Conditions: HIV-1-infection
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 49
Healthy volunteers: no

Brief summary:
Master protocol: The goal of this master clinical trial study is to learn how novel antiretrovirals (medicines that stop the virus from multiplying) affect the human immunodeficiency virus-1 (HIV-1) infection in people living with HIV (PWH).

Substudy-01 (GS-US-544-5905-01) will evaluate bavtavirine in PWH.

Substudy-02 (GS-US-544-5905-02) will evaluate GS-1720 in PWH.

Substudy-03 (GS-US-544-5905-03) will evaluate GS-6212 in PWH.

Detailed description:
This umbrella study will begin with a substudy of bavtavirine (Substudy-01), and later substudies GS-1720 (Substudy-02) and GS-6212 (Substudy-03) will be added. Substudies evaluating additional study drugs will be added in a staggered manner when relevant nonclinical and/or clinical data become available.

* Substudy-01 enrollment closed, actual enrollment is 13.
* Substudy-02 enrollment closed, actual enrollment is 28.
* Substudy-03 enrollment closed, actual enrollment is 8.

Arms:
arm 1: Participants receive a single dose of bavtavirine 675 mg tablet with a high-fat meal on Day 1. After assessments on Day 11 or upon early termination (ET), the participants initiate a regimen of B/F/TAF, or an alternative standard of care (SOC) antiretroviral (ART) regimen (example INSTI + NRTIs: dolutegravir (DTG)/abacavir (ABC)/3TC or DTG/3TC) up to Day 39. arm 2: Participants receive a single dose of bavtavirine 1200 mg tablet with a low-fat meal on Day 1. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39. arm 3: Participants receive bavtavirine 900 mg tablet with a high-fat meal on Days 1 and 2. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 39. arm 4: Participants receive a single dose of GS-1720 450 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60. arm 5: Participants receive a single dose of GS-1720 150 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60. arm 6: Participants receive a single dose of GS-1720 30 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60. arm 7: Participants receive a single dose of GS-1720 900 mg tablet on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 60. arm 8: Participants receive GS-6212 100 mg tablet twice daily on Days 1 through 10. After assessments on Day 11 or upon ET, the participants initiate a regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC) up to Day 25.

Interventions: intervention 1: Bavtavirine intervention 2: B/F/TAF intervention 3: Standard of Care (Substudy 01) intervention 4: GS-1720 intervention 5: Standard of Care (Substudy 02) intervention 6: GS-6212 intervention 7: Standard of Care (Substudy 03)
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Antiretroviral therapy, administered orally

Non-NNRTIs, examples: ABC/DTG/3TC; DTG plus (TAF or TDF) plus (FTC or 3TC) intervention 4: Administered orally intervention 5: Antiretroviral therapy, administered orally

Example INSTIs: DTG/ABC/3TC or DTG/3TC intervention 6: Administered orally intervention 7: Antiretroviral therapy, administered orally

Protocol document:
SAP_004.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to 
Evaluate Safety, Pharmacokinetics, and Antiviral Activity of 
Novel Antiretrovirals in Participants With HIV-1 Sub study 02: 
GS-1720
Name of Test Drug:
GS-1720
Study Number:
GS-US–544–5905-02
Master Protocol Version 
(Date):
Original
(03 August 2022)
Amendment 1 (27 September 2022)
Amendment 2 (24 February 2023)
Substudy Protocol Version 
(Date):
Original (27 February 2023)
Amendment 1 (02 March 2023)
Amendment 2 (05 May 2023)
Analysis Type:
Final Analysis (Substudy 02)
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
16 May 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF APPENDICES.................................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................8
1.2.
Study Design .............................................................................................................................................8
1.3.
Sample Size and Power .............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................10
2.1.
Interim Analysis ......................................................................................................................................10
2.2.
Dose Escalation Analysis ........................................................................................................................10
2.3.
Final Analysis..........................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................11
3.1.
Analysis Sets ...........................................................................................................................................11
3.1.1.
All Enrolled Analysis Set ......................................................................................................11
3.1.2.
Full Analysis Set....................................................................................................................11
3.1.3.
Safety Analysis Set................................................................................................................12
3.1.4.
Pharmacokinetic Analysis Set ...............................................................................................12
3.1.5.
Pharmacokinetic/Pharmacodynamic Analysis Set ................................................................12
3.2.
Participant Grouping ...............................................................................................................................12
3.3.
Strata and Covariates...............................................................................................................................13
3.4.
Examination of Participant Subgroups....................................................................................................13
3.5.
Multiple Comparisons .............................................................................................................................13
3.6.
Missing Data and Outliers.......................................................................................................................13
3.6.1.
Missing Data..........................................................................................................................13
3.6.2.
Outliers ..................................................................................................................................13
3.7.
Data Handling Conventions and Transformations ..................................................................................13
3.8.
Analysis Visit Windows..........................................................................................................................15
3.8.1.
Definition of Predose, Postdose, Study Day .........................................................................15
3.8.2.
Analysis Visit Windows........................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................18
4.
PARTICIPANT DISPOSITION ..........................................................................................................................19
4.1.
Participant Enrollment and Disposition...................................................................................................19
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................20
4.2.1.
Study Drug Exposure and Duration on Study .......................................................................20
4.3.
Protocol Deviations .................................................................................................................................21
4.4.
Assessment of COVID-19 Impact...........................................................................................................21
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................21
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................21
4.4.3.
Missed and Virtual Visits due to COVID-19 ........................................................................22
4.4.4.
Adverse Events Due to COVID-19 .......................................................................................22


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5.
BASELINE CHARACTERISTICS .....................................................................................................................23
5.1.
Demographics and Baseline Characteristics ...........................................................................................23
5.2.
Other Baseline Characteristics ................................................................................................................23
5.3.
Medical History.......................................................................................................................................23
6.
EFFICACY ANALYSES.....................................................................................................................................24
6.1.
Primary Efficacy Endpoint......................................................................................................................24
6.2.
Secondary Efficacy Endpoints ................................................................................................................24
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) on Day 8.........................24
6.2.2.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11 .....................................................................................................24
6.2.3.
Analysis of Other Efficacy Endpoints...................................................................................24
7.
SAFETY ANALYSES.........................................................................................................................................26
7.1.
Adverse Events and Deaths.....................................................................................................................26
7.1.1.
Adverse Event Dictionary .....................................................................................................26
7.1.2.
Adverse Event Severity .........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................26
7.1.4.
Relationship of Adverse Events to Study Procedure.............................................................26
7.1.5.
Serious Adverse Events.........................................................................................................26
7.1.6.
Treatment-Emergent Adverse Events....................................................................................27
7.1.6.1.
Definition of Treatment-Emergent Adverse Events........................................27
7.1.6.2.
Incomplete Dates .............................................................................................27
7.1.7.
Summaries of Adverse Events and Deaths............................................................................27
7.1.7.1.
Summaries of AE Incidence in Combined Severity Grade 
Subsets .............................................................................................................27
7.2.
Laboratory Evaluations ...........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................29
7.2.2.
Graded Laboratory Values ....................................................................................................30
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................30
7.2.2.2.
Summaries of Laboratory Abnormalities ........................................................30
7.3.
Body Weight, Height, and Vital Signs ....................................................................................................31
7.4.
Prior and Concomitant Medications and Disease Specific Medications.................................................31
7.4.1.
Prior and Disease-Specific Prior Medications.......................................................................31
7.4.2.
Concomitant Medications......................................................................................................31
7.5.
Electrocardiogram Results.......................................................................................................................32
7.5.1.
Investigator Electrocardiogram Assessment .........................................................................32
7.6.
Other Safety Measures ............................................................................................................................33
7.7.
Changes From Protocol-Specified Safety Analyses................................................................................33
8.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................34
8.1.
PK Sample Collection and Analyses.......................................................................................................34
8.1.1.
Estimation of PK Parameters.................................................................................................34
8.1.2.
PK Parameters .......................................................................................................................34
8.2.
Statistical Analysis Methods ...................................................................................................................35
8.2.1.
General considerations ..........................................................................................................35
8.2.2.
PK Analyses ..........................................................................................................................35
8.2.3.
PK/PD Analyses ....................................................................................................................36
8.3.
Sensitivity Analysis.................................................................................................................................37
9.
REFERENCES.....................................................................................................................................................38
10.
SOFTWARE.........................................................................................................................................................39
11.
SAP REVISION...................................................................................................................................................40


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12.
APPENDICES......................................................................................................................................................41
12.1.
Data Collection........................................................................................................................................44
12.2.
Determination of Missed and Virtual Visits............................................................................................44
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HIV-1 RNA................................................................................16
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including Thyrotropin), 
Urinalysis and eGFRCG............................................................................................................16
Table 3-3.
Analysis Visit Windows for Vital Signs and Weight..............................................................17
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests .....................................................17
Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage ................................................17
Table 3-6.
Analysis Visit Windows for Coagulation Tests ......................................................................18
Table 8-1.
Study Treatments and Associated Analyte..............................................................................34
Table 8-2.
PK Parameters for Each Analyte.............................................................................................35
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to Identify 
Missed/Virtual Visits...............................................................................................................44
LIST OF APPENDICES
Appendix 1.
Study Procedures Table...........................................................................................................41
Appendix 2.
Details for Statistical Programming ........................................................................................43
Appendix 3.
Data Collection of COVID-19 Data ........................................................................................44


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
BVY
Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide)
CCG
eCRF Completion Guidelines
CD4
cluster of differentiation type 4
CI
confidence interval
CK
creatine kinase
COVID-19
coronavirus disease 2019
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic Case Report Form
eGFRCG
estimated glomerular filtration rate (Cockcroft Gault formula)
ET
early termination
FAS
full analysis set
FIH
first-in-human
Hb
hemoglobin
HIV-1
human immunodeficiency virus type 1
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
INSTI
integrase strand-transfer inhibitor
LLT
lower-level term
LOQ
limit of quantitation
mAbs
monoclonal Antibodies
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA search term
NLP
natural language processing
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase Inhibitors
PD
pharmacodynamic
PEP
post-exposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic


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PrEP
pre-exposure prophylaxis
PT
preferred term
PWH
people with HIV
Q1, Q3
first quartile, third quartile
RNA
ribonucleic acid
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SMQ
standardized MedDRA query
SOC
system organ class
SRT
safety review team
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
%CV
coefficient of variation, defined as ratio of standard deviation to the mean


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PHARMACOKINETIC ABBREVIATIONS
AUC
area under the plasma/serum concentration versus time curve
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCinf
area under the concentration versus time curve from time zero to infinity
%AUCexp
Percentage of AUC extrapolated between AUClast and AUCinf
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ct
concentration at time t
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Vz/F
apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-544-5905-02 (Master Protocol GS-US-544-5905, Substudy 02). This SAP is 
based on the Study GS-US-544-5905 master protocol Amendment 2 dated 24 February 2023, 
Substudy GS-US-544-5905-02 protocol Amendment 2 dated 05 May 2023, and the electronic 
case report form (eCRF) for Study GS-US-544-5905-02. The SAP will be finalized before Study 
GS-US-544-5905-02 database finalization. Any changes made after the finalization of the SAP 
will be documented in the GS-US-544-5905-02 CSR.
1.1.
Study Objectives
The primary objective of this substudy is to evaluate the short-term antiviral activity of GS-1720 
with respect to the change from baseline in plasma HIV-1 RNA (log10 copies/mL) on Day 11 in 
people with HIV-1 (PWH) who are antiretroviral (ARV) treatment naive or treatment 
experienced but naive to the integrase strand-transfer inhibitor (INSTI) class, and have not 
received any antiretroviral therapy (ART) within 12 weeks of screening including medications 
received for pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP).
The secondary objectives of this substudy are as follows:
•
To evaluate the short-term antiviral activity of GS-1720 in reducing plasma HIV-1 RNA 
(log10 copies/mL)
•
To investigate the safety and tolerability of GS-1720 by dose cohort
•
To characterize the plasma pharmacokinetics (PK) of GS-1720
•
To characterize the PK/pharmacodynamic (PD) relationship between the exposure of 
GS-1720 and the viral dynamics of HIV-1
•
To determine the number and percentage of participants who achieve HIV-1 RNA 
< 50 copies/mL of the HIV-1 RNA assay by Day 11 at each dose level
•
To examine the emergence of resistance to the INSTI drug class
1.2.
Study Design
This is an open-label Phase 1b, single or multiple dose, multicenter, substudy to an umbrella 
study designed to evaluate safety, PK, and antiviral activity of GS-1720 given as monotherapy in 
PWH who are either treatment-naive or treatment experienced but naive to the study drug class, 
and have not received any ART within 12 weeks of screening, including medications received 
for preexposure prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior 
receipt of long-acting parenteral ARVs including: monoclonal antibodies (mAbs) targeting 
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This umbrella study will consist of a master protocol describing information relevant to all 
substudies; and each novel compound will have its own substudy. GS-1720 will be the second 
substudy protocol (GS-US-544-5905-02). This flexible clinical study design allows for opening 
new substudies as new agents become available and closing substudies with study drugs that 
demonstrate minimal clinical activity and/or unacceptable toxicity.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant. Participants will be required to return to the clinic for visits on 
Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on Day 11 or 
upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or an alternative 
standard-of-care (SOC) ART regimen selected by the investigator. If participants are switching 
to BVY, a sufficient supply will be given to provide coverage for the remainder of the study. 
Participants will be required to return to the clinic for follow-up visits on Days 25, 39 and 60.
Following study completion, the participant’s care will transferred to a primary health care 
provider who will determine the participant’s HIV long-term treatment plan. For participants 
who complete the study, 6 and 12 months (± 1 month) after enrollment the investigator (or 
delegate) will contact the participant’s primary health care provider to request and record all 
available plasma HIV-1 RNA and resistance testing results and, if applicable, changes in HIV 
treatment regimen with date of change. At each time point, the investigator (or delegate) should 
make and document at least 3 attempts of contact over a period of 4 weeks.
This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data.
The dose level and dosing regimen for study drug in each cohort will be selected based on a 
review of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint 
(Day 11) for this substudy, and/or relevant and available safety and PK data from the ongoing 
Phase 1a first-in-human (FIH) study for GS-1720.
Assessments will be conducted per the schedule of assessment table (see Schedule of 
Assessments, Appendix 1).
1.3.
Sample Size and Power
A sample size of 6 to 8 participants in each dose cohort will provide 83% to 94% power to detect 
a treatment difference of 1.0 log10 copies/mL in change from baseline in HIV-1 RNA on Day 11 
between at least one of the study drug dose groups and the historical placebo group (N = 21). In 
this power analysis, it is assumed that a standard deviation (SD) for the change from baseline in 
HIV-1 RNA on Day 11 is 0.662 log10 copies/mL for each study drug dose group and 
0.359 log10 copies/mL for the placebo group, and a 2-sided t-test is conducted at an alpha level 
of 0.05. Standard deviations were estimated from historical Phase 1b studies conducted by the 
sponsor (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072). The maximum SD from 
treatment groups was used for the study drug dose group and SD from the pooled placebo group 
was used for the placebo group.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
Before the final analysis for each substudy, interim analyses may be conducted and the analyses 
may be submitted to regulatory agencies to seek guidance for the overall clinical development 
program of GS-1720.
2.2.
Dose Escalation Analysis
A safety review team (SRT) will review the data from this substudy after all participants from 
Cohort 1 complete their Day 11 visit. The SRT review will include cumulative safety and HIV-1 
RNA data through the primary endpoint (Day 11) and available PK data from Cohort 1 of this 
substudy; and/or relevant and available safety and PK data from the Phase 1a FIH study for 
GS-1720 (as appropriate). This initial SRT review will facilitate decision-making for dose level, 
dosing regimen (including whether GS-1720 study drug will be taken in a fasted state, or with a 
low-fat or high-fat meal) and timing of dosing for Cohorts 2 to 4. Cohort 5 will not be initiated 
per SRT decision. Further 
reviews by the SRT may be needed to inform on dose 
selection for Cohorts 2 to 4 (and/or additional cohort[s], as applicable).
2.3.
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. The analysis of the primary endpoint (change from baseline in HIV-1 RNA [log10 
copies/mL] on Day 11) will be conducted at the time of the final analysis and will be tested at the 
0.05 significance level (2-sided test).
CCI-


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, SD or standard error (SE), median, first quartile 
(Q1), third quartile (Q3), minimum (Min), and maximum (Max) will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-participant listings will be presented for all participants in the All Enrolled Analysis Set and 
will be sorted by participant identification (ID) number, visit date, and time (if applicable), 
unless otherwise specified. Data collected on log forms, such as AEs, will be presented in 
chronological order within participants. The treatment group to which participants were initially 
assigned will be used in the listings. Age, sex at birth, race, and ethnicity will be included in the 
listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion as well as 
the number and percentage of participants who were excluded and the reasons for their exclusion 
will be summarized by treatment group in the disposition table as detailed in Section 4. A listing 
of reasons for exclusion from analysis sets will be provided by participant.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all participants who received a study participant ID number in 
the substudy after screening.
All Enrolled Analysis Set is the primary analysis set for by-participant listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all participants who are enrolled and receive a full dose[s] 
of GS-1720 study drug in this substudy. Participants with major eligibility violations that are 
identifiable based on pre-enrollment characteristics may be excluded. Participants will be 
grouped according to the GS-1720 cohort assigned at enrollment.
Participants who were randomized and assigned to receive placebo from 3 historical Gilead 
Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be used as a 
historical control through Study Day 11 for only the HIV-1 RNA endpoints.


