   
T Y P E O F P L A N N E D A N A L Y SI S...................................................................................................................... 1 2
2. 1.    I nteri m A nal ysis ...................................................................................................................................... 1 2
2. 2.    
Fi nal A nal ysis.......................................................................................................................................... 1 2
2. 3.    
C ha n ges fr o m Pr ot oc ol- S pecifie d A nal ysis............................................................................................. 1 2
3.    
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S............................................................................. 1 3
3. 1.     
A nal ysis Sets ........................................................................................................................................... 1 3
3. 1. 1.       
All E nr olle d  A nal ysis Set...................................................................................................... 1 3
3. 1. 2.      
Safet y A nal ysis Set................................................................................................................ 1 3
3. 1. 3.      
P har mac o ki netic A nal ysis Sets.............................................................................................. 1 3
3. 2.    
Strata a n d C o variates............................................................................................................................... 1 3
3. 3.    
E xa mi nati o n of Partici pa nt S u b gr o u ps.................................................................................................... 1 3
3. 4.      M ulti ple C o m paris o ns............................................................................................................................. 1 3
3. 5.      Missi n g Data a n d O utliers....................................................................................................................... 1 4
3. 5. 1.        Missi n g Data.......................................................................................................................... 1 4
3. 5. 2.       
O utliers.................................................................................................................................. 1 4
3. 6.     
Data Ha n dli n g C o n ve nti o ns a n d Tra nsf or mati o ns.................................................................................. 1 4
3. 7.     
Visit Defi niti o ns...................................................................................................................................... 1 6
3. 7. 1.       
Defi niti o n of Pre d ose, P ost d ose, a n d St u d y Da y................................................................... 1 6
3. 7. 2.       
A nal ysis Visits....................................................................................................................... 1 6
3. 7. 3.      
Selecti o n of Data i n t he E ve nt of M ulti ple Rec or ds o n t he Sa me Da y ................................. 1 7
4.   P A R TI CI P A N T DI S P O SI TI O N .......................................................................................................................... 1 8
4. 1.    
Partici pa nt E nr oll me nt a n d Dis p ositi o n................................................................................................... 1 8
4. 2.    
E xte nt of E x p os ure.................................................................................................................................. 1 8
4. 3.    
Pr ot oc ol De viati o ns................................................................................................................................. 1 9
4. 4.     
Assess me nt of C O VI D- 1 9 I m pact........................................................................................................... 1 9
4. 4. 1.      
St u d y Dr u g or St u d y Disc o nti n uati o n D ue t o C O VI D- 1 9..................................................... 1 9
4. 4. 2.      
Pr ot oc ol De viati o ns D ue t o C O VI D- 1 9 ................................................................................ 1 9
4. 4. 3.        Misse d a n d Virt ual Visits d ue t o C O VI D- 1 9........................................................................ 1 9
4. 4. 4.       
A d verse E ve nts D ue t o C O VI D- 1 9....................................................................................... 1 9
5.   
B A S E LI N E C H A R A C T E RI S TI C S..................................................................................................................... 2 0
5. 1.     
De m o gra p hics a n d Baseli ne C haracteristics ........................................................................................... 2 0
5. 2.     
Ot her Baseli ne C haracteristics ................................................................................................................ 2 0
5. 3.      Me dical Hist or y....................................................................................................................................... 2 0
6.   
E F FI C A C Y A N A L Y S E S..................................................................................................................................... 2 1


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3
1 9 Ja n uar y 2 0 2 4
7.   S A F E T Y A N A L Y S E S......................................................................................................................................... 2 2
7. 1.     
A d verse E ve nts a n d Deat hs..................................................................................................................... 2 2
7. 1. 1.       
A d verse E ve nt Dicti o nar y ..................................................................................................... 2 2
7. 1. 2.       
A d verse E ve nt Se verit y......................................................................................................... 2 2
7. 1. 3.      
Relati o ns hi p of A d verse E ve nts t o St u d y Dr u g..................................................................... 2 2
7. 1. 4.      
Relati o ns hi p of A d verse E ve nts t o St u d y Pr oce d ure............................................................. 2 2
7. 1. 5.      
Seri o us A d verse E ve nts......................................................................................................... 2 2
7. 1. 6.      
Treat me nt- E mer ge nt A d verse E ve nts.................................................................................... 2 2
7. 1. 6. 1.        Defi niti o n of Treat me nt E mer ge nt A d verse E ve nts ........................................ 2 2
7. 1. 6. 2.      
I nc o m plete Dates............................................................................................. 2 3
7. 1. 7.      
S u m maries of A d verse E ve nts a n d Deat hs............................................................................ 2 3
7. 1. 8.       
A d diti o nal A nal ysis of A d verse E ve nts ................................................................................ 2 4
7. 2.    
La b orat or y E val uati o ns ........................................................................................................................... 2 4
7. 2. 1.      
S u m maries of N u meric La b orat or y Res ults.......................................................................... 2 5
7. 2. 2.       
Gra de d La b orat or y Val ues .................................................................................................... 2 5
7. 2. 2. 1.      
Treat me nt- E mer ge nt La b orat or y A b n or malities ............................................. 2 5
7. 2. 2. 2.      
S u m maries of La b orat or y A b n or malities ........................................................ 2 5
7. 3.    
B o d y Wei g ht, Hei g ht, B MI, a n d Vital Si g ns........................................................................................... 2 6
7. 4.    
Pri or a n d C o nc o mita nt Me dicati o ns........................................................................................................ 2 6
7. 5.    
Electr ocar di o gra m Res ults....................................................................................................................... 2 6
7. 5. 1.      I n vesti gat or Electr ocar di o gra m Assess me nt ......................................................................... 2 7
7. 6.     
Ot her Safet y Meas ures ............................................................................................................................ 2 7
8.   P H A R M A C O KI N E TI C E V A L U A TI O N/ A N A L Y SI S........................................................................................ 2 8
8. 1.    
Esti mati o n of P har mac o ki netic Para meters............................................................................................. 2 8
8. 2.    
P har mac o ki netic Para meters ................................................................................................................... 2 8
8. 3.    
Statistical A nal ysis Met h o ds................................................................................................................... 2 9
8. 3. 1.       
Ge neral C o nsi derati o ns ......................................................................................................... 2 9
8. 3. 2.      
Statistical Met h o d ol o g y......................................................................................................... 3 1
8. 3. 2. 1.        A nal ysis of Dr u g- Dr u g I nteracti o n.................................................................. 3 1
8. 4.    
Se nsiti vit y A nal ysis................................................................................................................................. 3 2
9.   
R E F E R E N C E S..................................................................................................................................................... 3 3
1 0. 
S O F T W A R E......................................................................................................................................................... 3 4
1 1. 
S A P R E VI SI O N................................................................................................................................................... 3 5
1 2.  
A P P E N DI C E S...................................................................................................................................................... 3 6
LI S O F I N- T E X T T A B L E S
Ta ble 8- 1.       
St u d y Treat me nts a n d Ass ociate d A nal ytes ............................................................................ 2 8
Ta ble 8- 2.       
P har mac o ki netic Para meters f or Eac h A nal yte i n Plas ma....................................................... 2 9
Ta ble 8- 3.       
Statistical C o m paris o ns f or P har mac o ki netic A nal yses.......................................................... 3 1
Ta ble 1 2- 1.       
St u d y Pr oce d ures Ta ble f or C o h ort 1, Peri o d 1 a n d 2............................................................. 3 7
Ta ble 1 2- 2.       
St u d y Pr oce d ures Ta ble f or C o h ort 1, Peri o d 3....................................................................... 4 0
Ta ble 1 2- 3.       
St u d y Pr oce d ures Ta ble f or C o h ort 2, Peri o ds 1 a n d 2 ........................................................... 4 2
Ta ble 1 2- 4.       
E xa m ple Searc h Ter ms f or “ C O VI D- 1 9” a n d “ Virt ual” Use d t o I de ntif y 
Misse d/ Virt ual Visits............................................................................................................... 4 6
LI S T O F I N- T E X T FI G U R E S
Fi g ure 1.       
St u d y Sc he ma............................................................................................................................ 7


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4
1 9 Ja n uar y 2 0 2 4
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A R T
a ntiretr o viral t hera p y
B C R P      
breast ca ncer resista nce pr otei n
B L Q
bel o w t he li mit of q ua ntitati o n
B MI
b o d y mass i n de x
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
C O BI      
C o bicistat
C R F
case re p ort f or m
C S R
cli nical st u d y re p ort
C V
c oefficie nt of variati o n
d- R F B      
2 5- O- desacet ylrifa b uti n
D AI D S      
Di visi o n of Ai ds
D M C      
data m o nit ori n g c o m mittee
E C G
Electr ocar di o gra m
E T
earl y ter mi nati o n
F B X
Fe b u x ostat
Gilea d      
Gilea d Scie nces
G L S M      
ge o metric least-s q uares mea n
L O Q
li mit of q ua ntitati o n
Me d D R A      
Me dical Dicti o nar y f or Re g ulat or y Acti vities
P K
p har mac o ki netic
P T
preferre d ter m
Q 1, Q 3      
first q uartile, t hir d q uartile
R F B
Rifa b uti n
S A P
statistical a nal ysis pla n
S D
sta n dar d de viati o n
SI 
I nter nati o nal S yste m of U nits ( S yste me I nter nati o nal d’ U nites)
S O C
s yste m or ga n class
T E A E      
treat me nt-e mer ge nt a d verse e ve nt
T F Ls      
ta bles, fi g ures, a n d listi n gs
T O S T      
t w o o ne-si de d tests
U L N
u p per li mit of n or mal
V E S
Vesat oli m o d
V O R
V oric o naz ole
W H O
W orl d Healt h Or ga nizati o n


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 5
1 9 Ja n uar y 2 0 2 4
P H A R M A C O KI N E TI C A B B R E VI A TI O N S
z
ter mi nal eli mi nati o n rate c o nsta nt, esti mate d b y li near re gressi o n of t he ter mi nal eli mi nati o n 
p hase of t he l o g plas ma c o nce ntrati o n of dr u g vers us ti me c ur ve of t he dr u g
% A U C
e x p
perce nta ge of A U C e xtra p olate d bet wee n A U C last a n d A U Ci nf
A U C last
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o t he last q ua ntifia ble 
c o nce ntrati o n
A U C i nf
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve e xtra p olate d t o i nfi nite ti me, calc ulate d 
as A U C last + ( Clast/z)
A U C ta u
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve o ver t he d osi n g i nter val
C L/ F
a p pare nt oral cleara nce after a d mi nistrati o n of t he dr u g:
C L/ F = D ose/ A U C i nf, w here “ D ose” is t he d ose of t he dr u g
C last
last o bser ve d q ua ntifia ble plas ma c o nce ntrati o n of t he dr u g
C ma x
ma xi m u m o bser ve d plas ma c o nce ntrati o n of dr u g
C tr o u g h
o bser ve d plas ma c o nce ntrati o n of dr u g at t he e n d of t he d osi n g i nter val
t½
esti mate of t he ter mi nal eli mi nati o n half-life of t he dr u g i n plas ma, calc ulate d b y di vi di n g t he 
nat ural l o g of 2 b y t he ter mi nal eli mi nati o n rate c o nsta nt ( z)
T last
ti me ( o bser ve d ti me p oi nt) of C last
T ma x
ti me ( o bser ve d ti me p oi nt) of C ma x
V z/ F
a p pare nt v ol u me of distri b uti o n of t he dr u g V z/ F = D ose/( z* A U C i nf), w here “ D ose” is t he d ose 
of t he dr u g