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The Full Analysis Set will be the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all participants who took at least 1 dose of GS-1720 in this 
study. Participants who received treatment other than that assigned at enrollment will be 
analyzed according to the treatment that they received.
All data collected on/after first dose date of GS-1720 during the study will be included in the 
safety summaries.
The Safety Analysis Set is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all participants who were enrolled in the study, received any dose 
of GS-1720 in this study, and have at least 1 nonmissing post baseline concentration value for 
GS-1720.
The PK Analysis Set is the primary analysis set for all PK analyses.
3.1.5.
Pharmacokinetic/Pharmacodynamic Analysis Set
The PK/PD Analysis Set will include all participants who are in the FAS and have at least 1 
nonmissing PK parameter of interest (ie, CD8, Cavg, D1-8, CD11, Cavg, D1-11) and at least 1 nonmissing 
value for change from baseline in plasma HIV-1 RNA (log10 copies/mL). This is the primary 
analysis set for PK/PD analyses.
CD8, CD11 will be the plasma concentration of GS-1720 on Day 8 and Day 11 separately. Cavg, D1-8 
will be the average plasma concentration of GS-1720 up to Day 8. Cavg, D1-11 will be the average 
plasma concentration of GS-1720 up to Day 11.
3.2.
Participant Grouping
For analyses based on the FAS, participants will be grouped according to the GS-1720 cohort to 
which they were enrolled. Data from participants who were randomized and assigned to receive 
placebo from 3 historical Gilead Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and 
GS-US-200-4072) will be pooled to form a historical placebo group for HIV-1 RNA endpoints 
throughs Day 11. For all other analyses, participants will be grouped according to the actual 
GS-1720 treatment received in this study.
For enrollment, disposition, protocol deviations, demographics, baseline disease characteristics, 
AEs, vital signs, concomitant medications, and laboratory data summaries, an additional total 
column for all GS-1720 participants will be included.
For efficacy and PK summaries and the electrocardiogram (ECG) shift table, a total column for 
all GS-1720 participants will not be included.


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3.3.
Strata and Covariates
No covariates will be included in efficacy analyses.
3.4.
Examination of Participant Subgroups
There are no prespecified participant subgroups for efficacy or safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made in this proof-of-concept study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for 
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers of non-PK will be identified during the data management and data analysis process, but 
no sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected on Day 1 (in years) will be used for analyses and presented in listings. If 
age on Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the enrollment date will be used instead of the Day 1 visit date. For participant without an 
enrollment date the first informed consent was signed will be used for the age derivation. Age 
required for longitudinal and temporal calculations and analyses (eg, estimates of creatinine 
clearance, age at date of AE) will be based on age derived from date of birth and the date of the 
measurement or event, unless otherwise specified.


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.
•
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper LOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the lower or upper LOQ, 
respectively).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, change from baseline in HIV-1 RNA will 
be performed on the log10 transformed data) or nonparametric analysis methods may be used, as 
appropriate.
Data Handling for PK Summaries
Natural logarithm transformation will be used for analyzing non-BLQ concentrations and PK 
parameters in intensive PK samples. Concentration values that are BLQ will be presented as 
“BLQ” in the concentration data listing. Values that are below the limit of quantitation (BLQ) 
will be treated as 0 at predose and postdose time points for summary purposes. The number of 
samples will be summarized to reflect the actual number of samples assessed at that time point
At predose, if all concentration values are BLQ, then the mean, and order statistics (minimum, 
Q1, median, Q3, and maximum) will be displayed as 0 and the rest of the summary statistics (ie, 
SD and CV) will be missing. If any values are non-BLQ, then the number of samples, order 
statistics, and all summary statistics will be displayed.
At any given postdose time point, if more than one-third of the participants have a concentration 
value of BLQ, then only the number of samples and order statistics will be displayed; otherwise, 
order statistics and summary statistics will be displayed.
The following conventions will be used for the presentation of order statistics for intensive PK 
concentrations:
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”


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•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
Concentration related PK parameters (eg, Clast, Cmax, and Ctau) that are BLQ will be excluded 
before log transformation or statistical model fitting and displayed as described above.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Predose, Postdose, Study Day
Study day will be calculated from the first dosing date of study drug (or first dose date of placebo 
for placebo historical control group [HIV-1 RNA data only]) and derived as follows:
•
For postdose study days: Assessment Date – First Dosing Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of first dose of study drug administration.
Baseline is defined as the last available value collected on or prior to the first dose date 
(and time, where applicable) of study drug (ie, prior to taking first dose of study drug).
Postbaseline is defined as any value collected after the first dose of study drug.
Last Study Date is the latest of clinic visit dates and laboratory visit dates, including all 
follow-up visits for participants who prematurely discontinued study or who completed study 
according to the Study Completion eCRF.
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for HIV-1 RNA are provided in Table 3-1; for hematology, chemistry, 
urinalysis, and eGFRCG in Table 3-2; for vital signs and weight in Table 3-3; for ECGs and 
coagulation in Table 3-4; and CD4 cell count and percentage in Table 3-5.


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Table 3-1.
Analysis Visit Windows for HIV-1 RNA
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2
2
2
2
Day 3
3
3
3
Day 4
4
4
5
Day 7
7
6
7
Day 8
8
8
8
Day 9
9
9
9
Day 10
10
10
10
Day 11
11
11
11
Day 25
25
12
32
Day 39
39
33
49
Day 60
60
50
(none)
Each cohort for GS-1720 will be compared to the historical placebo control group through Study 
Day 11.
The percentage of participants with HIV-1 RNA < 50 copies/mL will be displayed by GS-1720 
cohort on Day 11 (last value prior to starting standard of care) and on Days 25, 39 and 60.
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including 
Thyrotropin), Urinalysis and eGFRCG 
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
5
Day 7
7
6
9
Day 11
11
10
11
Day 25
25
12
32
Day 39
39
33
49
Day 60
60
50
(none)


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Table 3-3.
Analysis Visit Windows for Vital Signs and Weight
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2*
2
2
2
Day 3
3
3
3
Day 4*
4
4
5
Day 7
7
6
9
Day 11
11
10
11
Day 25#
25
12
32
Day 39
39
33
49
Day 60
60
50
(none)
*Weight is not scheduled to be collected on Day 2 and Day 4 per protocol, so any weight collected on Day 2 will be considered 
for Day 3, any weight collected during Day 4 period will be considered for Day 7.
#Vital signs are not scheduled to be collected on Day 25 per protocol, so any vital signs collected during Day 25 will be 
considered for Day 39.
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 7
7
2
9
Day 11
11
10
11
Day 60
60
12
(none)
Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 11
11
2
11
Day 25
25
12
32
Day 39
39
33
49
Day 60
60
50
(none)


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Table 3-6.
Analysis Visit Windows for Coagulation Tests
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 7
7
2
9
Day 11
11
10
11
Day 60
60
12
(none)
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dose of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no 
time recorded on the same day, the baseline value will be the average of the measurements 
for continuous data (except for HIV-1 RNA, see below), or the measurement with the lowest 
severity (ie, normal will be selected over abnormal for safety ECG findings) for categorical 
data.
•
For postbaseline values:
The record closest to the nominal day for that visit will be selected (with the exception of 
CD4+ cell count and CD4% in which the latest record will be selected and HIV-1 RNA 
level [see below]).
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data (except for HIV-1 RNA, see below) and the worst severity will be taken 
for categorical data, unless otherwise specified.
•
For baseline and postbaseline HIV-1 RNA, the latest (considering both date and time) 
record(s) in the window will be selected. If both “Roche COBAS 6800” and 
“Roche COBAS 6800 Repeat” (ie, the HIV-1 RNA result obtained from an additional aliquot 
of the original sample) are available with the same collection time, the results from the 
“Roche COBAS 6800 Repeat” will be selected for analysis purposes; otherwise, if there are 
multiple “Roche COBAS 6800” records with the same collection time, the geometric mean 
will be taken for analysis purposes.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of key study dates will present the dates for: 1) first participant screened 2) first 
participant enrolled 3) last participant enrolled 4) last participant last visit for primary endpoint 
[Day 11] and 5) last participant last visit for clinical study report.
A summary of participant enrollment in this substudy will be provided by GS-1720 cohort (and 
overall) for each country, and investigator within country. This summary will present the number 
and percentage of participants enrolled. For each column, the denominator for the percentage 
calculation will be the total number of participants enrolled for that column.
A summary of participant disposition will present the number of participants screened for this 
substudy (denoted by an “B” contained within the participant screening number under the master 
protocol) and the number of participants who met all eligibility criteria but were not enrolled 
with the reasons that participants were not enrolled. An additional summary of participant 
disposition for participants in the All Enrolled Analysis Set will be provided by GS-1720 cohort 
and overall. The number and percentage of participants in each of the categories listed below will 
be summarized:
•
All Enrolled Analysis Set
•
Safety Analysis Set
•
Full Analysis Set
•
PK Analysis Set
•
PK/PD Analysis Set
•
Completed study drug
•
Did not complete study drug with reasons for premature discontinuation of study drug
•
Completed study
•
Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 
the percentage calculation will be the total number of participants in the Safety Analysis Set 
corresponding to that column.


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In addition, the total number of participants who were enrolled, and the number of participants in 
each of the disposition categories listed above will be displayed in a flowchart.
The randomization schedules used for the study will be provided as an appendix to the CSR.
The following by-participant listings will be provided by participant ID number in ascending 
order to support the above summary tables:
•
Reasons for premature study drug or study discontinuation (including those related to 
coronavirus disease 2019 [COVID-19])
•
Reasons for screen failure (will be provided by screening ID number in ascending order)
•
Analysis set status (participants excluded from any of the analysis sets)
4.2.
Extent of Study Drug Exposure and Adherence
A participant’s extent of exposure to study drug data will be examined by assessing the total 
duration of exposure to study drug. Study drug administration was performed at the study site; 
adherence will not be summarized.
4.2.1.
Study Drug Exposure and Duration on Study
Exposure to GS-1720 will be “Single dose of GS-1720 (Days 1 and 2)”. Drug exposure will be 
450 mg on Day 1 and Day 2 (fasted) for Cohort 1, 150 mg on Day 1 and Day 2 (fasted) for 
Cohort 2, 30 mg on Day 1 and Day 2 (fasted) for Cohort 3 and 900 mg on Day 1 and Day 2 
(fasted) for Cohort 4. Cohort 5 was not initiated per study team’s decision. Study drug exposure 
will be summarized based on data collected on the Study Drug Administration eCRF.
Duration on sponsor-provided Biktarvy® (BVY) as standard of care or alternative SOC will be 
summarized using descriptive statistics, and will be calculated as: (last dose date BVY or 
alternative SOC – first dose date of BVY or alternative SOC) + 1. The start and stop dates for 
BVY administered as standard of care are collected on the ARV eCRF with subcategory of 
“CURRENT”. Records with a BVY or alternative SOC start date on or after the last date in study 
will be excluded from calculations.
The number (ie, cumulative counts) and percentage of participants on BVY or alternative SOC 
for at least the following number of days will be summarized: 7 days, 14 days, 21 days, 28 days, 
35 days, 42 days, and 49 days. For the final analysis, a ± 2 day window will be applied for the 49 
days category (allows for the Day 60 [on Study] protocol specified visit window and participants 
starting BVY or alternative SOC on Day 11).
Duration on study (in days) will be defined as last date in study minus first dosing date plus 1. 
Last Study Date is the latest of clinic visit dates and laboratory visit dates, including all follow-up 
visits for participants who prematurely discontinued study or who completed study according to the 
Study Completion eCRF.


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Duration on study (in days) will be summarized using descriptive statistics and using the number 
(ie, cumulative counts) and percentage of participants still on study through each study 
visit: ≥ 1 day, ≥ 2 days, ≥ 3 days, ≥ 4 days, ≥ 7 days, ≥ 8 days, ≥ 9 days, ≥ 10 days, ≥ 11 days, 
≥ 25 days, ≥ 39 days, and ≥ 60 days. For the final analysis, a ± 2 day window will be applied for 
the ≥ 60 days category to allow for the Day 60 protocol specified visit window.
Summaries will be provided by GS-1720 cohort (and overall) for the Safety Analysis Set. 
Exposure data for GS-1720 study drug will be listed.
No formal statistical testing is planned.
BVY will be provided as standard of care by the Sponsor during the follow-up period and 
dispensing information will be recorded on the Accountability eCRF. Accountability data for 
BVY will be listed.
4.3.
Protocol Deviations
A by participants listing will be provided for those participants who did not meet at least 1 
eligibility (inclusion or exclusion) criteria. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that the participant did not meet and related comments, if 
collected.
Important protocol deviations occurring after participants entered the study are documented 
during routine monitoring. Any important deviations identified will be included in a by-
participant listing. The number and percentage of participants with important protocol deviations 
by deviation category (eg, eligibility criteria, informed consent) will be summarized by GS-1720 
cohort and overall for the Safety Analysis Set.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which has an 
impact on the study conduct. Some participants may not be able to attend onsite visits due to 
shelter in place guidelines, site closures, or other reasons. This section describes how special 
situations due to COVID-19 will be handled in the analysis.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-participant listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided, if applicable.
4.4.2.
Protocol Deviations Due to COVID-19
A by-participant listing will be provided for participants with important protocol deviations 
related to COVID-19, if applicable. A separate listing will be provided for participants with 
non-important protocol deviations related to COVID-19, if applicable.


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4.4.3.
Missed and Virtual Visits due to COVID-19
A by-participant listing of participants with missed or virtual visits due to COVID-19 will be 
provided by participant ID number in ascending order, if applicable.
Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields. A detailed 
explanation of the algorithm is given in Appendix 3.
4.4.4.
Adverse Events Due to COVID-19
AEs of COVID-19 will be included in analyses of AEs if applicable, which will be determined 
through a COVID-19 Standardized MedDRA Query (SMQ) narrow search or MedDRA Search 
Term (MST). A by-participant listing of AEs of COVID-19 will be provided, if applicable.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized by 
GS-1720 cohort and overall using descriptive statistics for continuous variables and using 
number and percentage of participants for categorical variables. The summary of demographic 
data will be provided for the Safety Analysis Set.
A by-participant demographic listing, including the informed consent date, will be provided by 
participant ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include HIV-1 RNA (log10 copies/mL), CD4 cell count (/μL), 
CD4 percentage (%), mode of infection (HIV risk factors), HIV disease status (AIDS, 
asymptomatic, or symptomatic HIV infection), years since HIV-1 diagnosis, years since starting 
HIV-1 treatment, resistance to any of the 4 ARV classes (yes, no) with a count of the number of 
subjects with resistance to each ARV class [NRTI, NNRTI, PI, and/or INSTI]), and ART status 
(ART-experienced or ART-naïve). These baseline characteristics will be summarized by GS-
1720 dose group and for all GS-1720 participants using descriptive statistics for continuous 
variables, and using number and percentage of participants for categorical variables. The 
summary of these baseline characteristics will be provided for the Safety Analysis Set. No 
formal statistical testing is planned.
Note: If only the month and year are collected for “date of HIV-1 diagnosis” and/or “start date of 
HIV-1 treatment”, the day will be set to ‘01’ when imputing the full date. If both the day and 
month are missing, then ‘01 July’ will be used for the day and month unless the full imputed date 
is after the first dose date of GS-1720 study drug. If HIV-1 diagnosis date or HIV-1 treatment 
start date is imputed to be after the first dose date of GS-1720 study drug, set the imputed HIV-1 
diagnosis date or treatment start date to the date of first dose of GS-1720 to avoid having a 
negative duration.
A by-participant listing of other baseline characteristics will be provided by participant 
ID number in ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will be coded using the MedDRA dictionary.
A by-participant listing of general medical history will be provided by participant ID number in 
ascending order. The listing will include relevant medical condition or procedure reported term, 
onset date, ongoing status, and resolution date (if applicable).


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in plasma HIV-1 RNA 
(log10 copies/mL) on Day 11.
Historical HIV-1 RNA data for placebo participants from 3 sponsor Phase 1b studies 
(GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be combined to form a single 
placebo group for the purpose of HIV-1 RNA analysis through Study Day 11. For 
Study GS-US-200-4072, HIV-1 RNA (log10 copies/mL) collected on Day 10 will be used for 
“Day 11” since HIV-1 RNA was not collected on Day 11 for this study. Each GS-1720 cohort 
will be compared to the pooled placebo group with respect to the primary efficacy endpoint, the 
change from baseline in plasma HIV-1 RNA (log10 copies/mL) on Day 11, using the 2 sided 
t-test conducted at an alpha level of 0.05. The analysis will be conducted using the FAS.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) on Day 8
The secondary efficacy endpoint change from baseline in plasma HIV-1 RNA (log10 copies/mL) 
on Day 8 will be analyzed using the same methods used for the primary endpoint. For study 
GS-US-120-0104, HIV-1 RNA (log10 copies/mL) collected on Day 7 will be used for “Day 8” 
since HIV-1 RNA was not collected on Day 8 for this study.
6.2.2.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11
The number and percentage of participants ever achieving HIV-1 RNA < 50 copies/mL 
postbaseline up to Day 11 will be summarized by GS-1720 cohort and for the placebo control 
group (using the FAS). For historical placebo control participants in study GS-US-120-0104 with 
HIV-1 RNA values analyzed using the HIV PCR Stand., 1.5 Cobas-CL assay with a LLOQ 
of 400 copies/mL, a value less than LLOQ (ie, < 400 copies/mL) was counted as meeting the 
endpoint (HIV-1 RNA < 50 copies/mL). A Fisher’s exact test will be used to compare each 
GS-1720 cohort to the historical placebo group if at least 1 participant has HIV-1 RNA 
< 50 copies./mL postbaseline up to Day 11.
6.2.3.
Analysis of Other Efficacy Endpoints
Maximum Reduction in Plasma HIV-1 RNA Postbaseline to Day 11
The maximum postbaseline reduction in plasma HIV-1 RNA (log10 copies/mL) from Day 2 
through Day 11 will be analyzed using the same statistical methods used for the primary 
endpoint analysis. Baseline value, lowest post-baseline HIV-1 RNA value from Day 2 to Day 11, 


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and the lowest change from baseline in HIV-1 RNA (log10 copies/mL) from Day 2 to Day 11 for 
each participant will be summarized by GS-1720 cohort and for the historical placebo group.
Change from Baseline in HIV-1 RNA by Visit
Baseline value, HIV-1 RNA (log10 copies/mL), and change from baseline in HIV-1 RNA 
(log10 copies/mL) will be summarized descriptively by visit for each GS-1720 cohort and for the 
historical placebo control group through Day 11.
Mean ± 95% confidence interval (CI) and median (Q1, Q3) of the change from baseline in 
HIV-1 RNA (log10 copies/mL) at each visit will be plotted through Day 11 using a line plot with 
a separate line displayed for each GS-1720 cohort and for the historical placebo group. Placebo 
data will be displayed for participants with a measurement collected in the analysis visit window.
Change from Baseline in CD4 by Visit
Baseline values, values at each postbaseline visit (Day 11, 25, 39 and 60), and the change from 
baseline in CD4 cell count (/μL) and CD4 percentage by visit will be summarized by GS-1720 
cohort.
Percentage of Participants with HIV-1 RNA < 50 copies/mL by Visit from Day 11 to Day 60
The number and percentage of participants with HIV1 RNA < 50 copies/mL (split into categories 
“< 20 copies/mL” [with subcategories “< 20 copies/mL Detectable”, “< 20 copies/mL Not 
Detectable”] and “20 to < 50 copies/mL”) by visit using the Cobas 6800 assay will be displayed 
for each GS-1720 cohort and overall using the missing = excluded method at the last visit prior 
to adding SOC (Day 11) and at visits after adding SOC (Days 25, 39 and 60).
For participants who did not meet the criteria HIV-1 RNA < 50 copies/mL at the visit, the 
number and percentage of participants with HIV-1 RNA in the following categories will be 
summarized:
•
50 to < 200 copies/mL
•
≥ 200 copies/mL
Missing data will be excluded in the computation of percentages (ie, missing data points will be 
excluded from both numerator and denominator in the computation). The denominator for 
percentages at a visit is the number of participants in the FAS with nonmissing HIV-1 RNA 
value at that visit. No statistical testing is planned.
All efficacy endpoints will include participants in the FAS.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA version 26.1. System organ class (SOC), high-level group term (HLGT), high-level 
term (HLT), preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events were graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity 
criteria specified in the protocol. A Grade 5 event indicates death. The severity grade of events 
for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings. The missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Relationship of Adverse Events to Study Procedure
Study procedure related AEs are those for which the investigator selected “Yes” on the AE CRF 
to the question of “Related to Study Procedures.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationships to study procedure will be considered related to study procedure for 
summary purposes. However, by-participant data listings will show the relationship as missing 
from that captured on the CRF.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AE met the 
definition of an SAE that was specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with those in the Gilead Patient Safety database before data 
finalization.


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7.1.6.
Treatment-Emergent Adverse Events
7.1.6.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date on or 
after the study drug start date. If the AE onset date is the same as the date of study drug start date 
then the AE onset time must be on or after the study drug start time. If the AE onset time is 
missing when the start dates are the same the AE will be considered treatment emergent.
7.1.6.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
the AE onset is the same as or after the month and year (or year) of the first dosing date of study 
drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.7.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.7.1.
Summaries of AE Incidence in Combined Severity Grade Subsets
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by GS-1720 cohort and overall 
for events with an onset date up to Day 11 (prior to adding SOC) and for the entire study.
•
TEAEs
•
TEAEs with Grade 3 or higher
•
TEAEs with Grade 2 or higher
•
TE treatment-related AEs
•
TE procedure-related AEs
•
TE treatment-related AEs with Grade 3 or higher
•
TE treatment-related AEs with Grade 2 or higher


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•
TE SAEs
•
TE treatment-related SAEs
•
TEAEs leading to premature discontinuation of study drug
•
TEAEs leading to premature discontinuation of study
•
TEAEs leading to death (ie, outcome of death)
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, PT, and GS-1720 cohort (and overall):
•
TEAEs, by maximum severity
•
TEAEs up to Day 11, by maximum severity
•
TEAEs with Grade 3 or higher, by maximum severity
•
TE treatment-related AEs, by maximum severity
•
TE procedure-related AEs, by maximum severity
•
TE treatment-related AEs with Grade 3 or higher, by maximum severity
•
TE SAEs
•
TE treatment-related SAEs
•
TEAEs leading to premature discontinuation of study
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual participant during the study.
In addition to the above summary tables, all TEAEs and TE treatment-related AEs will be 
summarized by PT only, in descending order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths


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•
All AEs with severity of Grade 3 or higher
•
All AEs leading to premature discontinuation of study drug or study
7.2.
Laboratory Evaluations
Laboratory data collected during the substudy will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include all data collected after the first dose date of study drug 
unless stated otherwise. The analysis will be based on values reported in conventional units. 
When values are below the LOQ, they will be listed as such, and the closest imputed value will 
be used for the purpose of calculating summary statistics as specified in Section 3.7.
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, coagulation, and urinalysis 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the DAIDS Toxicity Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities will be flagged in the data listings, as appropriate. 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.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by GS-1720 cohort (and overall) for selected laboratory 
tests specified in the study protocol as follows:
•
Baseline values
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3


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7.2.2.
Graded Laboratory Values
The DAIDS Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be used to assign toxicity grades (0 to 4) to laboratory results for analysis. 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline. If the relevant baseline laboratory value 
is missing, any abnormality of at least Grade 1 observed postbaseline will be considered 
treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and GS-1720 cohort (and overall); 
participants will be categorized according to the most severe postbaseline abnormality grade for 
a given lab test:
•
Graded laboratory abnormalities
•
Graded laboratory abnormalities collected up to Study Day 11 (prior to the participant 
initiating standard of care therapy on Day 11)
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with ≥ 1 nonmissing postbaseline value.
A by-participant listing of treatment-emergent laboratory abnormalities and a listing of 
treatment-emergent Grade 3 or 4 laboratory abnormalities will be provided by participant 
ID number and visit in chronological order. These listingss will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades and 
abnormal flags displayed.


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7.3.
Body Weight, Height, and Vital Signs
Descriptive statistics will be provided by GS-1720 cohort (and overall) for body weight, BMI, 
and vital signs as follows:
•
Baseline value
•
Value at each postbaseline time point [visit]
•
Change from baseline at each postbaseline time point [visit]
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing if 
space permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications and Disease Specific Medications
Prior and concomitant medications (ie, non-antiretroviral [non-ARV] medications) collected at 
screening and during the study will be coded using the current version of the World Health 
Organization (WHO) Drug Dictionary.
Disease-specific medications (ie, nonstudy drug ARV) used prior to, during, or after the study 
(if collected) will be coded using the Gilead-modified WHO Drug Dictionary.
7.4.1.
Prior and Disease-Specific Prior Medications
Prior and disease-specific prior medications are defined as any medications taken before a 
participant took their first dose of study drug.
A summary of prior or disease-specific prior medications will not be provided.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken on or after first dose date of study 
drug. Use of concomitant medications will be summarized by preferred name using the number 
and percentage of participants for each GS-1720 cohort (and overall). A participant reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of participants who received that medication. The summary will be ordered by 
preferred term in descending overall frequency. For drugs with the same frequency, sorting will 
be done alphabetically.


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For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug that continued to be taken after the first dosing date, or medications started after 
the first dosing date of study drug will be considered to be concomitant medications. 
Medications started and stopped on the same day as the first dosing date of study drug will also 
be considered concomitant. Medications with a stop date prior to the date of first dosing date of 
study drug will be excluded from the concomitant medication summary. If a partial stop date is 
entered, any medication with the month and year (if day is missing) or year (if day and month are 
missing) prior to the date of first study drug administration will be excluded from the 
concomitant medication summary. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) on or after the study 
drug start date will be included in the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. Summaries will be based on the Safety Analysis Set. No formal 
statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) and all nonstudy 
drug ARV medications will be provided in by-participant listings sorted by participant 
ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
Summaries of investigator assessment of ECG readings will be provided for the Safety Analysis 
Set for each scheduled visit. No formal statistical testing is planned.
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by GS-1720 cohort using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. If all participants have a 
baseline value then no missing category will be presented at baseline. The number and 
percentage of participants in each cross-classification group of the shift table will be presented. 
Participants with a missing value at baseline or postbaseline will not be included in the 
denominator for percentage calculation.
No formal statistical testing is planned.
A by-participant listing for ECG assessment results will be provided by participant ID number 
and visit in chronological order.


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7.6.
Other Safety Measures
A by-participant listing of subject pregnancies during the study will be provided by participant 
ID number. No additional safety measures are specified in the protocol.
Although not necessarily related to safety, a by-participant listing of all comments received 
during the study on the comments eCRF will be provided by participant ID number, and eCRF 
form for which the comment applies.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection and Analyses
Intensive PK samples are planned to be collected at several timepoints for all cohorts: predose, 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on respective 
days of dosing. For Cohorts 1-4, intensive PK visits will be required for Day 1 and Day 2. A 
single anytime PK collection will occur relative to study drug dosing on Day 1, at each 
postbaseline visit for all participants (on Days 2, 3, 4, 7, 8, 9, 10, 11, 25, 39, 60, or at early 
termination [if applicable]). Concentrations of GS-1720 in plasma will be determined using 
validated bioanalytical assays.
8.1.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software (version 8.2.0) using 
standard noncompartmental methods. The linear up/log down rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible. If the PK scientist identifies that another method is more appropriate, the reasons for 
this decision should be documented.
All predose sample times before time-zero will be converted to 0.
Area under the curve (AUC) will be calculated by the PK scientists. For AUC, samples BLQ of 
the bioanalytical assays occurring prior to the achievement of the first quantifiable concentration 
will be assigned a concentration value of zero to prevent overestimation of the initial AUC. 
Samples that are BLQ at all other time points will be treated as missing data in WinNonlin®. The 
nominal time point for a key event or dosing interval (τ) may be used to permit direct calculation 
of AUC over specific time intervals. The appropriateness of this approach will be assessed by the 
PK scientist on a profile-by-profile basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.1.2.
PK Parameters
PK parameters will be generated for all participants for whom parameters can be derived in the 
PK Analysis Set. The analyte presented in Table 8-1 will be evaluated if data are available.
Table 8-1.
Study Treatments and Associated Analyte
GS-1720 Cohort
Treatment
Analyte
All GS-1720 Cohorts
GS-1720
GS-1720
CCI


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The analyte and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The PK parameters to be estimated in this study are listed and defined in the PK 
Abbreviations section.
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-1720
AUClast, AUCinf, AUC0-t,%AUCexp, Cmax, Clast, Ct, Cavg, Tmax, Tlast, λz, CL/F, t1/2, and Vz/F
8.2.
Statistical Analysis Methods
8.2.1.
General considerations
Individual participant concentration data and individual participant PK parameters for GS-1720 
will be listed and summarized using descriptive statistics by GS-1720 cohort. Summary statistics 
(number of participants, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and 
Q3) will be presented for both individual participant concentration data by time point and 
individual participant PK parameters by GS-1720 cohort. Moreover, the geometric mean, 95% 
CI, %Geometric CV [%GCV], and the mean and SD of the natural log-transformed values will 
be presented for individual participant PK parameter data.
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number and percentage of 
participants with concentration BLQ, as well as an indicator if more than one-third of the 
participants are BLQ will be presented for each time point. For summary statistics, BLQ values 
will be treated as zero at predose and postdose time points. If more than one-third of the values at 
a postdose time point are BLQ then the mean and SD will not be presented at that time point 
Concentration values will be presented as received from the bioanalytical lab and summary 
statistics will be presented to three significant digits.
8.2.2.
PK Analyses
Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter. Data and summary statistics will be 
presented to three significant digits.
The following tables will be provided for GS-1720 by cohort:
•
Individual estimates and summary statistics of plasma pharmacokinetic parameters
•
Individual data and summary statistics of plasma concentration (ng/mL) at protocol-specified 
sampling times


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The following figures will be provided for GS-1720 by cohort:
•
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales). If more 
than one-third of the values at a postdose time point are BLQ, then the mean and SD will not 
be presented at that time point and remaining points connected. If lower error bar (mean-SD) 
is < 0 at a timepoint then it will not be presented at that timepoint.
•
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales). If 
more than one-third of the values at a postdose time point are BLQ then the median, Q1 and 
Q3 will not be presented at that time point and remaining points connected. If lower error bar 
(Q1) is BLQ at a timepoint then it will be presented as LLOQ at that timepoint.
•
Individual participant concentration data versus time (on linear and semilogarithmic scales). 
Values of BLQ will be displayed as 0 on the linear scale and missing on the semi-logarithmic 
scale.
The following listings will be provided:
•
Plasma PK sampling details by participant, including procedures, differences in scheduled 
and actual draw times, and sample age
•
Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient
8.2.3.
PK/PD Analyses
No formal PK/PD analysis is planned.
To characterize the PK/PD relationship between the exposure of GS-1720 and the viral dynamics 
of HIV-1, following figures will be provided using the PK/PD Analysis Set:
•
Relationship between reduction from baseline in HIV-1 RNA (log10 copies/mL) and 
GS-1720 concentration on Day 11
•
Relationship between reduction from baseline in HIV-1 RNA (log10 copies/mL) and 
GS-1720 average concentration up to Day 11
•
Relationship between reduction from baseline in HIV-1 RNA (log10 copies/mL) and 
GS-1720 concentration on Day 8
•
Relationship between reduction from baseline in HIV-1 RNA (log10 copies/mL) and 
GS-1720 average concentration up to Day 8


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8.3.
Sensitivity Analysis
Sensitivity analysis may be conducted for the key PK analyses if the PK scientist identifies PK 
data as questionable. The sensitivity analysis will exclude specific data from analyses, if 
appropriate. If a sensitivity analysis is deemed necessary, a listing of the PK parameter(s) data 
being excluded, with associated reason(s) provided by the PK scientist, will be generated.