V e s a  t oli  m o d 
G S-  U S- 3 8 2  -1 5 8 7 
St ati sti c al  A n al y si  s  Pl a n  -  Fi n a l A n al y  s i s 
L 
I  N T  R  O  D  U  C  T I  O  N 
V er si o n   1. 0 
T hi s  st atisti c al a n al ysis  pl a n  ( S  A P) d e s c ri b e s t h e st atisti c al a n al ysis m et h o ds  a n d  d at a 
pr e s e n t ati ons  t o b e  u s e d i n t abl es , fi gur es,  a n d  listi n g s ( T F Ls)  i n t h e cl i ni c al st u d y r e p o1t   (  C SR) 
f or St u d y  G S  -U S  -3 8 2 - 15 8 7 . T h i s S  A P  i s b a s e d  o n t h e  st u d y pr ot o c ol  A  m e  n d  m e nt  3  d at e d 
1 2  D e c e  m  b er  2 0 2 2  a n d  t h e el e ctr o n i c c a s e  r e p o 1t f 0 1  m ( e  C  R F). T h e  S  A P  wi  ll b e  fin a liz e d pr i or 
t o d at a b a s e  fi n ali z ati o n. A n y   c h a n g e s  m a d e   aft er  fin ali z ati o n of t h e S  A P  wi  ll b e  d o c u  m e nt e d i n 
t h e C S R. 
1. 1. 
S t u dy  O bj e  c tiv e s  a n d  E  n d p oi nt s 
P ri  m a r y  O bj  e c tiv e(s) 
T o  e v  al u a t e t he  i  m p a ct of th e f oll o  wi n g dr u g s o n V E S P  K 
•      C o bi ci s t at ( P-g p , B  C  R P  , a n d  str o n g  C  Y P 3  A  i n hi bit or) 
•      V ori c o n a z ol e ( str o n g C  Y P 3  A  i n hi bitor) 
•      Rif a b uti n  (m o d er at e   C  Y P 3  A  i n d u c er) 
T o  e v  al u a t e t he  s af et y of  V  E S a d  mi ni st er e d  al o n e  a n d i n 
c o  m bi n ati o n  wit h   i n hi bit ors  a n d  i n d u c er s of m et a b oli zi n g 
e n z y  m e s  a n d  tr a nsp o 1ters  i nv ol v e d i n V E S   di s p o siti o n 
---
1. 2. 
S t u dy  D e  si g n 
P ri  m a r y  E  n d p o i nt(s) 
P ri  m a1 y P  K p ar a  m et er s thr o u g h o ut  th e s t u d y 
•      V E S A  U C 1 as 1 , A  U Ci nf , C  m a x 
S e c o n d ar y P  K p ar a  m et er s thr o u g h o ut  th e s t u d y 
•      V E S   %  A  U C e x. p , T  m a x , C 1 as, , T 1ast, t cz, t1 1 2, 
C L/ F  , V/  F 
S af et y p ar a  m eter s 
•      I n ci d e n c e of T  E  A Es   a n d  l a b or ato 1 y 
a b n or  m ali ti es t h r o u g h o ut t h e s t u d y 
I I 
T hi s  is a n  o p e n -la b e l, m ulti c o h o 1t   P h a s e  1  st u d y t o e v al u at e  t h e i  m p a ct of i n hi bit ors  a n d i n d u c ers 
of C  Y P 3  A  a n d/ o r  P-g p  o n t h e P  K a n d  P  D of V E S   i n vi r ol o gi c ally  s u p pr e s s e d a du lts wit h   H I  V- 1 
o n a ntir etr o vir al t h er a p y (  A  R T). 
T h e  stu d y  wi  ll b e c o n d u ct e d i n 2  c o h o 1t s: 
•     C o h o 1t 1: A n o p e n- l a b el, si n gl e s e q u e n c e c o h o 1t  t o e v al u a t e t h e i  m p a ct of c o bi ci s t at (  C  O  BI; 
P- g p,  B  C  R P  ,  a n d str on g  C  Y P 3  A   i n hibit or)  a n d v o ri c o n a z ol e (  V  O  R; str o n g C  Y P 3  A  i n hibit o r) 
o n V E S P  K a n d  P  D 
•     C o h o 1t  2: A n o p e n- l a b el, si n gl e s e q u e n c e c o h o 1t  t o e v al u a t e t h e i  m p a ct of rif ab ut i n 
(  R F  B; m o d er at e   C  Y P 3  A   i n d u c er)  o n V E S   P  K  a n d  P  D 
C  O  N FI  D E  N TI  A L 
P a g e 6 
1 9 J a n u a 1 y 2 0 2 4 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 7
1 9 Ja n uar y 2 0 2 4
A safet y re vie w tea m will assess rele va nt a n d a vaila ble safet y data f or t he first 3 partici pa nts i n 
C o h ort 1 w h o are d ose d wit h C O BI ( u p t o a n d i ncl u di n g Peri o d 2 Da y 3) bef ore i nitiati o n of a n y 
a d diti o nal partici pa nts i n C o h ort 1.
T he st u d y sc he ma f or eac h c o h ort is s h o w n bel o w i n Fi g ure 1 .
Fi g ure 1.
St u d y Sc he m a
A R T = a ntiretr o viral t hera p y; C O BI = c o bicistat; D T G = d ol ute gra vir; R F B = rifa b uti n; S R T = safet y re vie w tea m; 
V E S = vesat oli m o d; V O R = v oric o naz ole
a     A n S R T re vie w of t he a vaila ble safet y data after t he first 3 partici pa nts w h o are d ose d wit h C O BI i n C o h ort 1 u p t o a n d 
i ncl u di n g Peri o d 2 Da y 3 s h o ul d occ ur bef ore i nitiati o n of t he rest of t he c o h ort.
b   
Pr os pecti ve partici pa nts s h o ul d be scree ne d wit hi n 3 5 da ys pri or t o a d mi nistrati o n of t he first d ose of st u d y dr u g.
c     
Was h o ut peri o d of 7 t o 1 4 da ys bet wee n treat me nts i n Peri o d 1 Da y 1 a n d Peri o d 2 Da y 1.
d     
Was h o ut of peri o d of 1 4 t o 2 1 da ys bet wee n treat me nts i n Peri o d 2 Da y 5 a n d Peri o d 3 Da y 1
P h ar m ac o ki netic Assess me nts
Pl as m a P K:
Plas ma sa m ples f or q ua ntificati o n of V E S c o nce ntrati o ns will be c ollecte d at t he f oll o wi n g ti me 
p oi nts relati ve t o V E S d osi n g i n eac h peri o d:
•
Pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 0. 2 5, 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, 8, 1 2, 2 4, 4 8, 
7 2, a n d 9 6 h o urs p ost d ose
Plas ma c o nce ntrati o ns of C O BI, V O R, a n d R F B ma y be deter mi ne d a n d P K para meters ma y be 
esti mate d.
I C o h o rt :IP' ' ]I 
I 
C o h o rt : 2 II 
S  U 
n f n g' 
(  D T  G- b ais e d A R T } 
V  O 
P  C!ti o d 1 
l ?l!'ti od  2 
D a y  :! . 
ll ay  2 
D. 3t, o, S 
\/ E S 2ffli 
o o e.I t s o,m, 
V E S 2 m 1 + 
o o e.I 1 s o  m, 
C  O B 1 1 S 0  m 1 
P erit > d 3 
O,;i: v 1 
l0.i:'f 2 . 
O;i y 3 
O, a, n 4 1 t o,  G 
A  MI 
P  M 
A  M 
P  M 
A  M 
P  M 
A  M 
I 
P  M 
O  O  m 1 1 
V' 0  R 4 0 0r n 1 
V  O A 2 0 0 1mf 
V  O  R 2 0 0  m 1 1 
V E S. 2: Mi + 
V  O  R 2 0 0  m 1 1       \/  O  R 2 0 0 llllll 
V  O  R 2 0 0  m g 
\l'  O  R.2 0 0  m g 
P   ti o d 1 
P r ai o d 
\/ E S 6  m g 
R F:  B 3 0 0 n, c 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 8
1 9 Ja n uar y 2 0 2 4
Ti me wi n d o ws all o we d f or P K sa m ples t o be c ollecte d are pr o vi de d i n Ta ble 8 of t he st u d y 
pr ot oc ol.
Cli nical staff s h o ul d ma ke e ver y eff ort t o e ns ure t hat t he sa m pli n g ti me is as cl ose as p ossi ble t o 
t he n o mi nal ti me. T he e xact ti me a n d date of t he bl o o d dra w m ust be rec or de d i n t he electr o nic 
data ca pt ure ( E D C) s yste m.
Bi o m ar ker Testi n g
Bi o mar ker sa m ples will be c ollecte d t o assess t he P D a n d safet y f oll o wi n g V E S a d mi nistrati o n.
Ser u m sa m ples f or bi o mar ker assess me nts will be c ollecte d at t he f oll o wi n g ti me p oi nts relati ve 
t o V E S d osi n g i n eac h peri o d:
•
Pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 4, 8, 1 2, 2 4, 4 8, a n d 9 6 h o urs p ost d ose
T he ser u m bi o mar kers t o be e val uate d ma y i ncl u de ( b ut n ot li mite d t o): i nterfer o n-al p ha (I F N- α), 
i nterle u ki n (I L)- 1 rece pt or a nta g o nist, i nterfer o n- ga m ma i n d uci ble pr otei n- 1 0, i nterfer o n-
i n d uci ble T cell al p ha c he m oattracta nt, i nterfer o n- ga m ma, I L- 1 beta, I L- 6, t u m or necr osis fact or 
al p ha, a n d C-reacti ve pr otei n.
W h ole bl o o d sa m ples f or I S G m R N A e x pressi o n (i ncl u di n g, b ut n ot li mite d t o, M X 1, I S G 1 5, 
O A S 1) will be c ollecte d at t he f oll o wi n g ti me p oi nts relati ve t o V E S d osi n g i n eac h peri o d:
•
Pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs p ost d ose
W h ole bl o o d f or i m m u ne cell p he n ot y pi n g will be c ollecte d at t he f oll o wi n g ti me p oi nts relati ve 
t o V E S d osi n g i n eac h peri o d
•
Pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 2 4, 7 2, a n d 9 6 h o urs p ost d ose
W h ole bl o o d t o e val uate V E S Tr u C ult ure c yt o ki ne res p o nse will be c ollecte d f or C o h ort 2 at t he 
f oll o wi n g visit i n Peri o d 1
•
O n Da y 1 ( pre d ose)
A ti me wi n d o w of ± 1 0 % will be all o we d f or bi o mar ker sa m ples c ollecte d t hr o u g h 8 h o urs 
p ost d ose. Bi o mar ker sa m ples c ollecte d be y o n d 8 h o urs p ost d ose will ha ve a ± 3 0- mi n ute 
wi n d o w.
Cli nical staff s h o ul d ma ke e ver y eff ort t o e ns ure t hat t he sa m pli n g ti me is as cl ose as p ossi ble t o 
t he n o mi nal ti me. T he e xact ti me a n d date of t he bl o o d dra w m ust be rec or de d i n t he E D C 
s yste m.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 9
1 9 Ja n uar y 2 0 2 4
P h ar m ac o ge netic Assess me nts
A p har mac o ge netics ( P G x) sa m ple will be c ollecte d o n Da y 1 Peri o d 1 if a p plica ble ( prefera bl y) 
or at a n y ot her ti me d uri n g t he st u d y f or t oll-li ke rece pt or 7 ( T L R 7) a n d B C R P (als o k n o w n as 
t he a de n osi ne tri p h os p hate- bi n di n g cassette tra ns p orter G 2; ge ne s y m b ol A B C G 2 ) ge n ot y pi n g.
C o h ort 1 ( o nl y): A P G x sa m ple f or C Y P 2 C 1 9 ge n ot y pi n g will be c ollecte d at scree ni n g as part of 
t he i ncl usi o n/e xcl usi o n criteria.
S afet y Assess me nts
Safet y assess me nts will i ncl u de a c o m plete a n d s y m pt o m- dri ve n p h ysical e xa mi nati o n, vital 
si g ns, hei g ht, wei g ht, cli nical la b orat or y tests, uri ne dr u g a n d alc o h ol assess me nts, 1 2-lea d 
electr ocar di o gra m ( E C G), pre g na nc y testi n g, H B V a n d H C V testi n g, HI V- 1 viral l oa d test, C D 4 
cell c o u nt test, S A R S- C o V- 2 test, a n d assess me nt of A Es.
All safet y assess me nts will be c o m plete d pre d ose u nless ot her wise s pecifie d.
•
C o m plete p hysic al ex a mi n ati o n: Scree ni n g, f oll o w- u p, a n d earl y ter mi nati o n ( E T) visits, 
if a p plica ble
•
Sy m pt o m- drive n p hysic al ex a mi n ati o n:  e ver y da y d uri n g c o nfi ne me nt, as nee de d, base d o n 
re p orte d si g ns a n d s y m pt o ms
•
Vit al si g ns ( bl o o d press ure, he art r ate, oxy ge n s at ur ati o n, a n d b o dy te m per at ure):

C o h ort 1: Scree ni n g, Peri o d 1 Da y 1 pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) a n d 2, 4, 
8, 1 2, a n d 2 4 h o urs p ost d ose; Peri o d 2 Da y 2 pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) 
a n d 2, 4, 8, 1 2, a n d 2 4 h o urs p ost d ose; Peri o d 3 Da y 3 pre d ose ( wit hi n 1 h o ur bef ore V E S 
d osi n g) a n d 2, 4, 8, 1 2, a n d 2 4 h o urs p ost d ose; at t he f oll o w- u p visit, a n d at t he E T visit, 
if a p plica ble

C o h ort 2: Scree ni n g, Peri o d 1 Da y 1 pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) a n d 2, 4, 
8, 1 2, a n d 2 4 h o urs p ost d ose; Peri o d 2 Da y 6 pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) 
a n d 2, 4, 8, 1 2, a n d 2 4 h o urs p ost d ose; at t he f oll o w- u p visit, a n d at t he E T visit, 
if a p plica ble
•
Hei g ht:  Scree ni n g
•
Wei g ht:  

C o h ort 1: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 5, Peri o d 2 Da y 6, Peri o d 3 
Da y 7, at t he f oll o w- u p visit, a n d at t he E T visit, if a p plica ble

C o h ort 2: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 5, Peri o d 2 Da y 1 0, at t he 
f oll o w- u p visit, a n d at t he E T visit, if a p plica ble


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 0
1 9 Ja n uar y 2 0 2 4
•
C oa g ulati o n pa nel: Scree ni n g
•
Cli nical la b orat or y tests ( he mat ol o g y, c he mistr y, calc ulate d creati ni ne cleara nce, a n d 
uri nal ysis): 

C o h ort 1: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 5, Peri o d 2 Da y 6, Peri o d 3 
Da y 7, at t he f oll o w- u p visit, a n d at t he E T visit, if a p plica ble

C o h ort 2: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 5, Peri o d 2 Da y 1 0, at t he 
f oll o w- u p visit, a n d at t he E T visit, if a p plica ble
•
Uri ne dr u g a n d alc o h ol assess me nts: 

C o h ort 1: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 3, Peri o d 2 Da y 4, a n d 
Peri o d 3 Da y 5

C o h ort 2: Scree ni n g, Da y −1 of eac h peri o d, Peri o d 1 Da y 3, a n d Peri o d 2 Da y 8
N ote: O n Da y −1 (a d missi o n), 2 sets of safet y la b orat or y res ults f or he mat ol o g y, c he mistr y, 
uri nal ysis, uri ne dr u g, a n d alc o h ol assess me nts will be c ollecte d u p o n st u d y ce nter 
a d missi o n. O ne will be se nt t o t he ce ntral la b orat or y a n d t he ot her will be se nt t o t he site’s 
l ocal la b orat or y t o o btai n res ults i n ti me f or e nr oll me nt o n Da y 1.
If a st u d y ce nter ca n n ot perf or m a uri ne alc o h ol test or recei ve res ults fr o m t he l ocal 
la b orat or y i n ti me f or e nr oll me nt o n Da y 1, t he n a n alc o h ol breat hal yzer test is acce pta ble.
•
1 2-lea d E C G: 

C o h ort 1: Scree ni n g; Peri o d 1 Da ys 1, 2, a n d 5; Peri o d 2 Da ys 2, 3, a n d 6; Peri o d 3 
Da ys 3, 4, a n d 7

C o h ort 2: Scree ni n g, Peri o d 1 Da ys 1, 2, a n d 5; a n d Peri o d 2 Da ys 6, 7, a n d 1 0
•
Ser u m or uri ne pre g n a ncy test ( p artici p a nts assi g ne d fe m ale at birt h of c hil d be ari n g 
p ote nti al o nly): Scree ni n g (ser u m),  Da y −1 of eac h peri o d (ser u m or uri ne), at t he f oll o w- u p 
visit ( uri ne), a n d at t he E T visit ( uri ne), if a p plica ble. F or C o h ort 2 o nl y, a n at- h o me uri ne 
pre g na nc y test will be c o m plete d 1 0 da ys after t he last d ose of R F B. Partici pa nts will be 
c o ntacte d b y tele p h o ne t o re p ort at- h o me pre g na nc y test res ults.
N ote:  Pre g na nc y test res ult is re q uire d pri or t o d osi n g. If Da y −1 ser u m pre g na nc y test res ult 
is n ot a vaila ble, a ne gati ve uri ne pre g na nc y test ( perf or me d l ocall y) is re q uire d.
•
F ollicle-sti m ulati n g h or m o ne ( partici pa nts assi g ne d fe male at birt h w h o are y o u n ger t ha n 
5 4 years, n ot o n h or m o nal c o ntrace pti o n, a n d w h o ha ve st o p pe d me nstr uati n g f or at least 
1 2 m o nt hs b ut d o n ot ha ve d oc u me ntati o n of o varia n h or m o nal fail ure): Scree ni n g
•
He patitis B vir us, he patitis C vir us: Scree ni n g


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 1
1 9 Ja n uar y 2 0 2 4
•
HI V- 1 viral l oa d testi n g: 

C o h ort 1: Scree ni n g, a n d Da y −1 of Peri o d 2 a n d Peri o d 3

C o h ort 2: Scree ni n g a n d Da y −1 of Peri o d 2
•
C D 4 cell c o u nt: Scree ni n g
•
S A R S- C o V- 2: Da y −1 of eac h peri o d
•
Assess me nt of A Es a n d c o nc o mita nt me dicati o ns will c o nti n ue t hr o u g h o ut t he st u d y. All 
cli nical a n d cli nicall y si g nifica nt la b orat or y t o xicities will be ma na ge d acc or di n g t o u nif or m 
g ui deli nes detaile d i n pr ot oc ol A p pe n di x 1 1. 4.
A d diti o nal details re gar di n g st u d y assess me nts ca n be f o u n d i n A p pe n di x 1 .
1. 3.       
S a m ple Size a n d P o wer
Wit h 1 8 e val ua ble partici pa nts per c o h ort, t he esti mate d 2-si de d 9 0 % CI of t he G L S M rati o of 
test vers us refere nce treat me nts wit h re gar ds t o A U C i nf a n d Cma x  will be wit hi n ( 0. 5 0, 2. 0 0) wit h 
at least 9 0 % pr o ba bilit y if t he tr ue G L S M rati o was 1. 0. T his is ass u mi n g a r o ot mea n s q uare 
err or of n o m ore t ha n 0. 6 o n a nat ural l o garit h m scale, w hic h is s u p p orte d b y t he pre vi o us 
St u d y G S- U S- 2 3 4- 0 1 0 1. Wit h 3 5 % a n d 1 0 % o vera ge f or C o h orts 1 a n d 2, a t otal sa m ple size of 
2 5 partici pa nts a n d 2 0 partici pa nts will be re q uire d f or C o h orts 1 a n d 2; res pecti vel y. 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 2
1 9 Ja n uar y 2 0 2 4
2.       
T Y P E O F P L A N N E D A N A L Y SI S
2. 1.       
I nteri m A n al ysis
Pri or t o t he fi nal a nal ysis, i nteri m a nal yses ma y be c o n d ucte d a n d t he a nal yses ma y be s u b mitte d 
t o re g ulat or y a ge ncies t o see k g ui da nce f or t he o verall cli nical de vel o p me nt pr o gra m.
A safet y re vie w tea m ( S R T) will be esta blis he d t o assess rele va nt a n d a vaila ble safet y data f or 
t he first 3 partici pa nts i n C o h ort 1 w h o are d ose d wit h C O BI ( u p t o a n d i ncl u di n g Peri o d 2 
Da y 3) t o deci de t o c o nti n ue or halt e nr oll me nt of a d diti o nal partici pa nts i n C o h ort 1.
2. 2.       
Fi n al A n al ysis
T he fi nal a nal ysis will be perf or me d after all partici pa nts ha ve c o m plete d t he st u d y, o utsta n di n g 
data q ueries ha ve bee n res ol ve d or a dj u dicate d as u nres ol va ble, a n d t he data ha ve bee n clea ne d 
a n d fi nalize d. T he a nal ysis of t he pri mar y e n d p oi nt will be c o n d ucte d at t he ti me of t he  fi nal 
a nal ysis.
2. 3.        
C h a n ges fr o m Pr ot oc ol- S pecifie d A n al ysis
2 5 partici pa nts were pla n ne d f or C o h ort 1. D ue t o sl o w e nr oll me nt, C o h ort 1 was cl ose d after 
1 5 partici pa nts e nr olle d i n t he c o h ort.
Rifa b uti n is a m o derate C Y P 3 A i n d ucer, a n d plas ma V E S e x p os ures were e x pecte d t o decrease 
w he n c o-a d mi nistere d wit h R F B. H o we ver, base d o n i nteri m P K res ults fr o m 2 partici pa nts, V E S 
e x p os ure was i ncrease d w he n c o-a d mi nistere d wit h R F B. Gi ve n t his fi n di n g, C o h ort 2 was 
cl ose d t o f urt her e nr oll me nt.