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9.
REFERENCES
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Version 2.1), July 2017, 5894
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf


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10.
SOFTWARE
SAS® Software, SAS Institute Inc., Cary, NC, USA.
nQuery, Statsols, Cork, Ireland.
Phoenix WinNonlin® software, Certara, Radnor, PA, USA


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table
tudy .Pro(edll!11t' 
('f euinga 
D •,I II 
D~ 
D
ll 
D;t 
D 
D 
D9 
DlO 
Dll11 
D ~)'ll' 
D3!)• 
DIS~ 
'ft 
'1si, Windo ' 
D 
:!: lD 
~lDi 
\\ rittcn i.nf.ormcd conscn_t 
X, 
dicaJ histOJY 311d d'.e:mography 
:x 
Compl~te physical e:wninalion 
X 
X 
X 
X 
ymptom-dri,'ffl physical exa.mina:tiOlJII 
Height 
X 
Weight 
X 
X 
X 
X 
:x 
X 
X 
:x 
X 
i.talsi~ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HB\ blood paod an H 
Sfflllogf 
X 
CD4 cell 001.mt! 
-
p, 
sample for HIV-
genotypinglphenotypingit 
-
PlAsm.!i HIV-] R.'\l'Af. 
X 
X, 
X 
X 
X 
X 
X 
H 
to.logy! 
X 
X 
X 
X 
X 
X 
X 
CoogulMion ~jf 
X 
X 
X 
X 
X 
X 
Chl!'lmstryt 
X 
X 
X 
X 
X 
X 
X 
X 
rinaiysis~ 
X 
-
-
ffllm _pticgnancy 
_, 
X, 
Urtn!' _l)Rgnancy 
X 
X 
X 
X 
mWJ.fSWJ 
X 
12-1.eadECG 
X 
X 
X 
X 
lwcm.ive pllasma PK.it.I 


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AE = adverse event; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); D = Day; ECG = electrocardiogram; eCRF = electronic case report form; 
ET = early termination; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetic(s); SAE = serious adverse event; SOC = 
standard of care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom-driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure after Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the evaluated compound. See Section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Participants assigned female at birth of childbearing potential only.
i
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
j
Serum FSH test is required for participants assigned female at birth and < 54 years old, not on hormonal contraception, and who have stopped menstruating for ≥ 12 months 
but do not have documentation of hormonal ovarian failure.
k
Intensive PK samples should be collected at these time points for all cohorts: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on 
respective days of dosing. Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-1720.
l
For Cohort 1, intensive PK visits will be required for Day 1 and Day 2.
m
Single anytime PK sampling will occur relative to study drug dosing on Day 1. Single anytime PK sampling will not be done if drug dosing and intensive PK sampling are 
performed on the same day.
n
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.
o
For Cohort 1, a single 450-mg dose of GS-1720 will be administered on both Day 1 and Day 2 in the fasted condition (Section 5.2.4). Subsequent cohort dose, dosing regimen 
(ie, single or multiple dose), meal requirements (fasted or with a low-fat or high-fat meal), and progression between cohorts will be adaptive and determined as summarized in 
Section 3.1.1.
p
BVY or SOC will be initiated on Day 11. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation (Section 6.4.1 of 
master protocol).
CCI
Smgle a11;'1imt :Pb: ma PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Revi.C'\\· AEs and concomi13ot medic:ation1;.a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Initiate study drug (G -17211) dosing° 
X 
BVY dispensaticm 
X 
B\i'Y or oc ell &ministration 
xP 
. 
f"oi: pmicipan,t;'l who coruplete the study 6 and 12 months(± l m011th) afierenrollmml the illve:itigator~o:r delegate) '!\'ill 
In.·csl al'.ar (or ddt art) follow-up with 
co11t1c·1 th~ psttri::ipant's prim;u:y heall1h r;an pi:-o,·ider to rtqucst .a:nd ttem'd all n"ll.!h1blt pl:isma HIV-l RNA an.d n:sistaIJCC 
primary health. Catt ()l!'O\'i.dC't' 
tes1i.ng resul!! and, if applicable, cbang't'S i.n HIV ttt"atm.eut ttgimai with. d3te of cb.a:ngt". 


GS-1720
Study GS-US-544-5905 Substudy 02
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 43
16 May 2024
Appendix 2.
Details for Statistical Programming
For continuous HIV-1 RNA endpoints change from baseline on Day 11, change from baseline on 
Day 8, and maximum change from baseline from Day 2 to Day 11, pairwise comparisons 
between each GS-1720 cohort and historical placebo group will be performed and p-values will 
be presented.
The following SAS code will be used to generate p-values:
**Assign treatment groups for testing**;
data trtgrp;
set trtgrp;
    if dose =’450 mg and meal=’Fasted’ then trt=1;
    else if dose =’150 mg and meal=’Fasted’ then trt=2;
    else if dose =’30 mg and meal=’Fasted’ then trt=3;
    else if dose =’900 mg’ and meal=’Fasted’ then trt=4;
    else if treatment=’Placebo’ then trt5;
run;
ods output estimates=estimate;
proc mixed data = trtgrp;
class trt ;
model chg  = trt / ddfm=kr;
/*least squares means*/
lsmeans trt / diff e;
/* p-values */
estimate 'Cohort 1 vs Placebo' trt  1 0 0 0 -1 / cl alpha=0.05;
estimate 'Cohort 2 vs Placebo' trt  0 1 0 0 -1 / cl alpha=0.05;
estimate 'Cohort 3 vs Placebo' trt  0 0 1 0 -1 / cl alpha=0.05;
estimate 'Cohort 4 vs Placebo' trt  0 0 0 1 -1 / cl alpha=0.05;
run;


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Version 1.0
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Appendix 3.
Data Collection of COVID-19 Data
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
12.1.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by Clinical 
Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
12.2.
Determination of Missed and Virtual Visits
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 12-1). The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit will be assigned as follows:
i)
If COVID-19 terms are identified through NLP and the visit date is missing, then 
result is ”Missed Visit”
ii) If COVID-19 and Virtual terms are identified through NLP for a visit, then result is 
“Virtual Visit”. When there are multiple records for the same participant and the same 
visit, if one record could be categorized as “Virtual Visit”, all records associated with 
this participant and this visit will be categorized as “Virtual Visit”
iii) Otherwise result is missing
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits.
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-544-5905-02_SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
16-May-2024
23:33:39
Biostatistics eSigned
17-May-2024
15:37:21
Clinical Pharmacology
eSigned
17-May-2024
21:31:13
PPD
PPD
PPD

Prot_002.pdf: 
CLINICAL SUBSTUDY-03 PROTOCOL
Study Title:
An Umbrella Phase 1b, Open-label, Multicohort Study to Evaluate 
Safety, Pharmacokinetics, and Antiviral Activity of Novel 
Antiretrovirals in Participants With HIV-1; Substudy-03: GS-6212
Plain Language Short 
Title:
Study of GS-6212 in Participants With HIV-1
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
162030
EU CT Number:
Not Applicable
ClinicalTrials.gov 
Identifier:
NCT05585307
Indication:
HIV-1 Infection
Protocol ID:
GS-US-544-5905-03
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol 
Version/Date:
Amendment 1:
18 August 2023
Amendment History:
Original:
08 June 2023
Amendment 1:
18 August 2023
High-level summaries of the history of amendment are provided in 
Appendix 11.4
This study will be conducted under United States Food and Drug Administration investigational 
new drug application regulations (21 Code of Federal Regulations Part 312); however, sites 
located in the European Economic Area, the United Kingdom, and Switzerland are not included 
under the investigational new drug application and are not considered to be investigational new 
drug application sites.
GILEAU 


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Amendment 1
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This study will be conducted in compliance with this protocol and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, and that are consistent with 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
regulatory requirements.
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.


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Amendment 1
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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................................5
SUBSTUDY PROTOCOL SYNOPSIS..........................................................................................................................7
SUBSTUDY-03 STUDY SCHEMA ............................................................................................................................11
STUDY PROCEDURES TABLE ................................................................................................................................12
1.
INTRODUCTION................................................................................................................................................14
1.1.
Rationale for Substudy-03.......................................................................................................................14
1.2.
Background on Study Interventions Used in Substudy-03......................................................................14
1.2.1.
GS-6212.................................................................................................................................14
1.3.
Rationale for Dose Selection of GS-6212 ...............................................................................................20
1.4.
Benefit-Risk Assessment for the Study...................................................................................................21
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................22
3.
STUDY DESIGN.................................................................................................................................................22
3.1.
Study Design Overview...........................................................................................................................22
3.1.1.
Dose Selection/Modification.................................................................................................23
3.2.
Duration of Intervention..........................................................................................................................23
3.3.
Substudy-03–Specific Discontinuation Criteria......................................................................................23
3.4.
Definitions for Time of Primary Endpoint and End of Study .................................................................23
4.
PARTICIPANT POPULATION..........................................................................................................................24
4.1.
Number of Participants and Participant Selection for Substudy-03........................................................24
4.2.
Substudy-03–Specific Inclusion Criteria.................................................................................................24
4.3.
Substudy-03–Specific Exclusion Criteria................................................................................................24
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................25
5.1.
Enrollment and Treatment Code Access .................................................................................................25
5.2.
Description and Handling of GS-6212 and BVY....................................................................................25
5.2.1.
Formulation ...........................................................................................................................25
5.2.2.
Packaging and Labeling ........................................................................................................25
5.2.3.
Storage and Handling ............................................................................................................26
5.2.4.
Dosage and Administration ...................................................................................................26
5.3.
Fasting and Meals (GS-6212 Dosing) .....................................................................................................27
5.4.
Prior and Concomitant Medications........................................................................................................28
5.5.
Accountability for Study Drug Supplies: Study Drug and SOC ART Provided by the Sponsor 
(BVY)......................................................................................................................................................28
6.
STUDY PROCEDURES......................................................................................................................................29
6.1.
Instructions for Study Procedures ...........................................................................................................29
6.1.1.
Pharmacokinetics...................................................................................................................29
6.1.2.
Suboptimal Virologic Response............................................................................................29
6.1.3.
Poststudy Care.......................................................................................................................30
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................31


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7.1.
Toxicity Management..............................................................................................................................31
7.1.1.
Grades 1 and 2 Laboratory Abnormalities or AEs ................................................................31
7.1.2.
Grade 3 Laboratory Abnormalities or AEs ...........................................................................31
7.1.3.
Grade 4 Laboratory Abnormalities or AEs ...........................................................................32
8.
STATISTICAL CONSIDERATIONS.................................................................................................................33
9.
RESPONSIBILITIES...........................................................................................................................................34
10.
REFERENCES.....................................................................................................................................................35
11.
APPENDICES......................................................................................................................................................36
11.1.
Investigator Signature Page.....................................................................................................................37
11.2.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........38
11.3.
Management of Clinical and Laboratory Adverse Events ......................................................................41
11.4.
Amendment History ................................................................................................................................42
Amendment 1 (18 August 2023) .............................................................................................................42
11.5.
Sponsor Signature Page...........................................................................................................................43
LIST OF IN-TEXT TABLES
Table 1.
Substudy-03 Study Procedures Table......................................................................................12
Table 2.
Study GS-US-469-6401: Preliminary PK Parameters of GS-6212 Following Single- 
or Multiple-Dose Administration of Oral GS-6212 (N = 8 Per Cohort) Under Fasted 
and/or Fed Conditions .............................................................................................................19
Table 3.
GS-6212 Dosage by Cohort.....................................................................................................27
LIST OF IN-TEXT FIGURES
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-03 .....................................11
Figure 2.
Study GS-US-469-6401: Preliminary Mean (SD) GS-6212 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of Oral GS-
6212 (N = 8 Per Cohort) Under Fasted and/or Fed Conditions...............................................17
Figure 3.
Study GS-US-469-6401: Preliminary Mean (SD) GS-6212 Plasma 
Concentration-Time Profiles Following Multiple-Dose Administration of Oral GS-
6212 (N = 8 Per Cohort) Under Fasted Conditions.................................................................18


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
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/λz)
BVY
bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®)
Cav,ss
average steady state plasma concentration during multiple dose administration
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
conc
concentration
CT
computed tomography
Ctrough
concentration at the end of the dosing interval
CV
coefficient of variation
D
Day
ECG
electrocardiogram
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IM
intramuscular
IND
investigational new drug
INSTI
integrase strand-transfer inhibitor
IQ
inhibitory quotient
LA
long-acting
LDL
low-density lipoprotein
MAD
multiple ascending dose
PEG
polyethylene glycol
PK
pharmacokinetic(s)
PWH
participant with HIV-1


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Final
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Amendment 1
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RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SOC
standard of care
SRT
Safety Review Team
t1/2
terminal elimination half-life
Tmax
time (observed time point) of Cmax
US, USA
United States, United States of America
WFI
water for injection


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 7
18 August 2023
SUBSTUDY PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: An Umbrella Phase 1b, Open-label, Multicohort Study to Evaluate Safety, 
Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1; 
Substudy-03: GS-6212
Plain Language Short Title: Study of GS-6212 in Participants With HIV-1
Regulatory Agency Identifier Number(s):
IND Number: 162030
EU CT Number: Not applicable
ClinicalTrials.gov Identifier: NCT05585307
Study Sites Planned: See master protocol synopsis for study centers planned.
Objectives and Endpoints: See master protocol synopsis for objectives and endpoints.
Study Design:
This substudy is being conducted as part of an umbrella study as described in the master 
protocol.
Substudy-03 is an open-label, Phase 1b, multiple-dose, multicohort study to evaluate the safety, 
pharmacokinetics (PK), and antiviral activity of GS-6212 given as monotherapy in participants 
with HIV-1 (PWH) who are either treatment-naive or treatment-experienced but naive to 
integrase strand-transfer inhibitors (INSTIs) and have not received any antiretroviral (ARV) 
therapy (ART) within 12 weeks of screening, including medications received for pre-exposure 
prophylaxis or postexposure prophylaxis. Any current or prior receipt of long-acting (LA) 
parenteral ARVs, such as monoclonal antibodies targeting HIV-1, injectable cabotegravir, or 
injectable rilpivirine, is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant (Figure 1). Participants will be required to return to the clinic for 
visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). Doses of GS-6212 will 
be administered orally at the clinic under observation by site staff on clinic visit days/times and 
at home by the participant on nonclinic visit days/times at approximately the same time each day. 
In cohorts where GS-6212 is administered more than once daily, in-clinic observation of dosing 
will be conducted for the morning dose only. Participants will record at-home dosing details in a 
dosing log.


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Final
Gilead Sciences, Inc.
Amendment 1
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After assessments on Day 11 or upon early termination (ET), participants will initiate a regimen 
of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or 
an alternative standard of care (SOC) ART regimen selected by the investigator. If participants 
are switching to BVY, a sufficient supply will be given to provide coverage for the remainder of 
the study. Participants will be required to return to the clinic for a follow-up visit on Day 25.
Overnight fasting (≥ 6 hours prior to dosing) is required for laboratory and/or PK analyses on 
Days 1 and 11. On all other days (Days 2 through 10), the AM doses should be taken on an 
empty stomach.
This substudy will enroll up to 5 cohorts, with at least 6 participants in each cohort. 
Initial participants will be enrolled in Cohort 1, with dosing in subsequent cohorts proceeding 
after Safety Review Team (SRT) review of emerging data from Cohort 1 and available data from 
the Phase 1a single ascending dose (SAD)/multiple ascending dose (MAD) 
Study GS-US-469-6401.
Sequential enrollment in cohorts, and order of assignment to substudies, are described in 
Section 5.1.1 of the master protocol.
The sponsor may elect to hold dosing, stop/pause substudy enrollment, or stop the study 
(or substudy, or specific cohort) at any time based on review of preliminary safety, efficacy, and 
PK data (see master protocol Section 5.1.1). If deemed unnecessary, the sponsor may choose not 
to initiate 1 or more cohorts.
Number of Participants Planned: Up to 5 cohorts, each containing at least 6 participants, will 
be enrolled.
Study Population: See master protocol synopsis for the target population.
Diagnosis and Main Eligibility Criteria: See master protocol for diagnosis and main eligibility 
criteria. For inclusion in this substudy, participants must also be willing to initiate BVY provided 
by the sponsor, or an alternative SOC ART regimen selected by the investigator, on Day 11 or 
upon ET, and be willing and able to comply with meal requirements.
Test Product, Dose, and Mode of Administration:
In Cohort 1, a 100-mg dose of GS-6212 will be administered orally twice daily (ie, once every 
12 hours ± 1 hour) on Days 1 through 10). The dose, dosing regimen, and meal requirements for 
administration of GS-6212 in Cohort 1 are provided in the table below. Subsequent cohort doses, 
dosing regimens, meal requirements (fasted or fed), and progression between cohorts will be 
adaptive. The maximum dose (to be administered each day at any given time) in subsequent 
cohorts will not exceed those indicated in the table below.
For participants who will be receiving GS-6212 once daily, study drug will be dispensed on 
Day 1. Bottles will be stored on site and administered in the clinic on Days 1 through 4. 
Participants will take doses at home on Days 5 and 6; doses on Days 7 through 10 will be 
administered in the clinic.