Vesat oli m o d
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Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 3
1 9 Ja n uar y 2 0 2 4
3.        
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S
A nal ysis res ults will be prese nte d usi n g descri pti ve statistics. F or cate g orical varia bles, t he n u m ber 
a n d perce nta ge of partici pa nts i n eac h cate g or y will be prese nte d; f or c o nti n u o us varia bles, t he 
n u m ber of partici pa nts ( n), mea n, sta n dar d de viati o n ( S D) or sta n dar d err or ( S E), me dia n, 
first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d ma xi m u m will be prese nte d.
B y- partici pa nt listi n gs will be prese nte d f or all partici pa nts i n t he All E nr olle d A nal ysis Set, a n d 
s orte d b y partici pa nt i de ntificati o n (I D) n u m ber i n asce n di n g or der, visit date, a n d ti me 
(if a p plica ble), u nless ot her wise s pecifie d. Data c ollecte d o n l o g f or ms, s uc h as A Es, will be 
prese nte d i n c hr o n ol o gical or der wit hi n partici pa nt. A ge, se x at birt h, race, a n d et h nicit y will be 
i ncl u de d i n t he listi n gs, as s pace per mits.
3. 1.        
A n al ysis Sets
A nal ysis sets defi ne t he partici pa nts t o be i ncl u de d i n a n a nal ysis. A nal ysis sets a n d t heir 
defi niti o ns are pr o vi de d i n t his secti o n. T he a nal ysis set will be i de ntifie d a n d i ncl u de d as a 
s u btitle of eac h ta ble, fi g ure, a n d listi n g.
F or eac h a nal ysis set, t he n u m ber a n d perce nta ge of partici pa nts eli gi ble f or i ncl usi o n will be 
pr o vi de d i n t he dis p ositi o n ta ble as detaile d i n Secti o n 4 . A listi n g of reas o ns f or e xcl usi o n fr o m 
a nal ysis sets will be pr o vi de d b y partici pa nt.
3. 1. 1.        
All E nr olle d  A n al ysis Set
T he All E nr olle d A nal ysis Set i ncl u des all partici pa nts w h o recei ve d a st u d y partici pa nt 
i de ntificati o n n u m ber i n t he st u d y after scree ni n g. T his is t he pri mar y a nal ysis set f or safet y 
listi n gs.
3. 1. 2.       
S afet y A n al ysis Set
T he Safet y A nal ysis Set i ncl u des all partici pa nts w h o t o o k at least 1 d ose of st u d y dr u g. T his is 
t he pri mar y a nal ysis set f or safet y a nal yses.
3. 1. 3.       
P h ar m ac o ki netic A n al ysis Sets
T he P K  A nal ysis Sets will i ncl u de all e nr olle d partici pa nts w h o t o o k at least 1 d ose of st u d y dr u g 
a n d ha ve at least 1 n o n missi n g p ost d ose c o nce ntrati o n val ue re p orte d b y t he P K la b orat or y f or 
t he c orres p o n di n g a nal ytes. T hese are t he pri mar y a nal ysis sets f or all P K a nal yses. 
3. 2.       
Str at a a n d C o v ari ates
T his st u d y d oes n ot use a stratifie d ra n d o mizati o n sc he d ule i n e nr olli n g partici pa nts. 
N o c o variates will be i ncl u de d i n t he a nal yses.
3. 3.       
E x a mi n ati o n of P artici p a nt S u b gr o u ps
T here are n o pres pecifie d partici pa nt s u b gr o u pi n gs f or a nal yses.
3. 4.        
M ulti ple C o m p aris o ns
A dj ust me nts f or m ulti plicit y will n ot be ma de, beca use n o f or mal statistical testi n g will be 
perf or me d i n t his st u d y.


Vesat oli m o d
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Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 4
1 9 Ja n uar y 2 0 2 4
3. 5.        
Missi n g D at a a n d O utliers
3. 5. 1.        
Missi n g D at a
I n ge neral, missi n g data will n ot be i m p ute d u nless met h o ds f or ha n dli n g missi n g data are 
s pecifie d. E xce pti o ns are prese nte d i n t his d oc u me nt. Missi n g P K sa m pli n g dates ma y be 
i m p ute d base d o n ot her visit i nf or mati o n. Missi n g P K sa m pli n g ti mes ma y be i m p ute d t o 
n o mi nal ti mes. Missi n g dr u g c o nce ntrati o ns will n ot be i m p ute d.
T he ha n dli n g of missi n g or i nc o m plete dates f or A E o nset is descri be d i n Secti o n 7. 1. 6. 2 .
3. 5. 2.        
O utliers
O utliers of n o n- P K data will be i de ntifie d d uri n g t he data ma na ge me nt a n d data a nal ysis pr ocess, 
b ut n o se nsiti vit y a nal yses will be c o n d ucte d. All data will be i ncl u de d i n t he data a nal ysis.
I n di vi d ual st u d y dr u g c o nce ntrati o n val ues ma y be i de ntifie d as o utliers b y t he cli nical 
p har mac o ki neticist a n d e xcl u de d fr o m c o nce ntrati o n s u m mar y ta bles a n d fi g ures a n d fr o m t he 
n o nc o m part me ntal P K a nal ysis. O utlier dr u g c o nce ntrati o ns will be i de ntifie d i n t he 
c o nce ntrati o n listi n g al o n g wit h t he j ustificati o n f or e xcl usi o n.
3. 6.        
D at a H a n dli n g C o n ve nti o ns a n d Tr a nsf or m ati o ns
T he f oll o wi n g c o n ve nti o ns will be use d f or t he i m p utati o n of date of birt h w he n it is partiall y 
missi n g or n ot c ollecte d:
•
If o nl y m o nt h a n d year of birt h is c ollecte d, t he n “ 1 5” will be i m p ute d as t he da y of birt h
•
If o nl y year of birt h is c ollecte d, t he n “ 0 1 J ul y” will be i m p ute d as t he da y a n d m o nt h of birt h
•
If year of birt h is missi n g, t he n date of birt h will n ot be i m p ute d
I n ge neral, a ge c ollecte d at Da y 1 (i n years) will be use d f or a nal yses a n d prese nte d i n listi n gs. If 
a ge at Da y 1 is n ot a vaila ble f or a partici pa nt, t he n a ge deri ve d base d o n date of birt h a n d t he 
Da y 1 visit date will be use d i nstea d. If a n e nr olle d partici pa nt was n ot d ose d wit h a n y st u d y 
dr u g, t he e nr oll me nt date will be use d i nstea d of t he Da y 1 visit date. F or partici pa nts wit h o ut a n 
e nr oll me nt date, t he date w he n t he first i nf or me d c o nse nt was si g ne d will be use d f or t he a ge 
deri vati o n. A ge re q uire d f or l o n git u di nal a n d te m p oral calc ulati o ns a n d a nal yses (e g, esti mates of 
creati ni ne cleara nce, a ge at date of A E) will be base d o n a ge deri ve d fr o m date of birt h a n d t he 
date of t he meas ure me nt or e ve nt, u nless ot her wise s pecifie d. 
N o n- P K Data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he l o wer li mit of q ua ntitati o n 
( L O Q) or a b o ve t he u p per L O Q will be i m p ute d as f oll o ws:
•
A val ue t hat is 1 u nit less t ha n t he l o wer L O Q at t he sa me precisi o n le vel of t he ori gi nall y 
re p orte d val ue will be use d t o calc ulate descri pti ve statistics if t he dat u m is re p orte d i n t he 
f or m of “ x” ( w here x is c o nsi dere d t he l o wer L O Q). F or e xa m ple, if t he val ues are re p orte d 
as < 5 0 a n d < 5. 0, val ues of 4 9 a n d 4. 9, res pecti vel y, will be use d t o calc ulate s u m mar y 
statistics. A n e xce pti o n t o t his r ule is a n y val ue re p orte d as < 1 or < 0. 1, etc. F or val ues 
re p orte d as < 1 or < 0. 1, a val ue of 0. 9 or 0. 0 9, res pecti vel y, will be use d t o calc ulate 
s u m mar y statistics.


Vesat oli m o d
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Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 5
1 9 Ja n uar y 2 0 2 4
•
A val ue t hat is 1 u nit a b o ve t he u p per L O Q will be use d t o calc ulate descri pti ve statistics if 
t he dat u m is re p orte d i n t he f or m of “ > x” ( w here x is c o nsi dere d t he u p per L O Q). Val ues 
wit h deci mal p oi nts will f oll o w t he sa me l o gic as t he b ullet p oi nt a b o ve.
•
T he l o wer or u p per L O Q will be use d t o calc ulate descri pti ve statistics if t he dat u m is 
re p orte d i n t he f or m of “ ≤ x” or “ ≥ x” ( w here x is c o nsi dere d t he l o wer or u p per L O Q).
D at a H a n dli n g f or P K S u m m aries
If met h o ds base d o n t he ass u m pti o n t hat t he data are n or mall y distri b ute d are n ot a de q uate, 
a nal yses ma y be perf or me d o n tra nsf or me d data or n o n para metric a nal ysis met h o ds ma y be use d, 
as a p pr o priate.
Nat ural l o garit h mic tra nsf or mati o n will be use d f or a nal yzi n g n o n- B L Q c o nce ntrati o ns a n d P K 
para meters. C o nce ntrati o n val ues t hat are bel o w t he li mit of q ua ntitati o n ( B L Q) will be prese nte d 
as “ B L Q” i n t he c o nce ntrati o n data listi n g. Val ues t hat are B L Q will be treate d as 0 at pre d ose 
a n d p ost d ose ti me p oi nts f or s u m mar y p ur p oses. T he n u m ber of sa m ples will be s u m marize d t o 
reflect t he act ual n u m ber of sa m ples assesse d at t hat ti me p oi nt.
At pre d ose, if all c o nce ntrati o n val ues are B L Q, t he n t he mea n, a n d or der statistics 
( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) will be dis pla ye d as 0 a n d t he rest of t he s u m mar y 
statistics (ie, S D a n d C V) will be missi n g. If a n y val ues are n o n- B L Q, t he n t he n u m ber of 
sa m ples, or der statistics, a n d all s u m mar y statistics will be dis pla ye d. 
At a n y gi ve n p ost d ose ti me p oi nt, if m ore t ha n o ne-t hir d of t he partici pa nts ha ve a c o nce ntrati o n 
val ue of B L Q, t he n o nl y t he n u m ber of sa m ples a n d or der statistics will be dis pla ye d; ot her wise, 
or der statistics a n d s u m mar y statistics will be dis pla ye d.
T he f oll o wi n g c o n ve nti o ns will be use d f or t he prese ntati o n of s u m mar y a n d or der statistics f or 
p ost d ose ti me p oi nts: 
•
If at least 1 partici pa nt has a c o nce ntrati o n val ue of B L Q f or t he ti me p oi nt, t he mi ni m u m 
val ue will be dis pla ye d as “ B L Q.”
•
If m ore t ha n 2 5 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m a n d Q 1 val ues will be dis pla ye d as “ B L Q.” 
•
If m ore t ha n 5 0 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, a n d me dia n val ues will be dis pla ye d as “ B L Q.” 
•
If m ore t ha n 7 5 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, me dia n, a n d Q 3 val ues will be dis pla ye d as “ B L Q.” 
•
If all partici pa nts ha ve c o nce ntrati o n data val ues of B L Q f or a gi ve n ti me p oi nt, all or der 
statistics ( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) will be dis pla ye d as “ B L Q.”


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 6
1 9 Ja n uar y 2 0 2 4
C o nce ntrati o n relate d P K para meters (e g, C
ma x ) t hat are B L Q will be e xcl u de d bef ore l o g 
tra nsf or mati o n or statistical m o del fitti n g a n d dis pla ye d as descri be d a b o ve. 
3. 7.        
Visit Defi niti o ns
3. 7. 1.        
Defi niti o n of Pre d ose, P ost d ose, a n d St u d y D a y
Pre d ose val ue is defi ne d as t he last a vaila ble off-treat me nt val ue c ollecte d pri or t o t he first d ose 
of st u d y dr u g. T his defi niti o n will be use d w he n o nl y o ne pre d ose is a vaila ble f or a gi ve n 
para meter. W he n a pre d ose val ue is a vaila ble f or eac h peri o d, eac h pre d ose val ue will be use d 
f or c ha n ge fr o m pre d ose calc ulati o ns.
P ost d ose val ue is defi ne d as a n y val ue c ollecte d after t he first d ose of st u d y dr u g, or after t he 
d ose i n eac h peri o d, as a p plica ble.
St u d y Da y will be calc ulate d fr o m date of first d ose of st u d y dr u g a d mi nistrati o n i n t he 
first peri o d a n d deri ve d as f oll o ws:
•
F or p ost d ose st u d y da ys: Assess me nt Date – First D osi n g Date i n t he first peri o d + 1
•
F or da ys pri or t o t he first d ose: Assess me nt Date – First D osi n g Date i n t he first peri o d 
T heref ore, st u d y da y 1 is t he da y of first d ose of st u d y dr u g a d mi nistrati o n i n t he first peri o d
Treat me nt Da y is t he da y relati ve t o t he first d ose of st u d y dr u g a d mi nistrati o n i n eac h peri o d. 
Treat me nt Da y 1 will be defi ne d as t he first d osi n g date of st u d y dr u g i n eac h peri o d.
Treat me nt Da y will be calc ulate d fr o m t he date of first d ose of st u d y dr u g a d mi nistrati o n i n eac h 
peri o d a n d deri ve d as f oll o ws:
•
F or p ost d ose st u d y da ys: assess me nt date – first d osi n g date i n eac h peri o d + 1
•
F or da ys pri or t o t he first d ose: assess me nt date – first d osi n g date i n eac h peri o d.
3. 7. 2.        
A n al ysis Visits
T he n o mi nal visit as rec or de d o n t he C R F will be use d w he n data are s u m marize d b y visit. A n y 
data relati n g t o u nsc he d ule d visits will n ot be assi g ne d t o a partic ular visit or ti me p oi nt a n d i n 
ge neral will n ot be i ncl u de d i n s u m maries. H o we ver, t he f oll o wi n g e xce pti o ns will be ma de:
•
A n u nsc he d ule d visit pri or t o t he first d ose of st u d y dr u g ma y be i ncl u de d i n t he calc ulati o n 
of pre d ose val ue, if a p plica ble.
•
U nsc he d ule d visits after t he first d ose of st u d y dr u g will be i ncl u de d i n deter mi ni n g t he 
ma xi m u m p ost d ose t o xicit y gra de.
•
F or partici pa nts w h o disc o nti n ue fr o m t he st u d y, earl y ter mi nati o n ( E T) data will be 
s u m marize d as a se parate visit, la bele d as “ Earl y Ter mi nati o n Visit”.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 7
1 9 Ja n uar y 2 0 2 4
3. 7. 3.       
Selecti o n of D at a i n t he E ve nt of M ulti ple Rec or ds o n t he S a me D a y 
De pe n di n g o n t he statistical a nal ysis met h o d, si n gle val ues ma y be re q uire d f or eac h da y. F or 
e xa m ple, c ha n ge fr o m pre d ose b y visit us uall y re q uires a si n gle val ue. 
If m ulti ple vali d, n o n missi n g o bser vati o ns e xist o n a da y, rec or ds will be c h ose n base d o n t he 
f oll o wi n g r ules if a si n gle val ue is nee de d:
•
F or pre d ose, t he last a vaila ble n o n- missi n g rec or d o n or pri or t o t he date a n d ti me of t he first 
d ose of st u d y dr u g will be selecte d, u nless s pecifie d differe ntl y. If t here are m ulti ple rec or ds 
wit h t he sa me ti me or n o ti me rec or de d o n t he sa me da y, t he pre d ose val ue will be t he 
a vera ge (arit h metic or ge o metric mea n, as a p pr o priate) of t he meas ure me nts f or c o nti n u o us 
data, or t he meas ure me nt wit h t he l o west se verit y (e g, n or mal will be selecte d o ver a b n or mal 
f or safet y electr ocar di o gra m [ E C G] fi n di n gs) f or cate g orical data. 
•
F or p ost d ose val ues: 

T he rec or d cl osest t o t he n o mi nal da y f or t hat visit will be selecte d.

If t here are 2 rec or ds t hat are e q ui dista nt fr o m t he n o mi nal da y, t he later rec or d will be 
selecte d.

If t here is m ore t ha n 1 rec or d o n t he selecte d da y, t he a vera ge will be ta ke n f or 
c o nti n u o us data a n d t he w orse se verit y will be ta ke n f or cate g orical data, u nless 
ot her wise s pecifie d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 8
1 9 Ja n uar y 2 0 2 4
4.       
P A R TI CI P A N T DI S P O SI TI O N
4. 1.       
P artici p a nt E nr oll me nt a n d Dis p ositi o n
Ke y st u d y dates  first partici pa nt e nr olle d, last partici pa nt e nr olle d, last partici pa nt last visit f or 
P K assess me nt, a n d last partici pa nt last visit f or t he cli nical st u d y re p ort) will be pr o vi de d.
A s u m mar y of partici pa nt e nr oll me nt a n d  dis p ositi o n will be pr o vi de d b y c o h ort a n d o verall. 
T his s u m mar y will prese nt t he n u m ber of partici pa nts e nr olle d, a n d t he n u m ber a n d perce nta ge 
of partici pa nts i n eac h of t he cate g ories liste d bel o w. F or t he Safet y A nal ysis Set cate g or y, t he 
de n o mi nat or f or t he perce nta ge calc ulati o n will be t he t otal n u m ber of partici pa nts e nr olle d  f or 
eac h c ol u m n. F or all ot her cate g ories, t he de n o mi nat or f or t he perce nta ge calc ulati o n will be t he 
t otal n u m ber of partici pa nts i n t he Safet y A nal ysis Set f or eac h c ol u m n.
•
Safet y A nal ysis Set
•
P K A nal ysis Set f or eac h a nal yte
•
C o m plete d st u d y dr u g
•
Di d n ot c o m plete st u d y dr u g wit h reas o n f or pre mat ure disc o nti n uati o n of st u d y dr u g
•
C o m plete d t he st u d y
•
Di d n ot c o m plete t he st u d y wit h reas o n f or pre mat ure disc o nti n uati o n of st u d y
I n a d diti o n, t he t otal n u m ber of partici pa nts w h o were e nr olle d, a n d t he n u m ber of partici pa nts i n 
eac h of t he dis p ositi o n cate g ories liste d a b o ve will be dis pla ye d i n a fl o wc hart.
T he f oll o wi n g b y- partici pa nt listi n gs will be pr o vi de d b y partici pa nt i de ntificati o n (I D) n u m ber 
i n asce n di n g or der t o s u p p ort t he a b o ve s u m mar y ta bles:
•
Partici pa nts w h o disc o nti n ue d st u d y dr u g
A b y- partici pa nt listi n g of partici pa nt dis p ositi o n i ncl u di n g c o h ort, date of t he last d ose of st u d y 
dr u g(s) (st u d y da y), last peri o d/ da y, st u d y dr u g c o m pleti o n stat us, reas o n f or st u d y dr u g 
disc o nti n uati o n, st u d y c o m pleti o n stat us, reas o n f or st u d y disc o nti n uati o n, a n d P K set stat us 
(i n dicati n g w het her or n ot a partici pa nt is i ncl u de d i n a P K a nal ysis set) will be pr o vi de d b y 
Partici pa nt I D n u m ber i n asce n di n g or der.
4. 2.       
E xte nt of E x p os ure 
A partici pa nt’s e xte nt of e x p os ure t o st u d y dr u g data a n d fasti n g stat us data will be ge nerate d 
fr o m t he st u d y dr u g a d mi nistrati o n pa ge i n t he e C R F. E x p os ure, fasti n g stat us, a n d meal 
a d mi nistrati o n (if a p plica ble) data will be liste d. 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1 9
1 9 Ja n uar y 2 0 2 4
4. 3.       
Pr ot oc ol De vi ati o ns 
A b y- partici pa nt listi n g will be pr o vi de d f or t h ose partici pa nts w h o di d n ot meet at least 1 
eli gi bilit y (i ncl usi o n or e xcl usi o n) criteri o n. T he listi n g will prese nt t he eli gi bilit y criteri o n 
( or criteria if m ore t ha n 1 vi olati o n) t hat partici pa nts di d n ot meet a n d relate d c o m me nts, if 
c ollecte d.
I m p orta nt pr ot oc ol de viati o ns occ urri n g after partici pa nts e ntere d t he st u d y are d oc u me nte d 
d uri n g r o uti ne m o nit ori n g. A n y i m p orta nt de viati o ns i de ntifie d will be i ncl u de d i n a 
b y- partici pa nt listi n g, a n d e val uate d t o deter mi ne if it j ustifies e xcl u di n g t he partici pa nt fr o m a n y 
a nal ysis sets.
4. 4.        
Assess me nt of C O VI D- 1 9 I m p act
T his st u d y was o n g oi n g d uri n g t he n o vel c or o na vir us ( C O VI D- 1 9) pa n de mic w hic h has a n 
i m pact o n t he st u d y c o n d uct. S o me partici pa nts mi g ht ha ve bee n u na ble t o atte n d o nsite visits 
d ue t o s helter i n place g ui deli nes, site cl os ures, or ot her reas o ns. T his secti o n descri bes h o w 
s pecial sit uati o ns d ue t o C O VI D- 1 9 will be ha n dle d i n t he a nal ysis.
4. 4. 1.       
St u d y Dr u g or St u d y Disc o nti n u ati o n D ue t o C O VI D- 1 9
A b y- partici pa nt listi n g of reas o ns f or pre mat ure st u d y dr u g or st u d y disc o nti n uati o n d ue t o 
C O VI D- 1 9 will be pr o vi de d if a p plica ble.
4. 4. 2.       
Pr ot oc ol De vi ati o ns D ue t o C O VI D- 1 9
A b y- partici pa nt listi n g will be pr o vi de d f or partici pa nts wit h i m p orta nt pr ot oc ol de viati o ns 
relate d t o C O VI D- 1 9 if a p plica ble. A se parate listi n g will be pr o vi de d f or partici pa nts wit h 
n o n-i m p orta nt pr ot oc ol de viati o ns relate d t o C O VI D- 1 9 if a p plica ble.
4. 4. 3.        
Misse d a n d Virt u al Visits d ue t o C O VI D- 1 9
A b y- partici pa nt listi n g of partici pa nts wit h misse d or virt ual visits d ue t o C O VI D- 1 9 will be 
pr o vi de d b y partici pa nt I D n u m ber i n asce n di n g or der.
I nf or mati o n re gar di n g misse d or virt ual visits d ue t o C O VI D- 1 9 will be c ollecte d as free te xt i n 
t he C R F c o m me nt fiel ds. T he deter mi nati o n of misse d or virt ual visits d ue t o C O VI D- 1 9 will be 
d o ne usi n g Nat ural La n g ua ge Pr ocessi n g ( N L P) t o searc h t he C R F c o m me nt fiel ds. A detaile d 
e x pla nati o n of t he al g orit h m is gi ve n i n Secti o n 1 2 .
4. 4. 4.        
A d verse E ve nts D ue t o C O VI D- 1 9
A Es of C O VI D- 1 9 will be i ncl u de d i n a nal yses of A Es if a p plica ble, w hic h will be deter mi ne d 
t hr o u g h C O VI D- 1 9 S M Q narr o w searc h. A b y- partici pa nt listi n g of A Es of C O VI D- 1 9 will be 
pr o vi de d if a p plica ble.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 0
1 9 Ja n uar y 2 0 2 4
5.       
B A S E LI N E C H A R A C T E RI S TI C S
5. 1.        
De m o gr a p hics a n d B aseli ne C h ar acteristics 
Partici pa nt de m o gra p hic varia bles (ie, a ge, se x, race, a n d et h nicit y) a n d baseli ne c haracteristics 
( b o d y wei g ht [i n k g], hei g ht [i n c m], a n d b o d y mass i n de x [ B MI; i n k g/ m 2]) will be s u m marize d 
b y c o h ort a n d o verall usi n g descri pti ve statistics f or c o nti n u o us varia bles a n d usi n g n u m ber a n d 
perce nta ge of partici pa nts f or cate g orical varia bles. F or baseli ne b o d y wei g ht, hei g ht, a n d B MI, 
descri pti ve statistics will als o be prese nte d b y se x i n t he sa me ta ble. T he s u m mar y of 
de m o gra p hic data will be pr o vi de d f or t he All E nr olle d A nal ysis Set.
A b y- partici pa nt de m o gra p hic listi n g, i ncl u di n g t he i nf or me d c o nse nt date, will be pr o vi de d b y 
partici pa nt I D n u m ber i n asce n di n g or der. 
5. 2.        
Ot her B aseli ne C h ar acteristics
A b y- partici pa nt listi n g of C P 2 C 1 9 ge n ot y pe a n d B C R P ge n ot y pe data will be pr o vi de d.
5. 3.        
Me dic al Hist or y
Me dical hist or y data will be c ollecte d at scree ni n g a n d liste d o nl y. Ge neral me dical hist or y data 
will n ot be c o de d.
A b y- partici pa nt listi n g of ge neral me dical hist or y will be pr o vi de d b y partici pa nt I D n u m ber i n 
asce n di n g or der. T he listi n g will i ncl u de rele va nt me dical c o n diti o n or pr oce d ure re p orte d ter m, 
o nset date, o n g oi n g stat us, a n d res ol uti o n date (if a p plica ble).


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 1
1 9 Ja n uar y 2 0 2 4
6.       
E F FI C A C Y A N A L Y S E S
Efficac y will n ot be e val uate d i n t he st u d y.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 2
1 9 Ja n uar y 2 0 2 4
7.       
S A F E T Y A N A L Y S E S
7. 1.        
A d verse E ve nts a n d De at hs
7. 1. 1.        
A d verse E ve nt Dicti o n ar y
Cli nical a n d la b orat or y a d verse e ve nts ( A Es) will be c o de d usi n g t he c urre nt versi o n of t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). S yste m or ga n class ( S O C), hi g h-le vel 
gr o u p ter m ( H L G T), hi g h-le vel ter m ( H L T), preferre d ter m ( P T), a n d l o wer-le vel ter m ( L L T) 
will be pr o vi de d i n t he A E dataset.
7. 1. 2.        
A d verse E ve nt Se verit y
A d verse e ve nts are gra de d b y t he i n vesti gat or as Gra de 1, 2, 3, 4, or 5 acc or di n g t o t o xicit y 
criteria s pecifie d i n t he pr ot oc ol. T he se verit y gra de  of e ve nts f or w hic h t he i n vesti gat or di d n ot 
rec or d se verit y will be cate g orize d as “ missi n g” f or ta b ular s u m maries a n d data listi n gs. T he 
missi n g cate g or y will be prese nte d last i n t he s u m mar y prese ntati o n.
7. 1. 3.        
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g
Relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Relate d” o n t he A E case re p ort f or m 
( C R F) t o t he q uesti o n of “ Relate d t o St u d y Treat me nt.” Relate d ness will al wa ys defa ult t o t he 
i n vesti gat or’s c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he i n vesti gat or di d n ot 
rec or d relati o ns hi p t o st u d y dr u g will be c o nsi dere d relate d t o st u d y dr u g f or s u m mar y p ur p oses. 
H o we ver, b y- partici pa nt data listi n gs will s h o w t he relati o ns hi p as missi n g.
7. 1. 4.        
Rel ati o ns hi p of A d verse E ve nts t o St u d y Pr oce d ure
St u d y pr oce d ure relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Yes” o n t he A E case 
re p ort f or m ( C R F) t o t he q uesti o n of “ Relate d t o St u d y Pr oce d ures.” Relate d ness will al wa ys 
defa ult t o t he i n vesti gat or’s c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he 
i n vesti gat or di d n ot rec or d relati o ns hi ps t o st u d y pr oce d ure will be c o nsi dere d relate d t o st u d y 
pr oce d ure f or s u m mar y p ur p oses. H o we ver, b y- partici pa nt data listi n gs will s h o w t he 
relati o ns hi p as missi n g fr o m t hat ca pt ure d o n t he C R F.
7. 1. 5.       
Seri o us A d verse E ve nts
Seri o us a d verse e ve nts ( S A Es) will be i de ntifie d a n d ca pt ure d as S A Es if t he A Es met t he 
defi niti o n of S A Es t hat were s pecifie d i n t he st u d y pr ot oc ol. S A Es ca pt ure d a n d st ore d i n t he 
cli nical data base will be rec o ncile d wit h t he S A E listi n gs fr o m t he Gilea d Patie nt Safet y data base 
bef ore data base fi nalizati o n.
7. 1. 6.       
Tre at me nt- E mer ge nt A d verse E ve nts
7. 1. 6. 1.        
Defi niti o n of Treat me nt E mer ge nt A d verse E ve nts
Treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as 1 or b ot h of t he f oll o wi n g:
•
A n y A Es wit h a n o nset date o n or after t he st u d y dr u g start date a n d n o later t ha n 3 0 da ys 
after per ma ne nt disc o nti n uati o n of st u d y dr u g.  


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 3
1 9 Ja n uar y 2 0 2 4
If t he A E o nset date is t he sa me as t he date of st u d y dr u g start date t he n t he A E o nset ti me m ust 
be o n or after t he st u d y dr u g start ti me. If t he A E o nset ti me is missi n g w he n t he start dates are 
t he sa me t he A E will be c o nsi dere d treat me nt e mer ge nt.
•
A n y A Es lea di n g t o disc o nti n uati o n of st u d y dr u g.
7. 1. 6. 2.       
I nc o m plete Dates
If t he o nset date of t he A E is i nc o m plete a n d t he A E st o p date is n ot pri or t o t he first d osi n g date 
of st u d y dr u g, t he n t he m o nt h a n d year ( or year al o ne if m o nt h is n ot rec or de d) of o nset will 
deter mi ne w het her a n A E is treat me nt e mer ge nt. T he e ve nt is c o nsi dere d treat me nt e mer ge nt if 
b ot h of t he f oll o wi n g 2 criteria are met:
•
T he A E o nset is t he sa me as or after t he m o nt h a n d year ( or year) of t he date of first d ose of 
st u d y dr u g, a n d
•
T he A E o nset date is t he sa me as or bef ore t he m o nt h a n d year ( or year) of t he date 
c orres p o n di n g t o 3 0 da ys after t he date of t he last d ose of st u d y dr u g.
A n A E wit h c o m pletel y missi n g o nset a n d st o p dates, or wit h t he o nset date missi n g a n d a st o p 
date later t ha n t he date of t he first d ose of st u d y dr u g, will be c o nsi dere d t o be treat me nt e mer ge nt. 
I n a d diti o n, a n A E wit h t he o nset date missi n g a n d i nc o m plete st o p date wit h t he sa me or later 
m o nt h a n d year ( or year al o ne if m o nt h is n ot rec or de d) as t he first d osi n g date of st u d y dr u g will 
be c o nsi dere d treat me nt e mer ge nt.
7. 1. 7.       
S u m m aries of A d verse E ve nts a n d De at hs
Treat me nt-e mer ge nt A Es will be s u m marize d base d o n t he Safet y A nal ysis Set.
A brief, hi g h-le vel s u m mar y of t he n u m ber a n d perce nta ge of partici pa nts w h o e x perie nce d at 
least 1 T E A E i n t he cate g ories descri be d bel o w will be pr o vi de d b y treat me nt gr o u p. All deat hs 
o bser ve d i n t he st u d y will als o be i ncl u de d i n t his s u m mar y. T he n u m ber a n d perce nta ge of 
partici pa nts w h o e x perie nce d at least 1 T E A E will be pr o vi de d a n d s u m marize d b y S O C, P T, a n d 
treat me nt gr o u p as f oll o ws:
•
T E A Es
•
T E A Es wit h Gra de 3 or hi g her
•
T E A Es b y gra de
•
T E treat me nt-relate d A Es
•
T E treat me nt-relate d A Es wit h Gra de 3 or hi g her
M ulti ple e ve nts will be c o u nte d o nl y o nce per partici pa nt i n eac h s u m mar y. A d verse e ve nts will be 
s u m marize d a n d liste d first i n al p ha betic or der of S O C a n d t he n b y P T i n desce n di n g or der of t otal 
fre q ue nc y wit hi n eac h S O C. F or s u m maries b y se verit y gra de, t he m ost se vere gra de will be use d 
f or t h ose A Es t hat occ urre d m ore t ha n o nce i n a n i n di vi d ual partici pa nt d uri n g t he st u d y. 