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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For participants who will be receiving GS-6212 twice daily, study drug bottles will be dispensed 
on Day 1. Participants will take the bottles home after the morning dose at the clinic and then 
bring the bottles back to the clinic for the next day’s morning dose at the clinic for Days 1 
through 4 and Days 7 through 10. For Days 5 and 6, participants will keep the bottles at home.
Doses of GS-6212 will be administered orally at the clinic under observation by site staff on 
clinic visit days/times and at home by the participant on nonclinic visit days/times at 
approximately the same time each day. In cohorts where GS-6212 is administered more than 
once daily, in-clinic observation of dosing will be conducted for the morning dose only. 
Participants will record at-home dosing details in a dosing log. In addition to the dosing log, site 
staff can remind the participant of evening dosing via phone call/text message, if feasible. 
The timing of all doses on Days 5 and 6 should be recorded in a dosing log.
Cohort
Treatment
Cohort 1
100 mg oral doses BID (ie, once every 12 hours 
± 1 hour) on Days 1 through 10:
-
The first AM dose (on Day 1) should be taken 
following overnight fasting (≥ 6 hours).
-
All other AM doses (on Days 2 through 10) should 
be taken around the same time every morning on 
an empty stomach (fasting for ≥ 2 hours).
-
Each PM dose should be taken around the same 
time every evening with or without food. 
Participants are required to keep the pattern of 
study drug intake consistent throughout the 
10 days of dosing as much as possiblea.
Cohort 2
on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 3
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 4
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 5
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
AM = before noon; BID = twice daily; PM = evening; QD = once daily
a
For instance, if a participant takes their first PM dose on an empty stomach, then they should try and take the remainder of 
their PM doses on an empty stomach and vice versa.
If BVY is initiated after assessments on Day 11 or upon ET, it will be administered orally, once 
daily, without regard to food.
CCI
CCI
CCI
CCI


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Amendment 1
CONFIDENTIAL
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Reference Therapy, Dose, and Mode of Administration: Not applicable
Duration of Intervention: Up to 25 days
Study Procedures/Frequency: After screening and meeting all eligibility criteria, study drug 
dosing will be initiated on Day 1 in the clinic for each participant. Participants will be required to 
return to the clinic for visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). 
After assessments on Day 11 or upon ET, participants will initiate a regimen of BVY provided 
by the sponsor or an alternative SOC ART regimen selected by the investigator. Participants will 
be required to return to the clinic for a visit on Day 25.
The detailed schedule of procedures for Substudy-03 is provided in Table 1.
Statistical Methods: See master protocol synopsis for statistical methods.


GS-6212
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Final
Gilead Sciences, Inc.
Amendment 1
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SUBSTUDY-03 STUDY SCHEMA
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-03
ART = antiretroviral therapy; BVY = bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®); 
PK = pharmacokinetic(s); SOC = standard of care
For Cohort 1, a dose of GS-6212 100 mg will be administered orally twice daily (ie, once every 12 hours ± 1 hour) on Days 1 
through 10 (for further details on dosing and meal requirements, see Section 5.2.4). Subsequent cohort doses, dosing regimens, 
meal requirements (fasted or fed), and progression between cohorts will be adaptive and determined as summarized in 
Section 3.1.1.
a
After assessments on Day 11 or upon early termination, participants will initiate a regimen of BVY provided by the sponsor 
or an alternative SOC ART regimen selected by the investigator. Participants who discontinue study drug before Day 11 
should start this regimen at the time of discontinuation (see Section 6.4.1 of the master protocol).
GS-6212 Treatment 
V 
Day 
-28 
Treatment 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 
PK 
A A A A A A A A A A 
* 
* 
• 
Clinic visi1 
0 
No clinic visit 
A GS-6212 dosing 
V Primary endpoint 
Initiate BVY (B/FfTAF) or SOC 
* Intensive PK 
Trough PK sampling 
BVY or SOC ART Treatmenta ) 
25 


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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 12
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STUDY PROCEDURES TABLE
Table 1.
Substudy-03 Study Procedures Table
Study Procedure
Screeninga
D1b
D2
D3
D4
D7
D8
D9
D10
D11b
D25
ETc
Visit Window
±2D
Written informed consent
X
Medical history and demography
X
Complete physical examination
X
X
X
X
Symptom-driven physical examinationd
X
X
X
X
Height 
X
Weight 
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
HBV blood panel and HCV serologyf
X
CD4 cell countf
X
X
X
X
X
Plasma sample for HIV-1 
genotyping/phenotypingf,g
X
X
X
Plasma HIV-1 RNAf
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyf
X
X
X
X
X
X
X
Coagulation panelf
X
X
X
X
X
X
Chemistryf
X
X
X
X
X
X
X
Urinalysisf
X
X
X
X
X
X
X
Serum pregnancy testf,h
X
Urine pregnancy testf,h,i
X
X
X
Serum FSHf,j
X
12-Lead ECG
X
X
X
X
X
X
Intensive plasma PKk
X
X
Single trough plasma PKl
X
X
X
X
X
X
X
X
Review AEs and concomitant medicationsm
X
X
X
X
X
X
X
X
X
X
X
X
Study drug (GS-6212) dispensationn
X
Study drug (GS-6212) dosingo, p
X
X
X
X
X
X
X
X
BVY dispensation, as applicable
X


GS-6212
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Final
Gilead Sciences, Inc.
Amendment 1
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Study Procedure
Screeninga
D1b
D2
D3
D4
D7
D8
D9
D10
D11b
D25
ETc
Visit Window
±2D
BVY or an alternative SOC administration
Xq
AE = adverse event; AM = before noon; BVY = bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®); CD4 = clusters of differentiation 4; 
D = Day; ECG = electrocardiogram; eCRF = electronic case report form; ET = early termination; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; 
HCV = hepatitis C  virus; HIV-1 = human immunodeficiency virus type 1; PK = pharmacokinetic(s); RNA = ribonucleic acid; SAE = serious adverse event; SOC = standard of 
care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours prior to dosing) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom-driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure at Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the study drug. See Section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Participants assigned female at birth and of childbearing potential only.
i
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
j
A serum FSH test is required for participants assigned female at birth who are younger than 54 years, not on hormonal contraception, and who have stopped menstruating for 
≥ 12 months but do not have documentation of ovarian hormonal failure.
k
Intensive PK samples should be collected at these time points for all cohorts (relative to AM dosing): predose (≤ 30 minutes before dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 
12 hours postdose (
) on respective days of dosing (ie, Days 1 and 10). Please note that the 12-hour postdose sample (if collected) on 
Days 1 and 10 should be sampled prior to the administration of the PM dose, as applicable.
l
Single trough PK sample should be drawn prior to AM drug dosing (as applicable) on the indicated dosing days (ie, Days 2, 3, 4, 7, 8, 9, and 11).
m
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.
n
Study drug bottles of GS-6212 will be dispensed on Day 1 (see Section 5.2.4).
o
For Cohort 1, a 100-mg dose of GS-6212 will be administered twice daily (ie, once every 12 hours ± 1 hour) on Days 1 through 10 (for further details on dosing and meal 
requirements, see Section 5.2.4). Subsequent cohort doses, dosing regimens, meal requirements (fasted or fed), and progression between cohorts will be adaptive and 
determined as summarized in Section 3.1.1.
p
Participants will take their study drug doses at home on Days 5 and 6.
q
After assessments on Day 11 or upon ET, participants will initiate a regimen of BVY provided by the sponsor or an alternative SOC ART regimen selected by the 
investigator. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation (see Section 6.4.1 of the master protocol).
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1.
INTRODUCTION
Substudy-03, conducted under the GS-US-544-5905 master protocol, will evaluate the safety, 
pharmacokinetics (PK), and antiviral activity of GS-6212 given as monotherapy in participants 
with HIV-1 (PWH) who are either treatment-naive or treatment-experienced but naive to the 
integrase strand-transfer inhibitor (INSTI) class, and have not received any antiretroviral (ARV) 
therapy (ART) within 12 weeks of screening (full population details provided in Section 4).
1.1.
Rationale for Substudy-03
An overall rationale for the development of long-acting (LA) ARV agents is provided in the 
GS-US-544-5905 master protocol.
A rationale for the development of GS-6212 is provided below in Section 1.2.1.
1.2.
Background on Study Interventions Used in Substudy-03
1.2.1.
GS-6212
1.2.1.1.
General Information
Integrase strand-transfer inhibitors have played an ever-growing role in disease treatment and are 
currently a key component of combination ARV therapies. There are currently 5 INSTIs 
approved for the treatment of HIV-1 infection. GS-6212 is a potent and selective INSTI with a 
favorable nonclinical pharmacology profile that supports its clinical development as a novel 
ARV agent for the treatment of HIV-1 infection, with the potential for injectable dosing once 
every 3 months. A broad spectrum of representative HIV-1 mutant variants resistant to 
nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, 
protease inhibitors, or capsid inhibitors remained fully sensitive to GS-6212, indicating that the 
compound should retain full antiviral potency against mutant variants from these ARV classes. 
Developing the novel INSTI GS-6212 to be combined with other LA ARVs would fulfill an 
unmet medical need for people with HIV-1 to provide safe and effective regimens that can be 
administered less frequently. For further information, refer to the current GS-6212 investigator’s 
brochure (IB), including the following:
1) Nonclinical PK
2) Nonclinical pharmacodynamics
3) Nonclinical toxicology
1.2.1.2.
Nonclinical Pharmacology and Toxicology
Nonclinical pharmacology and toxicology studies are provided in the GS-6212 IB.


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1.2.1.3.
Clinical Studies of GS-6212
1.2.1.3.1.
Study GS-US-469-6161
Study GS-US-469-6161 is an ongoing, Phase 1a, first-in-human, randomized, blinded 
(sponsor unblinded), placebo-controlled clinical study. In this study, healthy participants 
received or will receive single ascending doses (SAD) of GS-6212 using the following 
formulations and parenteral routes of administration: GS-6212 polyethylene glycol (PEG)/water 
for injection (WFI) suspension formulation (400 mg/mL) administered subcutaneously 
(SC, Part A), GS-6212 oil suspension formulation (350 mg/mL) administered SC (Part B), 
GS-6212 PEG/WFI suspension formulation (225 mg/mL) administered intramuscularly 
(IM, Part C), and GS-6212 PEG/WFI suspension formulation (400 mg/mL) administered IM 
(Part D). The study remains blinded, with follow-up ongoing.
Preliminary PK Summary
To characterize the PK of GS-6212 for injection, plasma samples will be collected up to Day 301 
in each cohort. Interim PK analysis of samples until at least Day 7 postdose from cohorts that 
have been dosed thus far in Parts A, B, C, and D is ongoing.
Safety Summary
As of 12 May 2023, 75 participants have received either GS-6212 or placebo (randomized 4:1) 
by injection in Part A (n = 30; 200, 600, and 1200 mg), Part B (n = 20; 200 and 525 mg), Part C 
(n = 20; 
and 225 mg) and Part D (n = 5; 200 mg). There have been no deaths, serious 
adverse events (SAEs), Grade 3 or higher adverse events (AEs), or discontinuations due to AEs 
reported. In a preliminary review of available safety data for 75 participants, as of 12 May 2023, 
the most common study drug (GS-6212 or placebo)–related AEs have been mild to moderate 
(Grade 1 and Grade 2) injection site reactions related to SC or IM administration and reported in 
30% to 100% of participants across the different cohorts. Noninjection-site reaction study 
drug-related AEs were reported as follows: headache (n = 6), rash and pruritis (n = 1), and 
diarrhea (n = 1); all were Grade 1 and resolved without intervention. Other AEs included 
1 participant who experienced presyncope related to micturition and 1 participant with 
asymptomatic atrial flutter at a Day 56 follow-up visit related to illicit drug use (cocaine). 
Both AEs resolved without intervention and were considered to be unrelated to GS-6212.
There were no clinically relevant changes from predose in values for hematology, clinical 
chemistry, urinalysis, or coagulation parameters in this preliminary review. Five participants had 
Grade 3 laboratory abnormalities; 3 participants had increased fasting low-density lipoprotein 
(LDL), 2 participants had increased fasting triglycerides, 1 participant had a decrease in CLcr and 
a corresponding increase in serum creatinine from baseline but both values remained in the 
normal range. None of these Grade 3 laboratory abnormalities were considered clinically 
relevant. No Grade 4 laboratory abnormalities were reported.
No notable changes from predose were observed in vital signs (systolic and diastolic blood 
pressure, pulse, temperature, and weight).
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GS-6212 
Protocol GS-US-544-5905-03 
Gilead Sciences, Inc. 
1.2.1.3.2. 
Study GS-US-469-6401 
Final 
Amendment 1 
Study GS-US-469-6401 is an ongoing, Phase la, randomized, blinded (sponsor unblinded), 
placebo-contrnlled clinical study. In this study, healthy paii icipants received or will receive SAD 
or multiple ascending doses (MAD) of oral GS-6212. This study is being conducted in 2 pa1is 
(SAD Coho1is 1 through 4 and MAD Coho1is 5 through 7) that will include up to 7 coho1is. 
Additionally, Cohorts 2 and 3 will be conducted as a 2-period fixed-sequence design of the same 
single-dose levels of oral GS-6212 to assess any potential food effect. 
Preliminary PK Summary 
Prelimina1y GS-6212 plasma concentration-time profiles and associated PK 
followin administration of single oral doses of 100 mg (Coho1i 1 
under fasted and/or fed conditions, and 
under fasted conditions ai·e presented 
in Figure 2, Figure 3, and Table 2 based on PK data available from Study GS-US-469-6401 as of 
21 April 2023. Phannacokinetic sainples were collected for up to 72 hours postdose. 
Following oral administration of GS-6212 with or without food, GS-6212 was absorbed quickly 
with Tmax observed from 1.0 to 4.0 hours postdose. The median oral GS-6212 t112 ranged from 
approximately-
hours across the evaluated dose levels. All but 1 paiiicipant attained 
~rotein-adjusted 95% effective concentration or inhibito1y quotient (IQ) 
-
for GS-6212 by up to 2.0 hours postdose across all coho1is. 
Over the dose range evaluated, the increase in AUC and Cma.x was less than dose-propo1i ional in 
the fasted state. These less than dose-proportional increases in exposure suggest that oral 
GS-6212 exhibits nonlineai·ity in the dose-exposure relationship likely due to solubility-limited 
absorption. 
Based on data from a limited sain le size, GS-6212 exp~as assessed by AUCinfand Cmax) 
followin 
of a GS-6212-
dose with a hi h-fat meal was on 
average, approxrmate y 
o er relative to GS-6212 
dosed in fasted 
conditions. In compai·ison, 
of a GS-6212 
dose with a 
high-fat meal led to,~ 
approximate 
increase in GS-6212 exposure 
relative to GS-6212- dosed in fasted conditions. 
In line with the observed t112 values, minimal accumulation in GS-6212 exposures was observed 
following 10 days of once-daily dosing in Cohorts 5 and 6. 
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GS-6212 
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Cohort 1 
Cohort 2 
(100 mg; -
Fasted) 
1590 
2790 
(17.2) 
(14.8) 
2.00 
2.00 
(1.00, 
(1.25, 
2.75) 
3.00) 
8.32 
26.1 
(44.5) 
(37.4) 
1.60 
3.94 
(26.7) 
(82.1) 
48.0 
72.0 
(39.0, 
(54.0, 
48.0) 
72.0) 
6420 
14,400 
(28.2) 
(19.1) 
6500 
14,800 
(28.1) 
(19.5) 
6520 
15,000 
(28.1) 
(20.5) 
0.259 
1.05 
(37.1) 
(213) 
6.42 
8.43 
(5.01, 
(6.68, 
10.1) 
12.5) 
Cohort 2 
.
; 
1830 
(37.8) 
3.00 
(1.25, 
4.00) 
25.2 
(56.0) 
4.06 
(94.8) 
72.0 
(54.0, 
72.0) 
11,200 
(38.4) 
11,600 
(39.1) 
11,600 
(39.2) 
0.440 
(46.7) 
9.33 
(8.15, 
14.8) 
Cohort 5 
Cohort 3 
Cohort 3 - · 
-
; 
.
; 
Day 1; 
Fasted) 
4720 
5140 
1430 
(37.8) 
(41.2) 
(47.8) 
2.50 
4.00 
1.00 
(2.00, 
(3.00, 
(0.625, 
3.00) 
4.00) 
3.50) 
120 
366 
12.7 
(195) 
(198) 
(78.2) 
2.87 
5.63 
12.7 
(1 18) 
(109) 
(78.2) 
72.0 
72.0 
24.0 
(72.0, 
(72.0, 
(24.0, 
72.0) 
72.0) 
24.0) 
26,200 
40,700 
6590 
(32.9) 
(48.9) 
(51.1) 
27,000 
42,900 
6590 
(35.2) 
(51.2) 
(51.1) 
27,100 
43,000 
6660 
(35.3) 
(51.2) 
(51.2) 
0.201 
0.183 
1.02 
(81.0) 
(55.4) 
(40.7) 
14.4 
11.4 
3.77 
(12.2, 
(7.20, 
(3.33, 
15.7) 
13.2) 
4.14) 
h = hom·; PK = phanuacokinetic(s); Ql = first qua1tile; Q3 = third qua1tile; QD = once daily 
Cohort 5 -
QD x 
10 days, 
Day 10; 
Fasted) 
1640 
(32.3) 
2.00 
(2.00, 
3.75) 
15.5 
(58.1) 
1.73 
(24.1) 
72.0 
(48.0, 
72.0) 
7460 
(38.6) 
7650 
(38.6) 
8.84 
(7.25, 
10.5) 
Final 
Amendment 1 
Cohort 6 
- · 
Day l ; 
Fasted) 
2900 
(37.2) 
2.00 
(0.625, 
3.75) 
17.0 
(55.0) 
17.0 
(55.0) 
24.0 
(24.0, 
24.0) 
13,400 
(40.3) 
13,400 
(40.3) 
13,500 
(40.4) 
0.597 
(26.8) 
3.46 
(3.28, 
3.55) 
PK parameters presented to 3 significant figures as mean (%CV) except t112, T1as1, and Tmax which are presented as median 
(Ql, Q3). 
Note: Analysis was conducted using nominal time points. 
Safety Summary 
As of21 April 2023, 50 paiiicipants have received at least 1 dose of either GS-6212 or-
acebo 
in SAD Coho1is 1 2 and 3 (100 mg, 
) and MAD Coho1is 5 and 6 
• 
and-
for 10 days). Preliminaiy GS-6212 exposures for each coho1i ai·e found 
m Table 2 wit t e 1 
est estimated exposure (preliminaiy AUCuu) of 43,000 h•ng/mL in 
Coho1i 3. In a preliminaiy blinded review of available safety data collected for 50 paiiicipants 
(SAD Coho1is 1, 2, and 3 and MAD Cohorts 5 and 6) as of 21 April 2023, there have been no 
deaths, SAEs, Grade 3 or higher AEs, or discontinuations due to AEs repo1ied. One paiiicipant 
experienced a study diug (GS-6212 or placebo )- related treatment-emergent AE of Grade 1 
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headache, which resolved. One participant in Cohort 6 experienced treatment-emergent AEs of 
Grade 1 nausea and vomiting, along with headache and dizziness, on Days 1 and 2 respectively, 
which resolved without treatment and were judged by the investigator to be related to study drug 
(GS-6212 or placebo). This same participant experienced Grade 3 laboratory abnormalities for 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) on Day 13 which returned 
to baseline on retesting by Day 25; bilirubin levels and international normalized ratio remained 
normal, and acute viral hepatitis testing was negative.
Three participants had Grade 3 laboratory abnormalities; 1 participant had increased ALT and 
AST (discussed above) and a Grade 3 decrease in CLcr from baseline with normal serum 
creatinine and normal CLcr, 1 participant had increased LDL, which returned to baseline on 
retesting, and 1 participant had an increased triglyceride level that decreased on repeat testing. 
With the exception of the participant with elevated ALT and AST, no Grade 3 laboratory 
abnormalities were clinically significant or judged to be related to study drug. There were no 
other clinically relevant changes from predose in values for hematology, clinical chemistry, 
urinalysis, or coagulation parameters. No notable changes from predose were observed in vital 
signs (systolic and diastolic blood pressure, pulse, temperature, and weight).
1.3.
Rationale for Dose Selection of GS-6212
Selection of the GS-6212 doses for this study takes into consideration the available safety, 
tolerability, and PK data for GS-6212 from the ongoing Phase 1a oral SAD and MAD study in 
healthy volunteers (Study GS-US-469-6401), as well as emerging preliminary safety and 
antiviral activity data in this substudy (as applicable).
As of 21 April 2023, 30 participants (24 active and 6 placebo) have received a 
 of 
either GS-6212 
 or placebo in SAD Cohorts 1, 2, and 3, and 20 participants 
(16 active and 4 placebo) have received multiple oral doses of either GS-6212 
 