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 4
1 9 Ja n uar y 2 0 2 4
I n a d diti o n t o t he a b o ve s u m mar y ta bles, all T E A Es will be s u m marize d b y P T o nl y, i n 
desce n di n g or der of t otal fre q ue nc y.
I n a d diti o n, data listi n gs will be pr o vi de d f or t he f oll o wi n g:
•
All A Es, i n dicati n g w het her t he e ve nt is treat me nt e mer ge nt
•
All T E A Es wit h se verit y of Gra de 3 or hi g her
•
All T E A Es lea di n g t o disc o nti n uati o n of st u d y dr u g 
•
All S A Es
•
All Deat hs
7. 1. 8.        
A d diti o n al A n al ysis of A d verse E ve nts
A ta ble of treat me nt-e mer ge nt a d verse e ve nts of fl u-li ke s y m pt o ms base d o n t he M S T list 
pr o vi de i n A p pe n di x 3  will be pr o vi de d b y treat me nt gr o u p, S O C, a n d P T usi n g partici pa nts i n 
t he Safet y A nal ysis Set.
7. 2.       
L a b or at or y E v al u ati o ns
La b orat or y data c ollecte d d uri n g t he st u d y will be a nal yze d a n d s u m marize d usi n g b ot h 
q ua ntitati ve a n d q ualitati ve met h o ds. S u m maries of la b orat or y data will be pr o vi de d f or t he 
Safet y A nal ysis Set a n d will i ncl u de data c ollecte d u p t o t he last d ose of st u d y dr u g pl us 3 0 da ys 
f or partici pa nts w h o ha ve per ma ne ntl y disc o nti n ue d st u d y dr u g or all a vaila ble data at t he ti me of 
t he data base s na ps h ot f or partici pa nts w h o were o n g oi n g at t he ti me of a n i nteri m a nal ysis. T he 
a nal ysis will be base d o n val ues re p orte d i n c o n ve nti o nal u nits. W he n val ues are B L Q, t he y will 
be liste d as s uc h, a n d t he i m p ute d val ue will be use d f or t he p ur p ose of calc ulati n g s u m mar y 
statistics. He m ol yze d test res ults will n ot be i ncl u de d i n t he a nal ysis, b ut t he y will be liste d i n 
b y- partici pa nt la b orat or y listi n gs.
A b y- partici pa nt listi n g f or la b orat or y test res ults will be pr o vi de d b y partici pa nt I D n u m ber a n d 
visit i n c hr o n ol o gical or der f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis se paratel y. Val ues 
falli n g o utsi de of t he rele va nt refere nce ra n ge a n d/ or ha vi n g a se verit y gra de of 1 or hi g her o n 
t he Gilea d Gra di n g Scale f or Se verit y of A d verse E ve nts a n d La b orat or y A b n or malities will be 
fla g ge d i n t he data listi n gs, as a p pr o priate.
N o f or mal statistical testi n g is pla n ne d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 5
1 9 Ja n uar y 2 0 2 4
7. 2. 1.       
S u m m aries of N u meric L a b or at or y Res ults
Descri pti ve statistics will be pr o vi de d b y c o h ort  f or eac h la b orat or y test s pecifie d i n t he st u d y 
pr ot oc ol as f oll o ws:
•
Pre d ose val ues 
•
Val ues at eac h p ost d ose ti me p oi nt [ visit]
•
C ha n ge  fr o m pre d ose at eac h p ost d ose ti me p oi nt [ visit]
Pre d ose a n d p ost d ose val ues will be defi ne d as descri be d i n Secti o n 3. 7. 1 . C ha n ge fr o m pre d ose 
t o a p ost d ose visit will be defi ne d as t he visit val ue mi n us t he pre d ose val ue. La b orat or y test 
res ults c ollecte d at u nsc he d ule d visits will be i ncl u de d f or t he pre d ose a n d p ost d ose ma xi m u m 
a n d mi ni m u m val ue selecti o n.  T he mea n, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m val ues will 
be dis pla ye d t o t he re p orte d n u m ber of di gits; S D val ues will be dis pla ye d t o t he re p orte d 
n u m ber of di gits pl us 1. 
I n t he case of m ulti ple val ues i n a n a nal ysis wi n d o w, data will be selecte d f or a nal ysis as 
descri be d i n Secti o n 3. 7. 3 . 
7. 2. 2.        
Gr a de d L a b or at or y V al ues
T he se verit y of la b orat or y a b n or malities will be gra de d ( 1 t o 4) usi n g t he Gilea d Gra di n g Scale 
f or Se verit y of A d verse E ve nts A nti viral T o xicit y Gra di n g Scale, V 0 1. Gra de 0 i ncl u des all 
val ues t hat d o n ot meet t he criteria f or a n a b n or malit y of at least Gra de 1. F or la b orat or y tests 
wit h criteria f or b ot h i ncrease d a n d decrease d le vels, a nal yses f or eac h directi o n (ie, i ncrease d, 
decrease d) will be prese nte d se paratel y. 
7. 2. 2. 1.       
Treat me nt- E mer ge nt La b orat or y A b n or malities
Treat me nt-e mer ge nt la b orat or y a b n or malities are defi ne d as val ues t hat i ncrease at least 
1 t o xicit y gra de fr o m pre d ose at a n y p ost d ose ti me p oi nt, u p t o a n d i ncl u di n g t he date of 
last d ose of st u d y dr u g pl us 3 0 da ys f or partici pa nts w h o per ma ne ntl y disc o nti n ue d st u d y dr u g, 
or t he last a vaila ble date i n t he data base s na ps h ot f or partici pa nts w h o were still o n treat me nt at 
t he ti me of a n i nteri m a nal ysis. If t he rele va nt pre d ose la b orat or y val ue is missi n g, a n y 
a b n or malit y of at least Gra de 1 o bser ve d wit hi n t he ti me fra me s pecifie d a b o ve will be 
c o nsi dere d treat me nt e mer ge nt.
7. 2. 2. 2.       
S u m maries of La b orat or y A b n or malities
La b orat or y data t hat are cate g orical will be s u m marize d usi n g t he n u m ber a n d perce nta ge of 
partici pa nts i n t he st u d y wit h t he gi ve n res p o nse at pre d ose a n d eac h sc he d ule d p ost d ose visit.
T he f oll o wi n g s u m maries ( n u m ber a n d perce nta ge of partici pa nts) f or treat me nt-e mer ge nt 
la b orat or y a b n or malities will be pr o vi de d b y la b test a n d treat me nt gr o u p; partici pa nts will be 
cate g orize d acc or di n g t o t he m ost se vere p ost d ose a b n or malit y gra de f or a gi ve n la b test:
•
Gra de d la b orat or y a b n or malities
•
Gra de 3 or 4 gra de d la b orat or y a b n or malities


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 6
1 9 Ja n uar y 2 0 2 4
F or all s u m maries of la b orat or y a b n or malities, t he de n o mi nat or is t he n u m ber of partici pa nts 
wit h n o n missi n g p ost d ose val ues u p t o 3 0 da ys after last d osi n g date.  
A b y- partici pa nt listi n g of treat me nt-e mer ge nt la b orat or y a b n or malities  will be pr o vi de d b y 
partici pa nt I D n u m ber a n d visit i n c hr o n ol o gical or der. T his listi n g will i ncl u de all test res ults 
t hat were c ollecte d t hr o u g h o ut t he st u d y f or t he la b test of i nterest, wit h all a p plica ble se verit y 
gra des dis pla ye d.
7. 3.       
B o d y Wei g ht, Hei g ht, B MI, a n d Vit al Si g ns
Descri pti ve statistics will be pr o vi de d b y c o h ort f or b o d y wei g ht, hei g ht, B MI, a n d vital si g ns as 
f oll o ws:
•
Pre d ose val ue
•
Val ues at eac h p ost d ose visit
•
C ha n ge fr o m pre d ose at eac h p ost d ose visit
Pre d ose a n d p ost d ose val ues will be defi ne d as descri be d i n Secti o n 3. 7. 1 . C ha n ge fr o m pre d ose 
t o a p ost d ose visit will be defi ne d as t he p ost d ose val ue mi n us t he pre d ose val ue. B o d y wei g ht 
a n d vital si g ns meas ure d at u nsc he d ule d visits will be i ncl u de d f or t he pre d ose val ue selecti o n.
I n t he case of m ulti ple val ues i n a n a nal ysis wi n d o w, data will be selecte d f or a nal ysis as 
descri be d i n Secti o n 3. 7. 3 . N o f or mal statistical testi n g is pla n ne d.
A b y- partici pa nt listi n g of vital si g ns will be pr o vi de d b y partici pa nt I D n u m ber a n d visit i n 
c hr o n ol o gical or der. B o d y wei g ht, hei g ht, a n d B MI will be i ncl u de d i n t he vital si g ns listi n g, if 
s pace per mits, ot her wise t he y will be pr o vi de d se paratel y.
7. 4.       
Pri or a n d C o nc o mit a nt Me dic ati o ns
Me dicati o ns c ollecte d at scree ni n g a n d d uri n g t he st u d y will be c o de d usi n g t he c urre nt versi o n 
of t he  W orl d Healt h Or ga nizati o n ( W H O) Dr u g dicti o nar y.
A s u m mar y of pri or a n d c o nc o mita nt me dicati o ns will n ot be pr o vi de d.
All pri or a n d c o nc o mita nt me dicati o ns ( ot her t ha n per- pr ot oc ol st u d y dr u gs) will be pr o vi de d i n a 
b y- partici pa nt listi n g s orte d b y partici pa nt I D n u m ber a n d a d mi nistrati o n date i n c hr o n ol o gical 
or der. 
7. 5.       
Electr oc ar di o gr a m Res ults
S u m maries of i n vesti gat or assess me nt of E C G rea di n gs will be pr o vi de d f or t he Safet y A nal ysis 
Set as descri be d bel o w. N o i nfere ntial statistics will be ge nerate d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 7
1 9 Ja n uar y 2 0 2 4
7. 5. 1.       
I n vesti g at or Electr oc ar di o gr a m Assess me nt
A s hift ta ble of t he i n vesti gat ors’ assess me nt of E C G res ults at eac h ti me p oi nt  c o m pare d wit h 
pre d ose val ues will be prese nte d b y c o h ort usi n g t he f oll o wi n g cate g ories: n or mal; a b n or mal, n ot 
cli nicall y si g nifica nt; a b n or mal, cli nicall y si g nifica nt; or missi n g. T he n u m ber a n d perce nta ge of 
partici pa nts i n eac h cr oss-classificati o n gr o u p of t he s hift ta ble will be prese nte d. Partici pa nts 
wit h a missi n g val ue at pre d ose or p ost d ose will n ot be i ncl u de d i n t he de n o mi nat or f or 
perce nta ge calc ulati o n. N o f or mal statistical testi n g is pla n ne d.
A b y- partici pa nt listi n g f or safet y E C G assess me nt res ults will be pr o vi de d b y partici pa nt I D 
n u m ber a n d ti me p oi nt i n c hr o n ol o gical or der.
7. 6.        
Ot her S afet y Me as ures
A b y- partici pa nt listi n g of partici pa nt pre g na ncies d uri n g t he st u d y will be pr o vi de d b y 
partici pa nt I D n u m ber. N o a d diti o nal safet y meas ures are s pecifie d i n t he pr ot oc ol.
Alt h o u g h n ot necessaril y relate d t o safet y, a b y- partici pa nt listi n g of all c o m me nts recei ve d 
d uri n g t he st u d y o n t he c o m me nts f or m will be pr o vi de d b y partici pa nt I D n u m ber, a n d f or m f or 
w hic h t he c o m me nt a p plies.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 8
1 9 Ja n uar y 2 0 2 4
8.       
P H A R M A C O KI N E TI C E V A L U A TI O N/ A N A L Y SI S
8. 1.       
Esti m ati o n of P h ar m ac o ki netic P ar a meters
P har mac o ki netic ( P K) para meters will be esti mate d usi n g P h oe ni x Wi n N o nli n
®  s oft ware usi n g 
sta n dar d n o nc o m part me ntal met h o ds. T he li near u p/l o g d o w n tra pez oi dal r ule will be use d i n 
c o nj u ncti o n wit h t he a p pr o priate n o nc o m part me ntal m o del, wit h i n p ut val ues f or d ose le vel, 
d osi n g ti me, plas ma c o nce ntrati o n, a n d c orres p o n di n g real-ti me val ues, base d o n dr u g d osi n g 
ti mes w he ne ver p ossi ble.
All pre d ose sa m ple ti mes bef ore ti me-zer o will be c o n verte d t o zer o f or t he calc ulati o n of P K 
para meters.
F or area u n der t he c ur ve ( A U C), sa m ples B L Q of t he bi oa nal ytical assa ys occ urri n g pri or t o t he 
ac hie ve me nt of t he first q ua ntifia ble c o nce ntrati o n will be assi g ne d a c o nce ntrati o n val ue of zer o 
t o pre ve nt o veresti mati o n of t he i nitial A U C. Sa m ples t hat are B L Q at all ot her ti me p oi nts will 
be treate d as missi n g data i n Wi n N o nli n. T he n o mi nal ti me p oi nt f or a ke y e ve nt or d osi n g 
i nter val (τ) ma y be use d t o per mit direct calc ulati o n of A U C o ver s pecific ti me i nter vals. T he 
a p pr o priate ness of t his a p pr oac h will be assesse d b y t he P K scie ntist o n a pr ofile- b y- pr ofile 
basis.
P har mac o ki netic para meters s uc h as A U C i nf, λz a n d t1/ 2 are de pe n de nt o n a n acc urate esti mati o n 
of t he ter mi nal eli mi nati o n p hase of t he dr u g. T he a p pr o priate ness of calc ulati n g t hese 
para meters will be e val uate d u p o n i ns pecti o n of P K data o n a pr ofile- b y- pr ofile basis b y t he P K 
scie ntist.
8. 2.       
P h ar m ac o ki netic P ar a meters
P har mac o ki netic para meters will be ge nerate d f or all partici pa nts f or w h o m para meters ca n be 
deri ve d. T he a nal yte(s) prese nte d i n Ta ble 8- 1  will be e val uate d if data are a vaila ble. 
T a ble 8- 1.       
St u d y Tre at me nts a n d Ass oci ate d A n al ytes
C o h ort
Tre at me nt
A n al yte(s)
1
V E S, V E S + C O BI, V E S + V O R
V E S, C O BI, a n d V O R
2
V E S, V E S + R F B
V E S, R F B, a n d d- R F B
T he a nal ytes a n d para meters prese nte d i n Ta ble 8- 2  will be use d t o e val uate t he P K o bjecti ves of 
t he st u d y. T he pri mar y P K para meters are A U C last, A U Ci nf, a n d Cma x  of V E S. T he P K para meters 
t hat ma y be esti mate d i n t his st u d y are liste d a n d defi ne d i n t he P har mac o ki netic A b bre viati o ns 
secti o n.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 2 9
1 9 Ja n uar y 2 0 2 4
T a ble 8- 2.       
P h ar m ac o ki netic P ar a meters f or E ac h A n al yte i n Pl as m a
A n al yte
C o h ort
Peri o d
Visit
P ar a meters
V E S
C o h orts 1 a n d 2
All peri o ds      
Vari o us
A U C last, A U Ci nf* , Cma x *, 
% A U C
e x p, Tma x , Clast, Tlast, 
λz, t 1/ 2, C L/ F, Vz/ F
Da y 2
A U C ta u, Cma x , Tma x
C O BI      
C o h ort 1      
Peri o d 2
Da ys 2, 3, 4, 5
C tr o u g h
Da y 3
A U C ta u, Cma x , Tma x
V O R
C o h ort 1      
Peri o d 3
Da ys 3, 4, 5, 6
C tr o u g h
Da y 6
A U C ta u, Cma x , Tma x
R F B
C o h ort 2      
Peri o d 2
Da ys 3, 4, 5, 6
C tr o u g h
*   
Para meter use d i n sa m ple size a n d p o wer calc ulati o ns.
8. 3.       
St atistic al A n al ysis Met h o ds
8. 3. 1.        
Ge ner al C o nsi der ati o ns
I n di vi d ual partici pa nt c o nce ntrati o n data a n d i n di vi d ual partici pa nt P K para meters f or C O BI, 
R F B, V E S, a n d V O R will be liste d a n d s u m marize d usi n g descri pti ve statistics b y c o h ort a n d 
treat me nt. S u m mar y statistics ( n u m bers of partici pa nts, mea n, S D, c oefficie nt of variati o n 
[ % C V], me dia n, mi ni m u m, ma xi m u m, Q 1, a n d Q 3) will be prese nte d f or b ot h i n di vi d ual 
partici pa nt c o nce ntrati o n data b y ti me p oi nt a n d i n di vi d ual partici pa nt P K para meters b y c o h ort 
a n d treat me nt. M ore o ver, t he ge o metric mea n, 9 5 % c o nfi de nce i nter val ( CI), % Ge o metric C V 
[ % G C V], a n d t he mea n a n d S D of t he nat ural l o g-tra nsf or me d val ues will be prese nte d f or 
i n di vi d ual partici pa nt P K para meter data. 
I n di vi d ual c o nce ntrati o n data listi n gs a n d s u m maries will i ncl u de all partici pa nts wit h 
c o nce ntrati o n data. O utlier dr u g c o nce ntrati o ns will be i de ntifie d i n t he c o nce ntrati o n listi n g. T he 
sa m ple size f or eac h ti me p oi nt will be base d o n t he n u m ber of partici pa nts wit h n o n missi n g 
c o nce ntrati o n data at t hat ti me p oi nt. T he n u m ber a n d perce nta ge of partici pa nts wit h 
c o nce ntrati o n B L Q, as well as a n i n dicat or if m ore t ha n o ne-t hir d of t he partici pa nts are B L Q 
will be prese nte d f or eac h ti me p oi nt. F or s u m mar y statistics, B L Q val ues will be treate d as zer o 
at pre d ose a n d p ost d ose ti me p oi nts. If m ore t ha n o ne-t hir d of t he val ues at a p ost d ose ti me p oi nt 
are B L Q t he n t he mea n a n d S D will n ot be prese nte d at t hat ti me p oi nt.  C o nce ntrati o n val ues will 
be prese nte d as recei ve d fr o m t he bi oa nal ytical la b a n d s u m mar y statistics will be prese nte d t o 
t hree si g nifica nt di gits.
I n di vi d ual P K para meter data listi n gs a n d s u m maries will i ncl u de all partici pa nts f or w h o m P K 
para meter(s) ca n be deri ve d. P K para meters mar ke d f or e xcl usi o n fr o m t he P K s u m mar y will be 
i de ntifie d. T he sa m ple size f or eac h P K para meter will be base d o n t he n u m ber of partici pa nts 
wit h n o n missi n g data f or t hat P K para meter. Data a n d s u m mar y statistics will be prese nte d t o 
t hree si g nifica nt di gits.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 0
1 9 Ja n uar y 2 0 2 4
T he f oll o wi n g ta bles will be pr o vi de d f or eac h a nal yte:
•
I n di vi d ual partici pa nt c o nce ntrati o n data a n d s u m mar y statistics b y c o h ort a n d treat me nt 
•
I n di vi d ual partici pa nt plas ma P K para meters a n d s u m mar y statistics b y 1) c o h ort a n d 
treat me nt, 2) b y treat me nt a n d B C R P ge n ot y pe (f or V E S Peri o d 1).
•
Res ults of statistical c o m paris o ns f or dr u g i nteracti o n assess me nt.
T he f oll o wi n g fi g ures will be pr o vi de d b y c o h ort:
•
I n di vi d ual partici pa nt c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic scales) 
will be dis pla ye d 1) b y treat me nt ( partici pa nts o verlai d; f or all a nal ytes) a n d 2) b y partici pa nt 
(treat me nts o verlai d; f or V E S). Val ues of B L Q will be dis pla ye d as 0 o n t he li near scale a n d 
missi n g o n t he se mi-l o garit h mic scale.
•
Mea n ( ± S D) c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic scales) will be 
dis pla ye d b y treat me nt (f or all a nal ytes). If m ore t ha n o ne-t hir d of t he val ues at a p ost d ose 
ti me p oi nt are B L Q t he n t he mea n a n d S D will n ot be prese nte d at t hat ti me p oi nt a n d 
re mai ni n g p oi nts c o n necte d. If l o wer err or bar ( mea n- S D) is < 0 at a ti me p oi nt t he n it will n ot 
be prese nte d at t hat ti me p oi nt.
•
Me dia n ( Q 1, Q 3) c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic scales) will 
be dis pla ye d b y treat me nt (f or all a nal ytes). If m ore t ha n o ne- half of t he val ues at a ti me p oi nt 
are B L Q t he n t he me dia n a n d q uartile val ues will n ot be prese nte d at t hat ti me p oi nt, a n d 
re mai ni n g p oi nts c o n necte d. If l o wer err or bar ( Q 1) is B L Q at a ti me p oi nt t he n it will be 
prese nte d as L L O Q at t hat ti me p oi nt.
•
I n di vi d ual partici pa nt C tr o u g h vers us st u d y da y ( o n li near a n d se mil o garit h mic scales) 
( partici pa nts o verlai d; f or C O BI, V O R, R F B, a n d d- R F B)
•
B o x pl ots of V E S A U C last, A U Ci nf, Cma x , a n d t1/ 2 b y 1) c o h ort a n d treat me nt a n d 2) b y c o h ort 
a n d B C R P ge n ot y pe (f or V E S Peri o d 1) (i ncl u de i n di vi d ual p oi nts o n t he b o x pl ots)
T he f oll o wi n g listi n gs will be pr o vi de d:
•
P K sa m pli n g details b y partici pa nt, i ncl u di n g pr oce d ures, differe nces i n sc he d ule d a n d act ual 
dra w ti mes, a n d sa m ple a ge
•
I n di vi d ual data o n deter mi nati o n of plas ma half-life a n d c orres p o n di n g re gressi o n c orrelati o n 
c oefficie nt


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 1
1 9 Ja n uar y 2 0 2 4
8. 3. 2.       
St atistic al Met h o d ol o g y
8. 3. 2. 1.        
A nal ysis of Dr u g- Dr u g I nteracti o n
T he statistical c o m paris o ns of t he nat ural l o g-tra nsf or me d P K para meters f or eac h a nal yte a n d 
treat me nt c o m paris o n of i nterest will be perf or me d. T he statistical m o deli n g will be base d o n t he 
P K a nal ysis set f or t he a nal yte u n der e val uati o n. F or eac h a nal yte, all partici pa nts wit h a vaila ble 
data f or t he P K para meter u n der e val uati o n will be i ncl u de d i n t he m o deli n g. 
Treat me nt c o m paris o ns of i nterest are s h o w n i n Ta ble 8- 3 .
T a ble 8- 3.       
St atistic al C o m p aris o ns f or P h ar m ac o ki netic A n al yses
C o m p aris o n
A n al yte(s)      
P ar a meter
Test
Refere nce
B o u n d ar y
A U C i nf
A U C last
C ma x
t 1/ 2
V E S
T ma x
C o h ort 1 ( V E S + C O BI) Faste d      
C o h ort 1 ( V E S al o ne) Faste d      
N ot Pres pecifie d
A U C i nf
A U C last
C ma x
t 1/ 2
V E S
T ma x
C o h ort 1 ( V E S + V O R) Faste d      
C o h ort 1 ( V E S al o ne) Faste d      
N ot Pres pecifie d
F or eac h a nal yte, a n d eac h P K para meter, a para metric ( n or mal t he or y) mi xe d-effects A N O V A 
m o del will be fitte d t o t he nat ural l o g-tra nsf or me d val ues of t he P K para meter u n der e val uati o n 
usi n g S A S  P R O C MI X E D. 
T he statistical m o del will i ncl u de treat me nt as a fi xe d effect a n d s u bject as a ra n d o m effect. T he 
f oll o wi n g S A S P R O C MI X E D c o de will pr o vi de t he c o h ort c o m paris o n a nal ysis a n d t he 9 0 % CI 
calc ulati o ns f or nat ural l o g-tra nsf or me d P K para meters.
pr oc mi xe d;
  w here a nal yte =‘ V E S a n d para m =‘ A U Ci nf’;
  class treat me nt;
  m o del l nest = treat me nt / d df m = kr;
  ra n d o m s u bji d; 
  ls mea ns treat me nt / diff cl al p ha = 0. 1;
  esti mate ‘ Test vers us Refere nce’ treat me nt - 1 1 / cl al p ha = 0. 1 0;
  o ds o ut p ut Esti mates = L S _ Diffs L S Mea ns = L S _ Mea ns C o v Par ms = M S E;
r u n;


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 2
1 9 Ja n uar y 2 0 2 4
T he E S TI M A T E state me nt will be use d t o pr o d uce t he p oi nt esti mate a n d t he c orres p o n di n g 
9 0 % CI of t he differe nce i n P K para meters of i nterest o n a l o garit h mic scale. T he 
test-t o-refere nce rati o a n d ass ociate d 9 0 % CI will be calc ulate d b y ta ki n g t he e x p o ne ntial of t he 
p oi nt esti mate a n d t he c orres p o n di n g l o wer a n d u p per li mits, w hic h is c o nsiste nt wit h t he 
t w o 1-si de d tests a p pr oac h {U. S. De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g 
A d mi nistrati o n Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R) 2 0 0 1 , U. S. De part me nt of 
Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n Ce nter f or Dr u g E val uati o n a n d 
Researc h ( C D E R) 2 0 0 3 }.
N o n para metric a nal yses f or certai n P K para meters (e g. t
ma x ) ma y be perf or me d. If nee de d, t hese 
a nal yses will be perf or me d usi n g t he Wilc o x o n si g ne d-ra n k f or fi xe d-se q ue nce bet wee n t he test 
a n d refere nce gr o u ps f or V E S.
8. 4.       
Se nsiti vit y A n al ysis
Se nsiti vit y a nal ysis ma y be c o n d ucte d f or t he ke y P K a nal yses if t he P K scie ntist i de ntifies P K 
data as q uesti o na ble. T he se nsiti vit y a nal ysis will e xcl u de s pecific data fr o m a nal yses, if 
a p pr o priate. If a se nsiti vit y a nal ysis is dee me d necessar y, a listi n g of t he P K para meter(s) data 
bei n g e xcl u de d, wit h ass ociate d reas o n(s) pr o vi de d b y t he P K scie ntist, will be ge nerate d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 3
1 9 Ja n uar y 2 0 2 4
9.        
R E F E R E N C E S
U. S. De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R). G ui da nce f or I n d ustr y. Statistical A p pr oac hes 
t o Esta blis hi n g Bi oe q ui vale nce.  Ja n uar y, 2 0 0 1.
U. S. De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R). G ui da nce f or I n d ustr y. Bi oa vaila bilit y a n d 
Bi oe q ui vale nce St u dies f or Orall y A d mi nistere d Dr u g Pr o d ucts - Ge neral 
C o nsi derati o ns ( Re visi o n 1).  Marc h, 2 0 0 3.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 4
1 9 Ja n uar y 2 0 2 4
1 0.       
S O F T W A R E
S A S ®  S oft ware Versi o n 9. 4. S A S I nstit ute I nc., Car y, N C, U S A.
P h oe ni x Wi n N o nli n ®  7. 0. P harsi g ht C or p orati o n, Pri ncet o n, NJ, U S A.
n Q uer y A d vis or( R) Versi o n 9. 2. 1. 0 Statistical S ol uti o ns, C or k, Irela n d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 5
1 9 Ja n uar y 2 0 2 4
1 1.       
S A P R E VI SI O N
Re visi o n D ate
( D D M M M Y Y Y Y)      
Secti o n      
S u m m ar y of Re visi o n
Re as o n f or Re visi o n


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 6
1 9 Ja n uar y 2 0 2 4
1 2.        
A P P E N DI C E S
A p pe n di x 1.      
Sc he d ule of A Ssess me nts
A p pe n di x 2.       
Data C ollecti o n of C O VI D- 1 9 Data
A p pe n di x 3.        M S T List f or c yt o ki ne release s y n dr o me


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 7
1 9 Ja n uar y 2 0 2 4
A p pe n di x 1.       
Sc he d ule of A Ssess me nts
T a ble 1 2- 1.       
St u d y Pr oce d ures T a ble f or C o h ort 1, Peri o d 1 a n d 2
St u d y D a y
Peri o d 1 ( V E S)
Peri o d 2 ( V E S + C O BI)
St u d y Pr oce d ure      
Scree ni n g a
−1 b
1      
2 c
3      
4      
5    
W as h o ut
d
−1 b
1      2      
3 c
4      
5      
6    
W as h o ut
e
Writte n i nf or me d 
c o nse nt
X
Eli gi bilit y criteria
X
C o m plete me dical 
hist or y
X
X
X
A R T hist or y f
X
C o m plete p h ysical 
e xa mi nati o n
X
S y m pt o m- dri ve n 
p h ysical e xa mi nati o n g
X      
X      
X
X      
X      X      
X
De m o gra p hics
X
Hei g ht 
X
Wei g ht
X
X
X
X
X
Vital si g ns h
X
X      
X
X      
X
1 2-lea d E C G i
X
X      
X
X
X      
X
X
HI V- 1 viral l oa d
X
X
C D 4 cell c o u nt
X
H B V a n d H C V 
testi n gj
X
S A R S- C o V- 2 k
X
X
Uri ne dr u g a n d 
alc o h ol scree n u
X
X
X
X
X
Pre g na nc y test 
( w o me n of 
c hil d beari n g 
p ote ntial) l
X
X
X
F S H ( p ost me n o pa usal 
w o me n) m
X