 or placebo in MAD Cohorts 5 and 6. In a preliminary blinded review of available safety 
data collected for 50 participants (Cohorts 1 through 3, and 5 and 6) as of 21 April 2023, 
GS-6212 dosed orally was generally safe and well-tolerated. A summary of preliminary safety 
data from Study GS-US-469-6401 is included in Section 1.2.
As of 21 April 2023, preliminary SAD PK data are available from Cohorts 1 through 3 at doses 
ranging from 100 
, and MAD PK data are available from Cohorts 5 and 6 at 
 
 doses from Study GS-US-469-6401 (Figure 2, Figure 3, and Table 2). For the purposes 
of dose selection, both Ctrough and the Cav,ss were taken into consideration given that steady state 
is attained rapidly via the oral route in comparison to the SC/IM profiles that are expected to be 
relatively flatter with sustained exposures spanning over a wider interval. This may facilitate the 
extrapolation of the antiviral GS-6212 data from oral dosing to relevant clinical concentrations 
achieved with SC or IM formulations. Based on modeling and simulation using a preliminary 
population PK model, a 100-mg dose of GS-6212 administered orally twice daily (ie, once every 
12 hours) from Days 1 through 10 will be used for Cohort 1 of this substudy. Modeling predicts 
that this regimen will result in a median GS-6212 Ctrough at Day 11 that is approximately 4.7-fold 
above the IQ, with the median Cav,ss predicted to be approximately 5.0-fold above the IQ5 
(the estimated therapeutic threshold). The mean Cmax of GS-6212 attained following a single oral 
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dose of 100 mg was approximately 1590 ng/mL (Table 2). Based on the available data, 
accumulation for GS-6212 exposures following twice daily dosing of 100 mg is expected to be 
minimal; the predicted median GS-6212 AUC and Cmax for the proposed 
 
 is approximately 3.0- to 3.5-fold lower than the highest observed AUC and Cmax from 
the available preliminary analysis of Study GS-US-469-6401. Overall, GS-6212 exposures 
projected for Cohort 1 of the current study are well covered by the systemic levels of GS-6212 
that have been shown to be safe in Study GS-US-469-6401 (see Section 1.2).
As part of this substudy, higher and/or lower GS-6212 doses/exposures relative to Cohort 1 will 
be evaluated in subsequent cohorts to target a wide range of IQ values that characterize the 
PK/pharmacodynamic relationship between GS-6212 PK and changes from baseline in HIV-1 
viral load. Doses in Cohorts 2 to 5 (as applicable) will be determined by the Safety Review Team 
(SRT) based on cumulative safety, PK, and virologic data from Cohort 1, as well as relevant and 
available safety and PK data from the Phase 1a study (GS-US-469-6401). Doses selected for 
Cohorts 2 to 5 will be adaptive and will have projected GS-6212 exposures approximately at or 
below the observed exposures in the Phase 1a study.
1.4.
Benefit-Risk Assessment for the Study
Potential risks to participants may include limited exposure to subtherapeutic concentrations of 
study drug. This could lead to the HIV-1 virus developing resistance to the study drug, and 
potentially to the study drug class, which could limit future treatment options. Strategies to 
mitigate this risk, and additional risk/benefit assessments applicable to Substudy-03 and 
GS-6212, are described in Section 1.4 of the master protocol.
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2.
OBJECTIVES AND ENDPOINTS
Objectives and endpoints are described in Section 2 of the master protocol.
3.
STUDY DESIGN
3.1.
Study Design Overview
This substudy is being conducted as part of an umbrella study as described in the master 
protocol.
Substudy-03 is an open-label, Phase 1b, multiple-dose, multicohort study to evaluate the safety, 
PK, and antiviral activity of GS-6212 given as monotherapy in PWH who are either 
treatment-naive or treatment-experienced but naive to INSTIs and have not received any ART 
within 12 weeks of screening, including medications received for pre-exposure prophylaxis or 
postexposure prophylaxis. Any current or prior receipt of LA parenteral ARVs, such as 
monoclonal antibodies targeting HIV-1, injectable cabotegravir, or injectable rilpivirine, is 
exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant (Figure 1). Participants will be required to return to the clinic for 
visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). Doses of GS-6212 will 
be administered orally at the clinic under observation by site staff on clinic visit days/times and 
at home by the participant on nonclinic visit days/times at approximately the same time each day. 
In cohorts where GS-6212 is administered more than once daily, in-clinic observation of dosing 
will be conducted for the morning dose only. Participants will record at-home dosing details in a 
dosing log.
After assessments on Day 11 or upon early termination (ET), participants will initiate a regimen 
of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or 
an alternative standard of care (SOC) ART regimen selected by the investigator. If participants 
are switching to BVY, a sufficient supply will be given to provide coverage for the remainder of 
the study. Participants will be required to return to the clinic for a follow-up visit on Day 25.
Overnight fasting (≥ 6 hours prior to dosing) is required for laboratory and/or PK analyses on 
Days 1 and 11 (see Section 5.3). On all other days (Days 2 through 10), the AM doses should be 
taken on an empty stomach (for additional details see Section 5.3).
The selection of doses and dosing regimens for GS-6212 is described in Section 3.1.1.
This substudy will enroll up to 5 cohorts, with at least 6 participants in each cohort. 
Initial participants will be enrolled in Cohort 1, with dosing in subsequent cohorts proceeding 
after SRT review of emerging data from Cohort 1 and available data from the Phase 1a 
SAD/MAD Study GS-US-469-6401, as described in Section 3.1.1.


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Sequential enrollment in cohorts, and order of assignment to substudies, are described in 
Section 5.1.1 of the master protocol.
The sponsor may elect to hold dosing, stop/pause substudy enrollment, or stop the study 
(or substudy, or specific cohort) at any time based on review of preliminary safety, efficacy, and 
PK data (see master protocol Section 5.1.1). If deemed unnecessary, the sponsor may choose not 
to initiate 1 or more cohorts.
3.1.1.
Dose Selection/Modification
Enrollment and dosing with GS-6212 will begin with Cohort 1. The dose and regimen of 
GS-6212 for Cohort 1 is defined in Section 5.2.4.
A summary of planned SRT reviews, dose decisions, and cohort progression applicable to this 
substudy is included in Section 3.1.1 of the master protocol.
3.2.
Duration of Intervention
Participants will be under evaluation in this Substudy-03 for 25 days.
Participants will receive doses of GS-6212 from Days 1 through 10; dosage and frequency will 
be specified as described in Section 5.2.4. Participants will then initiate a BVY or alternative 
SOC regimen following study assessments on Day 11 or upon ET for the remainder of the study. 
Participants will be required to return to the clinic for a follow-up visit on Day 25.
3.3.
Substudy-03–Specific Discontinuation Criteria
Criteria for early discontinuation for individual participants, each substudy, and each substudy 
cohort are described in Section 3.3 of the master protocol.
3.4.
Definitions for Time of Primary Endpoint and End of Study
Definitions for the time of the primary endpoint and end of study for each substudy are described 
in Section 3.4 of the master protocol.


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection for Substudy-03
In Substudy-03, up to 5 cohorts, each containing at least 6 participants, will be enrolled. 
Participant replacement is described in Section 4.1.1 of the master protocol.
4.2.
Substudy-03–Specific Inclusion Criteria
Inclusion criteria applicable to all substudies are provided in Section 4.2 of the master protocol. 
In addition to meeting the inclusion criteria in the master protocol, participants must also meet 
the following inclusion criteria to be eligible for participation in this substudy:
S03-1. Willing to initiate an SOC ART regimen on Day 11 or upon ET as stated in Section 4.2 
of the master protocol. For this substudy, willing to initiate BVY provided by the sponsor or an 
alternative SOC ART regimen selected by the investigator on Day 11 or upon ET.
S03-2. Willing and able to comply with meal requirements.
4.3.
Substudy-03–Specific Exclusion Criteria
Exclusion criteria applicable to all substudies are provided in Section 4.3 of the master protocol. 
In addition to not meeting any of the exclusion criteria in the master protocol, participants must 
not meet the following exclusion criterion to be eligible for participation in this substudy:
S03-1. Requirement for ongoing therapy with any prohibited medication listed in Section 5.4.


GS-6212 
Protocol GS-US-544-5905-03 
Gilead Sciences, Inc. 
5.1. 
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS 
Enrollment and Treatment Code Access 
Final 
Amendment 1 
Paiiicipant emollment procedures ai·e described in Section 5 .1 of the master protocol. 
5.2. 
Description and Handling of GS-6212 and BVY 
BVY will be provided by the sponsor for use during the study, as applicable. 
5.2.1. 
Formulation 
BVY tablets (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) ai·e 
capsule-shaped, film-coated, pmp lish brown, de bossed with "GSI" on one side of the tablet and 
"9883" on the other side of the tablet. Each tablet core contains 50 mg of bictegravir 
(equivalent to 52.5 mg ofbictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir 
alafenamide (equivalent to 28 mg oftenofovir alafenamide fumai·ate). In addition to the active 
ingredients, the BVY tablets contain croscannellose sodium, magnesium stearate, and 
microc1ystalline cellulose. The tablet cores ai·e film-coated with iron oxide red, iron oxide black, 
PEG, polyvinyl alcohol, talc, and titanium dioxide. Additional details are provided in local 
prescribing infonnation for BVY product. 
5.2.2. 
Packaging and Labeling 
GS-6212 tablets ai·e packaged in white, high-density polyethylene bottles. Each bottle contains 
30 tablets and a silica gel desiccant. Each bottle is enclosed with a white, continuous-thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner. GS-6212 
-
bottle configurations contain polyester packaging material. GS-6212 
bottle configuration does not contain polyester packaging material. 
BVY tablets ai·e packaged in white, high-density polyethylene bottles. Each bottle contains 
30 tablets, silica gel desiccant, and polyester packaging material. Each bottle is enclosed with a 
white, continuous-thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner. 
CONFIDENTIAL 
Page 25 
18 August 2023 


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Amendment 1
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Study drug(s) to be distributed to study sites in the United States (US) and other participating 
countries shall be labeled to meet applicable requirements of the US Food and 
Drug Administration (FDA), European Union (EU) Guideline to Good Manufacturing 
Practice-Annex 13 (Investigational Medicinal Products) for Common Technical Document, or 
Annex 6 for Clinical Trial Regulation, as applicable, and/or other local regulations.
5.2.3.
Storage and Handling
GS-6212 tablets should be stored below 30 °C. BVY should be stored according to the storage 
conditions specified on the label.
GS-6212 and BVY should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of GS-6212 and BVY and proper identification, the drug 
product should not be stored in a container other than that in which it is supplied.
5.2.4.
Dosage and Administration
In Cohort 1, a dose of GS-6212 100 mg will be administered orally twice daily (ie, once every 
12 hours ± 1 hour) on Days 1 through 10. The dose, dosing regimen, and meal requirements for 
administration of GS-6212 in Cohort 1 are provided in Table 3. Subsequent cohort doses, dosing 
regimens, meal requirements (fasted or fed), and progression between cohorts will be adaptive, 
as described in Section 3.1.1. The maximum dose (to be administered each day at any given 
time) in subsequent cohorts will not exceed those indicated in Table 3.
For participants who will be receiving GS-6212 once daily, study drug will be dispensed on 
Day 1. Bottles will be stored on site and administered in the clinic on Days 1 through 4. 
Participants will take doses at home on Days 5 and 6; doses on Days 7 through 10 will be 
administered in the clinic.
For participants who will be receiving GS-6212 twice daily, study drug bottles will be dispensed 
on Day 1. Participants will take the bottles home after the morning dose at the clinic and then 
bring the bottles back to the clinic for the next day’s morning dose at the clinic for Days 1 
through 4 and Days 7 through 10. For Days 5 and 6, participants will keep the bottles at home.
Doses of GS-6212 will be administered orally at the clinic under observation by site staff on 
clinic visit days/times and at home by the participant on nonclinic visit days/times at 
approximately the same time each day. In cohorts where GS-6212 is administered more than 
once daily, in-clinic observation of dosing will be conducted for the morning dose only. 
Participants will record at-home dosing details in a dosing log. In addition to the dosing log, 
site staff can remind the participant of evening dosing via phone call/text message, if feasible. 
The timing of all doses on Days 5 and 6 should be recorded in a dosing log.