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 8
1 9 Ja n uar y 2 0 2 4
St u d y D a y
Peri o d 1 ( V E S)
Peri o d 2 ( V E S + C O BI)
St u d y Pr oce d ure      
Scree ni n g a
−1 b
1      
2 c
3      
4      
5    
W as h o ut
d
−1 b
1      2      
3 c
4      
5      
6    
W as h o ut
e
Bl o o d c he mistr y u
X
X
X
X
X
Calc ulate d C L cr u
X
X
X
X
X
C oa g ulati o n pa nel
X
He mat ol o g y u
X
X
X
X
X
Uri nal ysis u
X
X
X
X
X
A d verse e ve nts
X
X      
X      
X      
X      
X      
X      
X      
X      
X      X      
X      
X      
X      
X      
X
C o nc o mita nt 
me dicati o ns
X
X      
X      
X      
X      
X      
X
X      
X      X      
X      
X      
X      
X
E nr oll me nt
X
C o nfi ne me nt n
X      
X      
X
X      
X      X      
X
V E S d osi n g
X
X
C O BI d osi n g
X      X      
X      
X      
X
Plas ma V E S a n d 
per petrat or P K o
X      
X      
X      
X      
X
X      
X      
X      
X      
X
Ser u m bi o mar kers p
X      
X      
X
X
X      
X      
X
X
W h ole bl o o d I S G 
m R N A q
X      
X      
X      
X      
X
X      
X      
X      
X      
X
P G x ( T L R 7 a n d 
B C R P) r
X
P G x C Y P 2 C 1 9 s
X
I m m u ne cell 
p he n ot y pi n g t
X      
X
X      
X
X      
X
X      
X
A E = a d verse e ve nt; A R T = a ntiretr o viral t hera p y; B C R P = breast ca ncer resista nce pr otei n; C D 4 = cl usters of differe ntiati o n 4; C L
cr = creati ni ne cleara nce; C O BI = c o bicistat; 
C Y P = c yt oc hr o me P 4 5 0 e nz y me; C R S = c yt o ki ne release s y n dr o me; E C G = electr ocar di o gra m; F S H = f ollicle-sti m ulati n g h or m o ne; H Bs A g = he patitis B vir us s urface a nti ge n; 
H B V = he patitis B vir us; H C V = he patitis C vir us; I S G = i nterfer o n-sti m ulate d ge nes; m R N A = messe n ger R N A; P G x = p har mac o ge netics; P K = p har mac o ki netics; 
T L R 7 = t oll-li ke rece pt or 7; V E S = vesat oli m o d 
a    Pr os pecti ve partici pa nts s h o ul d be scree ne d wit hi n 3 5 da ys pri or t o a d mi nistrati o n of t he first d ose of st u d y dr u g.
b     A d missi o n t o cli nic.
c     Disc har ge fr o m cli nic.
d    T here will be a was h o ut peri o d of 7 t o 1 4 da ys bet wee n treat me nts i n Peri o d 1 Da y 1 a n d Peri o d 2 Da y 1. Partici pa nts s h o ul d i nf or m t he site of a n y A E d uri n g t he was h o ut 
peri o d.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 3 9
1 9 Ja n uar y 2 0 2 4
e    T here will be a was h o ut peri o d of 1 4 t o 2 1 da ys bet wee n treat me nts i n Peri o d 2 Da y 5 a n d Peri o d 3 Da y 1 . Partici pa nts s h o ul d i nf or m t he site of a n y A E d uri n g t he was h o ut 
peri o d.
f    
C ollect A R T hist or y f or at least t he past 1 2 m o nt hs.
g    E ver y da y d uri n g c o nfi ne me nt, as nee de d, base d o n re p orte d si g ns a n d s y m pt o ms.
h     Vital si g ns i ncl u de bl o o d press ure, heart rate, o x y ge n sat urati o n, a n d b o d y te m perat ure. Vital si g ns will be c ollecte d at pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) a n d 2, 4, 8, 
1 2, a n d 2 4 h o urs after eac h d ose of V E S.
i    
1 2-lea d E C Gs will be c ollecte d after t he partici pa nt has reste d f or at least 5 mi n utes i n t he s u pi ne p ositi o n. A 1 2-lea d E C G will be c ollecte d 2 h o urs after eac h d ose of V E S.
j      H B V c ore a nti b o d y, H Bs A g, a n d H C V a nti b o d y at scree ni n g.
k    C O VI D- 1 9 testi n g i n acc or da nce wit h t he l ocal g ui deli nes will be c o n d ucte d a n d re vie we d per site-s pecific p olic y at a d missi o n ( Da y −1) a n d as nee de d pri or t o t he ne xt 
sc he d ule d test base d u p o n s y m pt o ms. Ter mi nati o n of t he c o h ort f or a n y p ositi ve viral test res ult will be at t he discreti o n of t he s p o ns or a n d t he i n vesti gat or.
l    F or partici pa nts assi g ne d fe male at birt h a n d of c hil d beari n g p ote ntial. Ser u m pre g na nc y test is re q uire d at scree ni n g. Ser u m or uri ne pre g na nc y test at Da y −1 of eac h peri o d 
is acce pta ble. Pre g na nc y test res ult is re q uire d pri or t o d osi n g. If Da y −1 ser u m pre g na nc y test res ult is n ot a vaila ble, a ne gati ve uri ne pre g na nc y test ( perf or me d l ocall y) is 
re q uire d.
m  
F or partici pa nts assi g ne d fe male at birt h w h o are y o u n ger t ha n 5 4 years, n ot o n h or m o nal c o ntrace pti o n, a n d w h o ha ve st o p pe d me nstr uati n g f or at least 1 2 m o nt hs b ut d o n ot 
ha ve d oc u me ntati o n of o varia n h or m o nal fail ure.
n    I n Peri o d 1, partici pa nts will be c o nfi ne d be gi n ni n g Da y −1 u ntil c o m pleti o n of assess me nts o n Da y 2. I n Peri o d 2, partici pa nts will be c o nfi ne d be gi n ni n g o n Da y - 1 u ntil 
c o m pleti o n of assess me nts o n Da y 3. Partici pa nts ma y re mai n c o nfi ne d f or a l o n ger d urati o n wit hi n eac h treat me nt peri o d if t his is preferre d. If a partici pa nt is e x perie nci n g 
si g ns a n d s y m pt o ms of C R S, t he partici pa nt will re mai n c o nfi ne d (f or C R S s y m pt o ms of Gra de 1) or i m me diatel y be tra nsferre d t o a h os pital or e mer ge nc y de part me nt 
(f or C R S s y m pt o ms of ≥ Gra de 2) u ntil s y m pt o ms res ol ve.
o     V E S a n d per petrat or P K sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 0. 2 5, 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs after eac h 
d ose of V E S. Ti me wi n d o ws all o we d f or P K sa m ples t o be c ollecte d are pr o vi de d i n Ta ble 8 of t he st u d y pr ot oc ol.
p   
Ser u m bi o mar ker sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 4, 8, 1 2, 2 4, 4 8, a n d 9 6 h o urs after eac h d ose of V E S. A ti me wi n d o w of ± 1 0 % 
will be all o we d f or bi o mar ker sa m ples c ollecte d t hr o u g h 8 h o urs p ost d ose. Bi o mar ker sa m ples c ollecte d be y o n d 8 h o urs p ost d ose will ha ve a ± 3 0 mi n ute wi n d o w.
q     
W h ole bl o o d sa m ples f or I S G m R N A e x pressi o n a n d tra nscri pti o nal pr ofile will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs 
p ost d ose relati ve t o V E S. A ti me wi n d o w of ± 1 0 % will be all o we d f or w h ole bl o o d sa m ples c ollecte d at 8 h o urs p ost d ose. W h ole bl o o d sa m ples c ollecte d be y o n d 8 h o urs 
p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
r     
A P G x sa m ple will be c ollecte d o n Da y 1 ( prefera bl y) or at a n y ot her ti me d uri n g t he st u d y.
s    Res ults m ust be re vie we d pri or t o e nr oll me nt.
t      W h ole bl o o d sa m ple f or i m m u ne cell p he n ot y pi n g will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g), a n d 2 4, 7 2, a n d 9 6 h o urs p ost d ose relati ve t o V E S. W h ole bl o o d 
sa m ples c ollecte d p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
u    O n Da y −1 (a d missi o n), 2 sets of safet y la b orat or y res ults f or he mat ol o g y, c he mistr y, uri nal ysis, uri ne dr u g, a n d alc o h ol assess me nts will be c ollecte d u p o n st u d y ce nter 
a d missi o n. O ne will be se nt t o t he ce ntral la b orat or y a n d t he ot her will be se nt t o t he site’s l ocal la b orat or y t o o btai n res ults i n ti me f or e nr oll me nt o n Da y 1. If a st u d y ce nter 
ca n n ot perf or m a uri ne alc o h ol test or recei ve res ults fr o m t he l ocal la b orat or y i n ti me f or e nr oll me nt o n Da y 1, t he n a n alc o h ol breat hal yzer test is acce pta ble. 
All cli nical a n d cli nicall y si g nifica nt la b orat or y t o xicities will be ma na ge d acc or di n g t o u nif or m g ui deli nes detaile d i n pr ot oc ol A p pe n di x 1 1. 4.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 0
1 9 Ja n uar y 2 0 2 4
T a ble 1 2- 2.       
St u d y Pr oce d ures T a ble f or C o h ort 1, Peri o d 3
St u d y D a y
Peri o d 3 ( V E S + V O R)
St u d y Pr oce d ure
−1 a
1      
2      
3      
4 b
5      
6      
7      
F oll o w- u p c/ E Td
C o m plete p h ysical e xa mi nati o n
X
S y m pt o m- dri ve n p h ysical e xa mi nati o n e
X      
X      
X      
X      
X
Wei g ht
X
X
X
Vital si g ns f
X      
X
X
1 2-lea d E C G g
X      
X
X
HI V- 1 viral l oa d
X
S A R S- C o V- 2 h
X
Uri ne dr u g a n d alc o h ol scree n
q
X
X
Pre g na nc y test ( w o me n of c hil d beari n g p ote ntial) i
X
X
Bl o o d c he mistr y q
X
X
X
Calc ulate d C L cr q
X
X
X
He mat ol o g y q
X
X
X
Uri nal ysis q
X
X
X
A d verse e ve nts
X      
X      
X      
X      
X      
X      
X      
X
X
C o nc o mita nt me dicati o ns
X      
X      
X      
X      
X      
X      
X      
X
X
C o nfi ne me nt j
X      
X      
X      
X      
X
V E S d osi n g k
X
V O R d osi n g l
X      
X      
X      
X      
X      
X
Plas ma V E S a n d per petrat or P K m
X      
X      
X      
X      
X
Ser u m bi o mar kers n
X      
X      
X
X
W h ole bl o o d I S G m R N A
o
X      
X      
X      
X      
X
I m m u ne cell p he n ot y pi n g p
X      
X
X      
X
C L cr = creati ni ne cleara nce; C R S = c yt o ki ne release s y n dr o me; E C G = electr ocar di o gra m; E T = earl y ter mi nati o n; I S G = i nterfer o n-sti m ulate d ge nes; m R N A = messe n ger R N A; 
P K = p har mac o ki netics; V E S = vesat oli m o d; V O R = v oric o naz ole
a     A d missi o n t o cli nic.
b     Disc har ge fr o m cli nic.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 1
1 9 Ja n uar y 2 0 2 4
c    Partici pa nts will ret ur n f or a n i n-cli nic f oll o w- u p visit 1 0 ( ± 3) da ys after t he last d ose of V E S.
d     Assess me nts will be perf or me d wit hi n 7 2 h o urs of E T fr o m t he st u d y, if p ossi ble.
e    E ver y da y d uri n g c o nfi ne me nt, as nee de d, base d o n re p orte d si g ns a n d s y m pt o ms. 
f     
Vital si g ns i ncl u de bl o o d press ure, heart rate, o x y ge n sat urati o n, a n d b o d y te m perat ure. Vital si g ns will be c ollecte d at pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) a n d 2, 4, 8, 
1 2, a n d 2 4 h o urs after t he V E S d ose i n Peri o d 3.
g   
1 2-lea d E C Gs will be c ollecte d after t he partici pa nt has reste d f or at least 5 mi n utes i n t he s u pi ne p ositi o n. A 1 2-lea d E C G will be c ollecte d 2 h o urs after t he V E S d ose i n 
Peri o d 3.
h    C O VI D- 1 9 testi n g i n acc or da nce wit h t he l ocal g ui deli nes will be c o n d ucte d a n d re vie we d per site-s pecific p olic y at a d missi o n ( Da y −1) a n d as nee de d base d u p o n s y m pt o ms. 
Ter mi nati o n of t he c o h ort f or a n y p ositi ve viral test res ult will be at t he discreti o n of t he s p o ns or a n d t he i n vesti gat or.
i    F or partici pa nts assi g ne d fe male at birt h a n d of c hil d beari n g p ote ntial. Ser u m pre g na nc y test is re q uire d at scree ni n g. Ser u m or uri ne pre g na nc y test at Da y −1 of eac h peri o d 
is acce pta ble. Pre g na nc y test res ult is re q uire d pri or t o d osi n g. If Da y −1 ser u m pre g na nc y test res ult is n ot a vaila ble, a ne gati ve uri ne pre g na nc y test ( perf or me d l ocall y) is 
re q uire d. Uri ne pre g na nc y testi n g is re peate d at t he f oll o w- u p visit a n d E T visit, if a p plica ble.
j    I n Peri o d 3, partici pa nts will be c o nfi ne d be gi n ni n g o n Da y −1 u ntil c o m pleti o n of assess me nts o n Da y 4. Partici pa nts ma y re mai n c o nfi ne d f or a l o n ger d urati o n if t his is 
preferre d. If a partici pa nt is e x perie nci n g si g ns a n d s y m pt o ms of C R S, t he partici pa nt will re mai n c o nfi ne d (f or C R S s y m pt o ms of Gra de 1) or i m me diatel y be tra nsferre d t o a 
h os pital or e mer ge nc y de part me nt (f or C R S s y m pt o ms of ≥ Gra de 2) u ntil s y m pt o ms res ol ve.
k     V E S will be d ose d i n t he m or ni n g.
l      V O R will be d ose d t wice dail y.
m    V E S a n d per petrat or P K sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 0. 2 5, 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs after 
a d mi nistrati o n of V E S. Ti me wi n d o ws all o we d f or P K sa m ples t o be c ollecte d are pr o vi de d i n Ta ble 8 of t he st u d y pr ot oc ol.
n   
Ser u m bi o mar ker sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 4, 8, 1 2, 2 4, 4 8, a n d 9 6 h o urs after a d mi nistrati o n of V E S. A ti me wi n d o w of 
± 1 0 % will be all o we d f or bi o mar ker sa m ples c ollecte d t hr o u g h 8 h o urs p ost d ose. Bi o mar ker sa m ples c ollecte d be y o n d 8 h o urs p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
o     
W h ole bl o o d sa m ples f or I S G m R N A e x pressi o n a n d tra nscri pti o nal pr ofile will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs 
p ost d ose relati ve t o V E S. A ti me wi n d o w of ± 1 0 % will be all o we d f or w h ole bl o o d sa m ples c ollecte d at 8 h o urs p ost d ose. W h ole bl o o d sa m ples c ollecte d be y o n d 8 h o urs 
p ost d ose will ha ve a ± 3 0 mi n ute wi n d o w.
p     
W h ole bl o o d sa m ple f or i m m u ne cell p he n ot y pi n g will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g), a n d 2 4, 7 2, a n d 9 6 h o urs p ost d ose relati ve t o V E S. W h ole bl o o d 
sa m ples c ollecte d p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
q    O n Da y −1 (a d missi o n), 2 sets of safet y la b orat or y res ults f or he mat ol o g y, c he mistr y, uri nal ysis, uri ne dr u g, a n d alc o h ol assess me nts will be c ollecte d u p o n st u d y ce nter 
a d missi o n. O ne will be se nt t o t he ce ntral la b orat or y a n d t he ot her will be se nt t o t he site’s l ocal la b orat or y t o o btai n res ults i n ti me f or e nr oll me nt o n Da y 1. If a st u d y ce nter 
ca n n ot perf or m a uri ne alc o h ol test or recei ve res ults fr o m t he l ocal la b orat or y i n ti me f or e nr oll me nt o n Da y 1, t he n a n alc o h ol breat hal yzer test is acce pta ble. 
All cli nical a n d cli nicall y si g nifica nt la b orat or y t o xicities will be ma na ge d acc or di n g t o u nif or m g ui deli nes detaile d i n pr ot oc ol A p pe n di x 1 1. 4.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 2
1 9 Ja n uar y 2 0 2 4
T a ble 1 2- 3.       
St u d y Pr oce d ures T a ble f or C o h ort 2, Peri o ds 1 a n d 2
St u d y D a y
Peri o d 1 ( V E S)
Peri o d 2 ( V E S + R F B)
St u d y 
Pr oce d ure      
Scree ni n g a
−1 b
1     
2 c
3    
4     
5
W as h 
o ut d
−1 b
1    
2    3    4    
5    6   
7 c
8   
9  1 0 F oll o w- u p e/ E Tf
Tele p h o ne 
c o nt act g
Writte n 
i nf or me d 
c o nse nt
X
Eli gi bilit y 
criteria
X
C o m plete 
me dical hist or y
X      
X
X
A R T hist or y h
X
C o m plete 
p h ysical 
e xa mi nati o n
X
X
S y m pt o m- dri ve n 
p h ysical 
e xa mi nati o n i
X      
X      X
X      X    
X    X    X    
X    X    X
De m o gra p hics
X
Hei g ht 
X
Wei g ht
X      
X
X
X
X      
X
Vital si g ns j
X
X      X
X    X
X
1 2-lea d E C G k
X
X      X
X
X    X
X
HI V- 1 viral l oa d      
X
X
C D 4 cell c o u nt      
X
H B V a n d H C V 
testi n gl
X
S A R S- C o V- 2 m
X
X
Uri ne dr u g a n d 
alc o h ol scree n n
X      
X
X
X
X