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Gilead Sciences, Inc.
Amendment 1
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Table 3.
GS-6212 Dosage by Cohort
Cohort
Treatment
Cohort 1
100 mg oral doses BID (ie, once every 12 hours 
± 1 hour) on Days 1 through 10:
-
The first AM dose (on Day 1) should be taken 
following overnight fasting (≥ 6 hours).
-
All other AM doses (on Days 2 through 10) should 
be taken around the same time every morning on 
an empty stomach (fasting for ≥ 2 hours; 
see Section 5.3).
-
Each PM dose should be taken around the same 
time every evening with or without food. 
Participants are required to keep the pattern of 
study drug intake consistent throughout the 
10 days of dosing as much as possiblea 
(see Section 5.3).
Cohort 2
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 3
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 4
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
Cohort 5
 on 
Days 1 through 10; dosing intervals and meal 
requirements (fasted or fed) to be determined based on 
relevant and available data from earlier cohorts.
AM = before noon; BID = twice daily; PM = evening; QD = once daily
a
For instance, if a participant takes their first PM dose on an empty stomach, then they should try and take the remainder of 
their PM doses on an empty stomach and vice versa.
If BVY is initiated after assessments on Day 11 or upon ET, it will be administered orally, once 
daily, without regard to food.
5.3.
Fasting and Meals (GS-6212 Dosing)
Cohort 1:
All GS-6212 doses will be administered at approximately the same time on each day 
(morning/evening) with 240 mL of water.
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Amendment 1
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AM dosing:
The first AM dose of the study drug (on Day 1) should be administered following an overnight 
fast (no food or drinks, except water) for at least 6 hours. Participants should continue to fast 
until after collection of the 2-hour intensive PK sample, relative to time of dosing on Day 1. 
Additionally, participants will be restricted from water consumption 1 hour before and until 
1 hour after dosing, except for the 240 mL given with the study drug on Day 1.
On all other days (ie, Days 2 through 10), participants should take the study drug on an empty 
stomach (no food or drinks except water, for at least 2 hours) and continue to fast until 1-hour 
postdose.
PM dosing:
Study drug should be taken every evening on an empty stomach (no food or drinks, except water, 
for at least 2 hours and continue to fast until 1-hour postdose) or with food. Additionally, 
overnight fasting (no food or drinks, except water) for at least 6 hours, is required for safety 
assessments on Day 11.
Participants are required to keep the pattern of study drug intake consistent throughout the 
10 days of dosing as much as possible (for instance, if a participant takes their first PM dose on 
an empty stomach, then they should try and take the remainder of their PM doses on an empty 
stomach and vice versa).
Note: Fasting and meal requirements for the subsequent cohorts will be confirmed following 
availability of data from Cohort 1, and relevant and available data from the Phase 1a SAD/MAD 
Study GS-US-469-6401.
5.4.
Prior and Concomitant Medications
See Section 5.3 of the master protocol for information on prior or concomitant medication rules 
applicable to this substudy, including restricted medications through Day 11. The investigator 
should reach out to the sponsor for guidance prior to the use of any concomitant medication from 
Day 1 through the end of study.
From Day 11 (following administration of BVY or an alternative SOC) through the last visit, the 
investigator should follow the local prescribing information for BVY or other ART taken as SOC 
(as applicable) by an individual participant.
5.5.
Accountability for Study Drug Supplies: Study Drug and SOC ART 
Provided by the Sponsor (BVY)
Guidance related to accountability, return, and disposal of study drug supplies (study drug 
[GS-6212 for this substudy] and SOC ART provided by the sponsor [BVY for this substudy]) is 
provided in Section 5.4 of the master protocol.


GS-6212 
Protocol GS-US-544-5905-03 
Gilead Sciences, Inc. 
STUDY PROCEDURES 
Final 
Amendment 1 
Study procedures applicable to all substudies are listed in Section 6 of the master protocol. 
Study procedures specific to Substudy-03 are listed in the sections below. The time points for 
study procedures are specified in Table 1. Substudy-specific info1med consent fo1ms will be 
required for Substudy-03. 
6.1. 
6.1.1. 
Instructions for Study Procedures 
Pharmacokinetics 
Blood samples will be collected to detennine GS-6212 PK (and metabolites, if appropriate) in 
plasma as indicated in Table 1. 
6.1.2. 
Suboptimal Virologic Response 
Management of suboptimal virologic response is described in Section 6.3 .9 .1.3 of the master 
protocol. 
6.1.2.1. 
Management ofVirologic Rebound 
Management ofvirologic rebound is described in Section 6.3.9.1.3 of the master protocol. 
6.1.2.2. 
Resistance Analysis at Paiiicipant's Last Visit 
Resistance analysis at a paiiicipant's last visit is described in Section 6.3.9.1.3 of the master 
protocol. 
CONFIDENTIAL 
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6.1.3.
Poststudy Care
The investigators will counsel and refer the participants to long-term care, including a human 
immunodeficiency virus treatment facility, and any medication assistance programs. Please see 
Section 3.5 of the master protocol.


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Amendment 1
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Adverse events are specified in Section 7 of the master protocol. Information regarding toxicity 
management that is specific to GS-6212 is described below and included in Appendix 11.3. 
Pregnancy precautions, definition of childbearing potential, and contraceptive requirements 
specific to GS-6212 are included in Appendix 11.2.
7.1.
Toxicity Management
All clinically significant laboratory toxicities will be managed according to uniform guidelines 
detailed in Appendix 11.3 and as outlined below.
•
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 or 4 laboratory abnormality (eg, creatine kinase elevation after 
strenuous exercise, triglyceride elevation that is nonfasting or can be medically managed). 
Recurrences of laboratory abnormalities considered unrelated to study drug may not require 
permanent discontinuation.
•
Grade 3 or 4 AEs, if considered unrelated to study drug, may not require dose interruption; 
continuation of study drug is at the discretion of the investigator.
7.1.1.
Grades 1 and 2 Laboratory Abnormalities or AEs
•
Continue study drug dosing at the discretion of the investigator.
7.1.2.
Grade 3 Laboratory Abnormalities or AEs
•
For a Grade 3 clinically significant laboratory abnormality confirmed by repeat testing that is 
considered related to study drug, the study drug should be permanently discontinued, and the 
investigator should consult the medical monitor and manage as clinically indicated. BVY or 
an alternative SOC should be initiated if clinically appropriate.
•
For a Grade 3 AE considered to be related to the study drug, the study drug should be 
permanently discontinued, and the investigator should consult the medical monitor and 
manage as clinically indicated. BVY or an alternative SOC should be initiated if clinically 
appropriate.


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Amendment 1
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7.1.3.
Grade 4 Laboratory Abnormalities or AEs
•
For a Grade 4 AE or clinically significant laboratory abnormality confirmed by repeat testing 
considered related to study drug, the study drug should be permanently discontinued, BVY or 
an alternative SOC should be initiated if clinically appropriate, 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 comes 
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 sponsor’s medical monitor, and the appropriate course of action will be discussed and 
decided. Whether or not considered treatment-related, all participants experiencing an AE must 
be monitored periodically until symptoms subside, any abnormal laboratory values have resolved 
or returned to baseline levels or are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the sponsor’s medical 
monitor.


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Final
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Amendment 1
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8.
STATISTICAL CONSIDERATIONS
Details of statistical methods will be provided in the statistical analysis plan for this substudy, 
including any deviations from the original statistical analyses planned. Statistical considerations 
for this substudy are described in Section 8 of the master protocol.


GS-6212
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Final
Gilead Sciences, Inc.
Amendment 1
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9.
RESPONSIBILITIES
Details regarding responsibilities are specified in Section 9 of the master protocol.


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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10.
REFERENCES
None.


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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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11.
APPENDICES


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Amendment 1
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11.1.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
An Umbrella Phase 1b, Open-label, Multicohort Study to Evaluate Safety, Pharmacokinetics, 
and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1; Substudy-03: 
GS-6212
Amendment 1, 18 August 2023
CLINICAL STUDY PROTOCOL ACKNOWLEDGMENT
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


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Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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11.2.
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 of age with amenorrhea of at least 12 months may also 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.
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 Participants Assigned Female at Birth
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-6212 is contraindicated in pregnancy, as a malformative effect due to human 
teratogenicity/fetotoxicity is unknown. GS-6212 has insufficient data to exclude the possibility 
of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy. Therefore, hormonal contraception is not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Refer to the latest 
version of the GS-6212 investigator’s brochure for additional information.
Refer to the prescribing information for pregnancy and contraception information for the 
standard of care regimen.
b.
Contraception Requirements for Participants Assigned Female at Birth 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 hormone-containing contraceptives as a form of birth control during 
the study. They must have a negative serum pregnancy test at screening and a negative urine 
pregnancy test at the Day 1 visit before enrollment. Pregnancy tests will be performed at monthly 
intervals thereafter until the end of contraception requirement.


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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Duration of required contraception for participants assigned female at birth in this clinical study 
should start from the screening visit until the end of the protocol-defined follow-up period.
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 any of the following methods of birth control listed below:
•
Nonhormonal intrauterine device
•
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 during treatment and until the end of contraception 
requirement.
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 the 
end of the protocol-defined follow-up period. If the partner assigned female at birth and of 
childbearing potential is not pregnant, additional contraception recommendations should also be 
considered.
Participants assigned male at birth must also refrain from sperm donation and cryopreservation 
of germ cells during treatment and until the end of contraception requirement.


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Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5)
Procedures to be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from the start of the study until the end of the 
protocol-defined follow-up period.
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study until the end of the protocol-defined follow-up period must also 
report the information to the investigator. Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.4.2.3 of the master protocol.


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
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11.3.
Management of Clinical and Laboratory Adverse Events
BVY = bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®); SOC = standard of care
Grade 1 
Continue study drng 
dosing at the discretion of 
the investigator 
Grade 2 
Grade 3 
I 
I 
Grade 4 
l 
l 
Repeat laboratmy test to 
confum toxicity grade 
For Grade 3 or 4 clinically significant laboratmy 
abno1malities confumed by repeat testing and 
considered to be related to study diug or adverse 
events considered to be related to study diug, the 
study di·ug should be pe1manently discontinued, and 
the investigator should consult tl1e medical monitor 
and manage as clinically indicated. 
BVY or another SOC should be initiated if clinically 
appropriate. 


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
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11.4.
Amendment History
A high-level summary of this amendment is provided in tabular form in the subsection below, 
with changes listed in order of importance. Minor changes such as the correction of typographic 
errors, grammar, or formatting are not detailed.
A separate tracked change (red-lined) document comparing the original protocol to this 
amendment will be made available upon the publication of this protocol.
11.4.1.
Amendment 1 (18 August 2023)
Rationale for Key Changes Included in Amendment 1
Affected Sections
A formulation for the new GS-6212 
 has been added.
Sections 5.2.1 and 5.2.2
Minor changes such as the correction of typographic errors, grammar, or 
formatting.
Throughout, as needed.
CCI-


GS-6212
Protocol GS-US-544-5905-03
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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11.5.
Sponsor Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
An Umbrella Phase 1b, Open-label, Multicohort Study to Evaluate Safety, Pharmacokinetics, 
and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1; Substudy-03: 
GS-6212
Amendment 1, 18 August 2023
APPROVAL OF CLINICAL STUDY PROTOCOL
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
[See appended electronic signature]
Name (Printed)
Senior Director, Clinical Development
Signature
[See appended electronic signature]
Date
PPD


Prot-GS-US-544-5905-03-amd-1
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Project Team
Leader eSigned
18-Aug-2023
22:26:00
PPD

SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to 
Evaluate Safety, Pharmacokinetics, and Antiviral Activity of 
Novel Antiretrovirals in Participants With HIV-1 Substudy 01: 
GS-5894
Name of Test Drug:
GS-5894
Study Number:
GS-US–544–5905-01
Master Protocol Version 
(Date):
Original
(03 August 2022)
Amendment 1 (27 September 2022)
Amendment 2 (24 February 2023)
Substudy Protocol Version 
(Date):
Original (03 August 2022)
Amendment 1 (27 September 2022)
Analysis Type:
Final Analysis (Substudy 01)
Analysis Plan Version:
Version 1
Analysis Plan Date:
15 September 2023
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


GS-5894
Study GS-US-544-5905 Substudy 01
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 2
15 September 2023
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF APPENDICES.................................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................8
1.2.
Study Design .............................................................................................................................................8
1.3.
Sample Size and Power .............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................10
2.1.
Interim Analysis ......................................................................................................................................10
2.2.
Dose Escalation Analysis ........................................................................................................................10
2.3.
Final Analysis..........................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................11
3.1.
Analysis Sets ...........................................................................................................................................11
3.1.1.
All Enrolled Analysis Set ......................................................................................................11
3.1.2.
Full Analysis Set....................................................................................................................11
3.1.3.
Safety Analysis Set................................................................................................................12
3.1.4.
Pharmacokinetic Analysis Set ...............................................................................................12
3.1.5.
Pharmacokinetic/Pharmacodynamic Analysis Set ................................................................12
3.2.
Participant Grouping ...............................................................................................................................12
3.3.
Strata and Covariates...............................................................................................................................13
3.4.
Examination of Participant Subgroups....................................................................................................13
3.5.
Multiple Comparisons .............................................................................................................................13
3.6.
Missing Data and Outliers.......................................................................................................................13
3.6.1.
Missing Data..........................................................................................................................13
3.6.2.
Outliers ..................................................................................................................................13
3.7.
Data Handling Conventions and Transformations ..................................................................................13
3.8.
Analysis Visit Windows..........................................................................................................................15
3.8.1.
Definition of Study Day ........................................................................................................15
3.8.2.
Analysis Visit Windows........................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................17
4.
PARTICIPANT DISPOSITION ..........................................................................................................................18
4.1.
Participant Enrollment and Disposition...................................................................................................18
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................19
4.2.1.
Study Drug Exposure and Duration on Study .......................................................................19
4.3.
Protocol Deviations .................................................................................................................................20
4.4.
Assessment of COVID-19 Impact...........................................................................................................20
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................20
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................20
4.4.3.
Missed and Virtual Visits due to COVID-19 ........................................................................20
4.4.4.
Adverse Events Due to COVID-19 .......................................................................................21


GS-5894
Study GS-US-544-5905 Substudy 01
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 3
15 September 2023
5.
BASELINE CHARACTERISTICS .....................................................................................................................22
5.1.
Demographics and Baseline Characteristics ...........................................................................................22
5.2.
Other Baseline Characteristics ................................................................................................................22
5.3.
Medical History.......................................................................................................................................22
6.
EFFICACY ANALYSES.....................................................................................................................................23
6.1.
Primary Efficacy Endpoint......................................................................................................................23
6.2.
Secondary Efficacy Endpoints ................................................................................................................23
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) at Day 8..........................23
6.2.2.
Correlation of PK Parameter(s) and Primary Endpoint.........................................................23
6.2.3.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11 .....................................................................................................23
6.2.4.
Percentage of Participants with Emergence of NNRTI Resistance.......................................23
6.2.5.
Analysis of Other Efficacy Endpoints...................................................................................24
7.
SAFETY ANALYSES.........................................................................................................................................25
7.1.
Adverse Events and Deaths.....................................................................................................................25
7.1.1.
Adverse Event Dictionary .....................................................................................................25
7.1.2.
Adverse Event Severity .........................................................................................................25
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................25
7.1.4.
Serious Adverse Events.........................................................................................................25
7.1.5.
Treatment-Emergent Adverse Events....................................................................................25
7.1.6.
Summaries of Adverse Events and Deaths............................................................................26
7.2.
Laboratory Evaluations ...........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................28
7.2.2.
Graded Laboratory Values ....................................................................................................28
7.3.
Body Weight, Height, and Vital Signs ....................................................................................................29
7.4.
Prior and Concomitant Medications and Disease-Specific Medications ................................................30
7.4.1.
Prior and Disease-Specific Prior Medications.......................................................................30
7.4.2.
Concomitant Medications......................................................................................................30
7.5.
Electrocardiogram Results.......................................................................................................................31
7.5.1.
Investigator Electrocardiogram Assessment .........................................................................31
7.6.
Other Safety Measures ............................................................................................................................31
7.7.
Changes From Protocol-Specified Safety Analyses................................................................................31
8.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................32
8.1.
PK Sample Collection and Analyses.......................................................................................................32
8.1.1.
Estimation of PK Parameters.................................................................................................32
8.1.2.
PK Parameters .......................................................................................................................32
8.1.3.
PK/PD Analyses ....................................................................................................................34
9.
REFERENCES.....................................................................................................................................................35
10.
SOFTWARE.........................................................................................................................................................36
11.
SAP REVISION...................................................................................................................................................37
12.
APPENDICES......................................................................................................................................................38
12.1.
Data Collection........................................................................................................................................41
12.2.
Determination of Missed and Virtual Visits............................................................................................41


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HIV-1 RNA................................................................................15
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including Thyrotropin), 
Urinalysis and eGFRCG............................................................................................................16
Table 3-3.
Analysis Visit Windows for Vital Signs and Weight..............................................................16
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests .....................................................16
Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage ................................................17
Table 8-1.
Study Treatments and Associated Analyte..............................................................................32
Table 8-2.
PK Parameters for Each Analyte.............................................................................................33
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to Identify 
Missed/Virtual Visits...............................................................................................................41
LIST OF APPENDICES
Appendix 1.
Schedule of Assessments.........................................................................................................38
Appendix 2.
Details for Statistical Programming ........................................................................................40
Appendix 3.
Data Collection of COVID-19 Data ........................................................................................41


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
BVY
Biktarvy ® (bictegravir/emtricitabine/tenofovir alafenamide)
CCG
eCRF Completion Guidelines
CD4
Cluster of Differentiation type 4
CI
confidence interval
CK
creatine kinase
COVID-19
Coronavirus Disease 2019
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic Case Report Form
eGFRCG
estimated Glomerular Filtration Rate (Cockcroft Gault formula)
ET
early termination
FAS
Full Analysis Set
FIH
first-in-human
Hb
hemoglobin
HIV-1
Human Immunodeficiency Virus Type 1
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
Identification
LLT
lower-level term
LOQ
limit of quantitation
mAbs
monoclonal Antibodies
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA Search Term
NLP
Natural Language Processing
NNRTI
Non-nucleoside Reverse Transcriptase Inhibitor
PD
Pharmacodynamic
PEP
Post-Exposure Prophylaxis
PK
pharmacokinetic
PrEP
Pre-Exposure Prophylaxis
PT
preferred term
PWH
people with HIV