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 3
1 9 Ja n uar y 2 0 2 4
St u d y D a y
Peri o d  1 ( V E S)
Peri o d  2 ( V E S + R F B)
St u d y 
Pr oce d ure      
Scree ni n g a
−1 b
1     
2 c
3    
4     
5
W as h 
o ut d
−1 b
1    
2    3    4    
5    6   
7 c
8   
9  1 0 F oll o w- u p e/ E Tf
Tele p h o ne 
c o nt act g
Pre g na nc y test 
( w o me n of 
c hil d beari n g 
p ote ntial) o
X      
X
X
X
X
F S H 
( p ost me n o pa usal 
w o me n) p
X
Bl o o d 
c he mistr y n
X      
X
X
X
X      
X
Calc ulate d C L cr n
X      
X
X
X
X      
X
C oa g ulati o n 
pa nel
X
He mat ol o g y n
X      
X
X
X
X      
X
Uri nal ysis n
X      
X
X
X
X      
X
A d verse e ve nts      
X      
X      
X      X     
X    
X     
X      
X      
X      X    
X    X    X    
X    X    X    
X   
X   X      
X
C o nc o mita nt 
me dicati o ns
X      
X      
X      X     
X    
X     
X
X      X    
X    X    X    
X    X    X    
X   
X   X      
X
E nr oll me nt
X
C o nfi ne me nt o
X      
X      X
X      X    
X    X    X    
X    X    X
V E S d osi n g
X
X
R F B d osi n g
X    
X    X    X    
X    X    X    
X   
X
Plas ma V E S a n d 
per petrat or P K r
X      X     
X    
X     
X
X    X    
X   
X   X
Ser u m 
bi o mar kers s
X      X     
X      
X
X    X    
X      
X
W h ole bl o o d 
I S G m R N At
X      X     
X    
X     
X
X    X    
X   
X   X


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 4
1 9 Ja n uar y 2 0 2 4
St u d y D a y
Peri o d  1 ( V E S)
Peri o d  2 ( V E S + R F B)
St u d y 
Pr oce d ure      
Scree ni n g a
−1 b
1     
2 c
3    
4     
5
W as h 
o ut d
−1 b
1    
2    3    4    
5    6   
7 c
8   
9  1 0 F oll o w- u p e/ E Tf
Tele p h o ne 
c o nt act g
P G x ( T L R 7 a n d 
B C R P) u
X
I m m u ne cell 
p he n ot y pi n g v
X      X      
X     
X
X    X      
X   X
Tr u C ult ure 
c yt o ki ne 
res p o nsew
X
A R T = a ntiretr o viral t hera p y; B C R P = breast ca ncer resista nce pr otei n; C D 4 = cl usters of differe ntiati o n 4; C L
cr = creati ni ne cleara nce; C R S = c yt o ki ne release s y n dr o me; 
E C G = electr ocar di o gra m; E T = earl y ter mi nati o n; F S H = f ollicle-sti m ulati n g h or m o ne; H Bs A g = he patitis B vir us s urface a nti ge n; H B V = he patitis B vir us; H C V = he patitis C 
vir us; I S G = i nterfer o n-sti m ulate d ge nes; m R N A = messe n ger R N A; P G x = p har mac o ge netics; P K = p har mac o ki netics; R F B = rifa b uti n; T L R 7 = t oll-li ke rece pt or 7; 
V E S = vesat oli m o d
a    Pr os pecti ve partici pa nts s h o ul d be scree ne d wit hi n 3 5 da ys pri or t o a d mi nistrati o n of t he first d ose of st u d y dr u g.
b     A d missi o n t o cli nic.
c     Disc har ge fr o m cli nic.
d    T here will be a was h o ut peri o d of 7 t o 1 4 da ys bet wee n treat me nts i n Peri o d 1 Da y 1 a n d Peri o d 2 Da y 1. Partici pa nts s h o ul d i nf or m t he site of a n y A E d uri n g t he was h o ut 
peri o d.
e    Partici pa nts will ret ur n f or a n i n-cli nic f oll o w- u p visit 1 0 ( ± 3) da ys after t he last d ose of V E S.
f     
Assess me nts will be perf or me d wit hi n 7 2 h o urs of E T fr o m t he st u d y, if p ossi ble.
g   
F or partici pa nts assi g ne d fe male at birt h of c hil d beari n g p ote ntial, a n at- h o me uri ne pre g na nc y test will be c o m plete d 1 0 da ys after t he last d ose of R F B. Partici pa nts will be 
c o ntacte d b y tele p h o ne t o re p ort at- h o me pre g na nc y test res ults.
h    C ollect A R T hist or y f or at least t he past 1 2 m o nt hs.
i    
E ver y da y d uri n g c o nfi ne me nt, as nee de d, base d o n re p orte d si g ns a n d s y m pt o ms. 
j      Vital si g ns i ncl u de bl o o d press ure, heart rate, o x y ge n sat urati o n, a n d b o d y te m perat ure. Vital si g ns will be c ollecte d at pre d ose ( wit hi n 1 h o ur bef ore V E S d osi n g) a n d 2, 4, 8, 
1 2, a n d 2 4 h o urs after eac h d ose of V E S.
k   
1 2-lea d E C Gs will be c ollecte d after t he partici pa nt has reste d f or at least 5 mi n utes i n t he s u pi ne p ositi o n. A 1 2-lea d E C G will be c ollecte d 2 h o urs after eac h d ose of V E S.
l      H B V c ore a nti b o d y, H Bs A g, a n d H C V a nti b o d y at scree ni n g.
m    C O VI D- 1 9 testi n g i n acc or da nce wit h t he l ocal g ui deli nes will be c o n d ucte d a n d re vie we d per site-s pecific p olic y at a d missi o n ( Da y −1) a n d as nee de d pri or t o t he ne xt 
sc he d ule d test base d u p o n s y m pt o ms. Ter mi nati o n of t he c o h ort f or a n y p ositi ve viral test res ult will be at t he discreti o n of t he s p o ns or a n d t he i n vesti gat or.
n    O n Da y −1 (a d missi o n), 2 sets of safet y la b orat or y res ults f or he mat ol o g y, c he mistr y, uri nal ysis, uri ne dr u g, a n d alc o h ol assess me nts will be c ollecte d u p o n st u d y ce nter 
a d missi o n. O ne will be se nt t o t he ce ntral la b orat or y a n d t he ot her will be se nt t o t he site’s l ocal la b orat or y t o o btai n res ults i n ti me f or e nr oll me nt o n Da y 1. If a st u d y ce nter 
ca n n ot perf or m a uri ne alc o h ol test or recei ve res ults fr o m t he l ocal la b orat or y i n ti me f or e nr oll me nt o n Da y 1, t he n a n alc o h ol breat hal yzer test is acce pta ble. 
o    F or partici pa nts assi g ne d fe male at birt h a n d of c hil d beari n g p ote ntial. Ser u m pre g na nc y test is re q uire d at scree ni n g. Ser u m or uri ne pre g na nc y test at Da y −1 of eac h peri o d 
is acce pta ble. Pre g na nc y test res ult is re q uire d pri or t o d osi n g. If Da y −1 ser u m pre g na nc y test res ult is n ot a vaila ble, a ne gati ve uri ne pre g na nc y test ( perf or me d l ocall y) is 
re q uire d. Uri ne pre g na nc y testi n g is re peate d at t he f oll o w- u p visit a n d E T visit, if a p plica ble. 
p   
F or partici pa nts assi g ne d fe male at birt h w h o are y o u n ger t ha n 5 4 years, n ot o n h or m o nal c o ntrace pti o n, a n d w h o ha ve st o p pe d me nstr uati n g f or at least 1 2 m o nt hs b ut d o n ot 
ha ve d oc u me ntati o n of o varia n h or m o nal fail ure.


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 5
1 9 Ja n uar y 2 0 2 4
q    I n Peri o d 1, partici pa nts will be c o nfi ne d be gi n ni n g Da y −1 u ntil c o m pleti o n of assess me nts o n Da y 2. I n Peri o d 2, partici pa nts will be c o nfi ne d be gi n ni n g o n Da y - 1 u ntil 
c o m pleti o n of assess me nts o n Da y 7. Partici pa nts ma y re mai n c o nfi ne d f or a l o n ger d urati o n wit hi n eac h treat me nt peri o d if t his is preferre d. If a partici pa nt is e x perie nci n g 
si g ns a n d s y m pt o ms of C R S, t he partici pa nt will re mai n c o nfi ne d (f or C R S s y m pt o ms of Gra de 1) or i m me diatel y be tra nsferre d t o a h os pital or e mer ge nc y de part me nt 
(f or C R S s y m pt o ms of ≥ Gra de 2) u ntil s y m pt o ms res ol ve.
r     
V E S a n d per petrat or P K sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 0. 2 5, 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs after eac h 
d ose of V E S. Ti me wi n d o ws all o we d f or P K sa m ples t o be c ollecte d are pr o vi de d i n Ta ble 8 of t he st u d y pr ot oc ol..
s    Ser u m bi o mar ker sa m ples will be c ollecte d at pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 4, 8, 1 2, 2 4, 4 8, a n d 9 6 h o urs after eac h d ose of V E S. A ti me wi n d o w of ± 1 0 % 
will be all o we d f or bi o mar ker sa m ples c ollecte d t hr o u g h 8 h o urs p ost d ose. Bi o mar ker sa m ples c ollecte d be y o n d 8 h o urs p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
t      W h ole bl o o d sa m ples f or I S G m R N A e x pressi o n a n d tra nscri pti o nal pr ofile will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g) a n d 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs 
p ost d ose relati ve t o V E S. A ti me wi n d o w of ± 1 0 % will be all o we d f or w h ole bl o o d sa m ples c ollecte d at 8 h o urs p ost d ose. W h ole bl o o d sa m ples c ollecte d be y o n d 8 h o urs 
p ost d ose will ha ve a ± 3 0- mi n ute wi n d o w.
u     A P G x sa m ple will be c ollecte d o n Da y 1 ( prefera bl y) or at a n y ot her ti me d uri n g t he st u d y.
v     
W h ole bl o o d sa m ple f or i m m u ne cell p he n ot y pi n g will be c ollecte d pre d ose ( wit hi n 0. 5 h o urs bef ore d osi n g), a n d 2 4, 7 2, a n d 9 6 h o urs p ost d ose relati ve t o V E S. W h ole bl o o d 
sa m ples c ollecte d p ost d ose will ha ve a ± 3 0 mi n ute wi n d o w.
w    
W h ole bl o o d sa m ple f or Tr u C ult ure c yt o ki ne res p o nse will be c ollecte d o n Peri o d 1 Da y 1 ( pre d ose).
All cli nical a n d cli nicall y si g nifica nt la b orat or y t o xicities will be ma na ge d acc or di n g t o u nif or m g ui deli nes detaile d i n pr ot oc ol A p pe n di x 1 1. 4


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 6
1 9 Ja n uar y 2 0 2 4
A p pe n di x 2.        
D at a C ollecti o n of C O VI D- 1 9 D at a
T his a p pe n di x descri bes t he cli nical trial site c ollecti o n of C O VI D- 1 9 data pertai ni n g t o 
misse d/ virt ual visits a n d t he data pr ocessi n g al g orit h m t hat will be use d t o deter mi ne w hic h visits 
are missi n g a n d w hic h visits are virt ual.
D at a C ollecti o n
A C O VI D- 1 9 s u p ple me nt t o t he e C R F C o m pleti o n G ui deli nes ( C C G) was pr o vi de d b y Cli nical 
Data Ma na ge me nt t o i nstr uct cli nical trial sites wit h data e ntr y e x pectati o ns pertai ni n g t o 
sce nari os relate d t o t he C O VI D- 1 9 pa n de mic. If a visit was misse d, sites were i nstr ucte d t o e nter 
“ Visit misse d d ue t o C O VI D- 1 9” a n d if a n i n- pers o n visit was c o n d ucte d virt uall y, sites were 
i nstr ucte d t o e nter “ Virt ual visit d ue t o C O VI D- 1 9”.
Deter mi n ati o n of Misse d a n d Virt u al Visits
Nat ural La n g ua ge Pr ocessi n g ( N L P) will be use d t o searc h t he C R F c o m me nt fiel ds t o i de ntif y 
i nsta nces of “ C O VI D- 1 9”, “ Virt ual”, or s y n o n y ms (see Ta ble 1 2- 4 ). T he searc h ter ms will be 
mai ntai ne d i n a gl o bal l o o k u p ta ble a n d ca n be m o difie d t o t u ne t he N L P m o del. A n y c o m me nts 
wit h C O VI D- 1 9 searc h ter ms, “ Misse d visit” or “ Virt ual visit will be assi g ne d as f oll o ws:
i.  
If C O VI D- 1 9 ter ms are i de ntifie d t hr o u g h N L P a n d t he visit date is missi n g, t he n res ult is 
“ Misse d Visit”
ii.  
If C O VI D- 1 9 a n d Virt ual ter ms are i de ntifie d t hr o u g h N L P f or a visit, t he n res ult is 
“ Virt ual Visit”. W he n t here are m ulti ple rec or ds f or t he sa me partici pa nt a n d t he sa me visit, 
if o ne rec or d c o ul d be cate g orize d as “ Virt ual Visit”, all rec or ds ass ociate d wit h t his 
partici pa nt a n d t his visit will be cate g orize d as “ Virt ual Visit”
iii.    
Ot her wise res ult is missi n g
T a ble 1 2- 4.       
E x a m ple Se arc h Ter ms f or “ C O VI D- 1 9 ” a n d “ Virt u al ” Use d t o 
I de ntif y Misse d/ Virt u al Visits.
Se arc h Ter ms f or “ C O VI D- 1 9 ”
Se arc h Ter ms f or “ Virt u al ”
C O VI D 1 9
VI R T U A L
C O R O N A
T E L E M E D
C O R O N A VI R U S
T E L E H E A L T H
P A N D E MI C
T E L E P H O N E
O U T B R E A K
R E M O T E
C RI SI S
T E L E M E DI CI N E
L O C K D O W N
T E L E C O N S U L T A TI O N
Q U A R A N TI N E
T E L E P H O NI C A L L Y
S H E L T E R
P H O N E
H O M E VI SI T
Z O O M
S K Y P E


Vesat oli m o d
G S- U S- 3 8 2- 1 5 8 7
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 7
1 9 Ja n uar y 2 0 2 4
A p pe n di x 3.        
M S T List f or c yt o ki ne rele ase s y n dr o me
T he selecte d P Ts of c yt o ki ne release s y n dr o me base d o n G SI de vel o pe d M S T are liste d as 
f oll o ws.
Selecte d P Ts B ase d o n G SI De vel o pe d M S T
1
Art hral gia
2
Ca pillar y lea k s y n dr o me
3
C hills
4
Fati g ue
5
Hea dac he
6
H y p ote nsi o n
7
H y p o xia
8
I nfl ue nza
9
I nfl ue nza li ke ill ness
1 0
Malaise
1 1
M yal gia
1 2
Na usea
1 3
P yre xia
1 4
S h oc k
1 5
Tac h y p n oea
1 6
V o miti n g
1 7
C yt o ki ne st or m
1 8
S yste mic i nfla m mat or y res p o nse s y n dr o me
1 9
C yt o ki ne release s y n dr o me
2 0
Hae m o p ha g oc ytic l y m p h o histi oc yt osis
2 1
M ulti ple or ga n d ysf u ncti o n s y n dr o me
2 2
C hr o nic i nfla m mat or y res p o nse s y n dr o me


G S- U S- 3 8 2- 1 5 8 7 S A P
E L E C T R O NI C SI G N A T U R E S
Si g n e d b y
M e a ni n g of Si g n at ur e    
S er v er D at e
( d d- M M M-
y y y y h h: m m: s s)
Cli ni c al P h ar m a c ol o g y
e Si g n e d
Bi o st ati sti c s e Si g n e d
Gl o b al D e v el o p m e nt
L e a d ( G D L) e Si g n e d
P P D
P P D
P P D
P P D
P P D
P P D