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Q1, Q3
first quartile, third quartile
RNA
ribonucleic acid
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
SMQ
Stardardized MedDRA Query
SOC
system organ class
SRT
Safety Review Team
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
%CV
coefficient of variation, defined as ratio of standard deviation to the mean


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PHARMACOKINETIC ABBREVIATIONS
AUC
Area under the plasma/serum concentration versus time curve
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCinf
area under the concentration versus time curve from time zero to infinity
%AUCexp
Percentage of AUC extrapolated between AUClast and AUCinf
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ct
concentration at time t
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Vz/F
Apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-544-5905-01 (Master Protocol GS-US-544-5905, Substudy 01). This SAP is 
based on the Study GS-US-544-5905 master protocol Amendment 2 dated 24 February 2023, 
Substudy GS-US-544-5905-01 protocol Amendment 1 dated 27 September 2022, and the 
electronic case report form (eCRF) for Study GS-US-544-5905-01. The SAP will be finalized 
before Study GS-US-544-5905-01 database finalization. Any changes made after the finalization 
of the SAP will be documented in the GS-US-544-5905-01 CSR.
1.1.
Study Objectives
The primary objective of this substudy is as follows:
To evaluate the short-term antiviral activity of GS-5894 with respect to the change from baseline 
in plasma HIV-1 RNA (log10 copies/mL) at Day 11 in people with HIV-1 (PWH) who are 
ARV treatment-naive or treatment-experienced but naive to the investigational ARV drug class 
(non-nucleoside reverse transcriptase inhibitor [NNRTI]).
The secondary objectives of this substudy are as follows:
•
To evaluate the short-term antiviral activity of GS-5894 in reducing plasma HIV-1 RNA 
(log10 copies/mL)
•
To investigate the safety and tolerability of GS-5894 by dose cohort
•
To characterize the plasma pharmacokinetics (PK) of GS-5894
•
To characterize the PK/pharmacodynamic (PD) relationship between the exposure of 
GS-5894 and the viral dynamics of HIV-1
•
To determine the number and percentage of participants who achieve HIV-1 RNA 
< 50 copies/mL of the HIV-1 RNA assay by Day 11 at each dose level
•
To examine the emergence of restance to the NNRTI drug class
1.2.
Study Design
This is an open-label Phase 1b, single or multiple dose, multicenter, substudy to an umbrella 
study designed to evaluate safety, PK, and antiviral activity of GS-5894 given as monotherapy in 
PWH who are either treatment-naive or treatment experienced but naive to the study drug class 
under investigation (NNRTI). Participants will not have received any ARVs within 12 weeks of 
screening, including medications received for pre-exposure prophylaxis (PrEP) or post-exposure 
prophylaxis (PEP). Any current or prior receipt of long-acting parenteral ARVs including: 
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This umbrella study will consist of a master protocol describing information relevant to all 
substudies; and each novel compound will have its own substudy. GS-5894 will be the first 
substudy protocol (GS-US-544-5905-01). This flexible clinical study design allows for opening 
new substudies as new agents become available and closing substudies with study drugs that 
demonstrate minimal clinical activity and/or unacceptable toxicity.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant. Participants will be required to return to the clinic for visits on 
Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on Day 11 or 
upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or another 
NNRTI-based standard of care ART regimen selected by the investigator. If participants are 
switching to BVY, a 30-day supply will be given to provide coverage for up to 5 half-lives of 
GS-5894. Participants will be required to return to the clinic for follow-up visits on Days 18, 25, 
and 39.
This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data.
The dose level and dosing regimen for study drug in each cohort will be selected based on a 
review of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint 
(Day 11) for this substudy, and/or relevant and available safety and PK data from the ongoing 
Phase 1a first-in-human (FIH) study for GS-5894.
Assessments will be conducted per the schedule of assessment table (see Schedule of 
Assessments, Appendix 1). 
1.3.
Sample Size and Power
A sample size of 6 to 8 participants in each dose cohort will provide 83% to 94% power to detect 
a treatment difference of 1.0 log10 copies/mL in the change from baseline in HIV-1 RNA at 
Day 11 between at least one of the study drug dose groups and the historical placebo group 
(N = 21). In this power analysis, it is assumed that a SD for the change from baseline in HIV-1 
RNA at Day 11 is 0.662 log10 copies/mL for each study drug dose group and 
0.359 log10 copies/mL for the placebo group, and a 2-sided t-test is conducted at an alpha level 
of 0.05. Standard deviations were estimated from historical Phase 1b studies conducted by the 
sponsor (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072). The maximum SD from 
treatment groups was used for the study drug dose group and SD from the pooled placebo group 
was used for the placebo group.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
Before the final analysis for each substudy, interim analyses may be conducted and the analyses 
may be submitted to regulatory agencies to seek guidance for the overall clinical development 
program of GS-5894.
2.2.
Dose Escalation Analysis
A safety review team (SRT) will review the data from this substudy after all participants from 
Cohort 1 complete their Day 11 visit. The SRT review will include cumulative safety and HIV-1 
RNA data through the primary endpoint (Day 11) and available PK data from Cohort 1 of this 
substudy; and/or relevant and available safety and PK data from the Phase 1a FIH study for 
GS-5894 (as appropriate). This initial SRT review will facilitate decision-making for dose level, 
dosing regimen (including whether GS-5894 study drug will be taken in a fasted state, or with a 
low-fat or high-fat meal) and timing of dosing for Cohorts 2 to 5. Further 
reviews by 
the SRT may be needed to inform on dose selection for Cohorts 2 to 5 (and/or additional 
cohort[s], as applicable).
2.3.
Final Analysis
The final analysis will be performed after all participants in Substudy 01 have completed the 
study, outstanding data queries have been resolved or adjudicated as unresolvable, and the data 
have been cleaned and finalized. The analysis of the primary endpoint (change from baseline in 
HIV-1 RNA [log10 copies/mL] at Day 11) will be conducted at the time of the final analysis and 
will be tested at the 0.05 significance level (2-sided test).
CCI-


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-participant listings will be presented for all participants in the All Enrolled Analysis Set and 
will be sorted by participant identification (ID) number, visit date, and time (if applicable). Data 
collected on log forms, such as AEs, will be presented in chronological order within the 
participant. The GS-5894 cohort to which participants were initially assigned will be used in the 
listings. Age, sex at birth, race, and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion, will be 
summarized by GS-5894 cohort and overall.
A listing of reasons for exclusion from analysis sets will be provided by participant.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all participants who received a study participant ID number in 
the substudy after screening.
All Enrolled Analysis Set is the primary analysis set for by-participant listings. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all participants who are enrolled and receive a full dose[s] 
of GS-5894 study drug in this substudy. Participants with major eligibility violations that are 
identifiable based on pre-enrollment characteristics may be excluded. Participants will be 
grouped according to the GS-5894 cohort assigned at enrollment.
Participants who were randomized and assigned to receive placebo from 3 historical Gilead 
Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be used as a 
historical control through Study Day 11 for only the HIV-1 RNA endpoints.
The Full Analysis Set will be the primary analysis set for efficacy analyses.


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3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all participants who took at least 1 dose of GS-5894 study drug 
in this substudy. Participants who received treatment other than that assigned at enrollment will 
be analyzed according to the treatment that they received.
All data collected on/after first dose date of GS-5894 during the substudy will be included in the 
safety summaries.
The Safety Analysis Set is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all participants who are enrolled, receive any dose of GS-5894 
study drug in this substudy, and have at least 1 nonmissing post baseline concentration value for 
GS-5894 study drug.
This is the primary analysis set for all PK analyses. 
3.1.5.
Pharmacokinetic/Pharmacodynamic Analysis Set 
The PK/PD Analysis Set will include all participants who are in the FAS for this substudy and 
have a nonmissing PK parameter (for PK parameter included in analysis) and a nonmissing value 
for change from baseline at Day 11 in plasma HIV-1 RNA (log10 copies/mL). This is the primary 
analysis set for PK/PD analysis.
A secondary analysis of PK/PD will be performed for the secondary endpoint change from 
baseline to Day 8 in HIV-1 RNA (log10 copies/mL) and will include all participants who are in 
the FAS for this substudy and have a nonmissing PK parameter (for PK parameter included in 
analysis) and a nonmissing value for change from baseline at Day 8 in plasma HIV-1 RNA 
(log10 copies/mL).
Analysis of these endpoints will be described in a separate PK/PD SAP.
3.2.
Participant Grouping
For analyses based on the FAS, participants will be grouped according to the GS-5894 cohort to 
which they were enrolled. Data from participants who were randomized and assigned to receive 
placebo from 3 historical Gilead Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and 
GS-US-200-4072) will be pooled to form a historical placebo group for HIV-1 RNA endpoints 
through Study Day 11. For all other analyses, participants will be grouped according to the actual 
GS-5894 treatment received in this substudy. 
For enrollment, disposition, protocol deviations, demographics, baseline disease characteristics, 
AEs, vital signs, concomitant medications, and laboratory data summaries, an additional total 
column for all GS-5894 participants will be included. 
For efficacy and PK summaries and the ECG shift table, a total column for all GS-5894 
participants will not be included. 


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3.3.
Strata and Covariates
No covariates will be included in efficacy analyses.
3.4.
Examination of Participant Subgroups
There are no prespecified participant subgroups for efficacy or safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made in this proof-of-concept study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected at Day 1 (in years) from the demographic eCRF will be used for 
analyses and presented in listings. If age at Day 1 is not available for a participant, then age 
derived based on date of birth and the Day 1 visit date will be used instead. If an enrolled 
participant was not dosed with any study drug, the enrollment date will be used instead of the 
Day 1 visit date. For screen failures, the date the first informed consent was signed will be used 
for the age derivation. Age required for longitudinal and temporal calculations and analyses 
(e.g., estimates of creatinine clearance, age at date of AE) will be based on age derived from date 
of birth and the date of the measurement or event, unless otherwise specified.


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.
•
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper LOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the lower or upper LOQ, 
respectively).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (e.g., change from baseline in HIV-1 RNA will 
be performed on the log10 transformed data) or nonparametric analysis methods may be used.
Natural logarithm transformation will be used for analyzing concentrations and PK parameters in 
intensive PK samples. Concentration values that are BLQ will be presented as “BLQ” in the 
concentration data listing. Values that are BLQ will be treated as 0 at predose time points, and 
one-half the value of the LOQ at postdose time points for summary purposes.
The following conventions will be used for the presentation of summary and order statistics for 
intensive PK concentrations: 
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug (or first dose date of placebo 
for placebo historical control group [HIV-1 RNA data only]) and derived as follows:
•
For postdose study days: Assessment Date – First Dosing Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of first dose of study drug administration.
Baseline is defined as the last available value collected on or prior to the first dose date 
(and time, where applicable) of study drug (i.e., prior to taking first dose of study drug). 
Postbaseline is defined as any value collected after the first dose of study drug. 
Last Study Date is the latest of clinic visit dates and laboratory visit dates, including all 
follow-up visits for participants who prematurely discontinued study or who completed study 
according to the Study Completion eCRF.
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for HIV-1 RNA are provided in Table 3-1; for hematology, chemistry, 
urinalysis, and eGFRCG in Table 3-2; for vital signs and weight in Table 3-3; for ECGs and 
coagulation in Table 3-4; and CD4 cell count and percentage in Table 3-5.
Table 3-1.
Analysis Visit Windows for HIV-1 RNA
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2
2
2
2
Day 3
3
3
3
Day 4
4
4
5
Day 7
7
6
7
Day 8
8
8
8
Day 9
9
9
9
Day 10
10
10
10
Day 11
11
11
11
Day 18
18
12
21
Day 25
25
22
32
Day 39
39
33
(none)


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Each cohort for GS-5894 will be compared to the historical placebo control group through Study 
Day 11. 
The percentage of participants with HIV-1 RNA < 50 copies/mL will be displayed by GS-5894 
cohort at Day 11 (last value prior to starting standard of care) and at Days 18, 25, and 39.
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including 
Thyrotropin), Urinalysis and eGFRCG 
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
5
Day 7
7
6
9
Day 11
11
10
11
Day 18
18
12
21
Day 25
25
22
32
Day 39
39
33
(none)
Table 3-3.
Analysis Visit Windows for Vital Signs and Weight
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2*
2
2
2
Day 3
3
3
3
Day 4
4
4
5
Day 7
7
6
9
Day 11
11
10
11
Day 25
25
12
32
Day 39
39
33
(none)
*Weight is not collected per protocol on Study Day 2. Any weight collected on Day 2 will be considered for Day 3.
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 7
7
2
9
Day 11
11
10
11
Day 39
39
12
(none)


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Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 11
11
2
11
Day 18
18
12
21
Day 25
25
22
32
Day 39
39
33
(none)
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value. 
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dose of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no 
time recorded on the same day, the baseline value will be the average of the measurements 
for continuous data (except for HIV-1 RNA, see below), or the measurement with the lowest 
severity (i.e., normal will be selected over abnormal for safety ECG findings) for categorical 
data.
•
For postbaseline values:
The record closest to the nominal day for that visit will be selected (with the exception of 
CD4+ cell count and CD4% in which the latest record will be selected and HIV-1 RNA 
level [see below]).
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data (except for HIV-1 RNA, see below) and the worst severity will be taken 
for categorical data, unless otherwise specified.
•
For baseline and postbaseline HIV-1 RNA, the latest (considering both date and time) 
record(s) in the window will be selected. If both “Roche COBAS 6800” and 
“Roche COBAS 6800 Repeat” (i.e., the HIV-1 RNA result obtained from an additional 
aliquot of the original sample) are available with the same collection time, the results from 
the “Roche COBAS 6800 Repeat” will be selected for analysis purposes; otherwise, if there 
are multiple “Roche COBAS 6800” records with the same collection time, the geometric 
mean will be taken for analysis purposes. 


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of key study dates for substudy 01 will present the dates for: 1) first participant 
screened 2) first participant enrolled 3) last participant enrolled 4) last participant last visit for 
primary endpoint [Day 11] and 5) last participant last visit for clinical study report. 
A summary of participant enrollment in this substudy will be provided by GS-5894 cohort (and 
overall) for each country, and investigator within country. The summary will present the number 
and percentage of participants enrolled. For each column, the denominator for the percentage 
calculation will be the total number of participants enrolled for that column.
A summary of participant disposition will present the number of participants screened for this 
substudy (denoted by an “A” contained within the participant screening number under the master 
protocol) and the number of participants who met all eligibility criteria but were not enrolled 
with the reasons that participants were not enrolled. An additional summary of participant 
disposition for participants in the All Enrolled Analysis Set will be provided by GS-5894 cohort 
and overall. The number and percentage of participants in each of the categories listed below will 
be summarized: 
•
All Enrolled Analysis Set 
•
Safety Analysis Set
•
Full Analysis Set 
•
PK Analysis Set
•
Completed study drug
•
Did not complete study drug with reasons for premature discontinuation of study drug
•
Completed study
•
Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 
the percentage calculation will be the total number of participants in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition. 


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The following by-participant listings will be provided by participant ID number in ascending 
order to support the above summary tables:
•
Reasons for premature study drug or study discontinuation (including those related to 
coronavirus disease 2019 [COVID-19])
•
Reasons for screen failure (will be provided by screening ID number in ascending order)
•
Analysis set status (participants excluded from any of the analysis sets)
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug. Study drug administration was performed at the study site; adherence will not be 
summarized.
4.2.1.
Study Drug Exposure and Duration on Study
Exposure to GS-5894 will be either “Single dose of GS-5894 (Day 1)” or “Single dose of 
GS-5894 (Days 1 and 2)” and will be summarized based on data collected on the Study Drug 
Administration eCRF. 
Duration on sponsor-provided Biktarvy® (BVY) as standard of care will be summarized using 
descriptive statistics, and will be calculated as: (last dose date BVY – first dose date of 
BVY) + 1. The start and stop dates for BVY administered as standard of care are collected on the 
ARV eCRF with subcategory of “CURRENT”. Records with a BVY start date on or after the last 
date in study will be excluded from calculations.
The number (i.e., cumulative counts) and percentage of participants on SOC for at least the 
following number of days will be summarized: Day 7, Day 14, Day 21, Day 28. For the final 
analysis, a ± 1 day window will be applied for the Day 28 category for Biktarvy® (allows for the 
Day 39 [on Study] protocol specified visit window and participants starting SOC on Day 11).
Duration on study (in days) will be defined as last date in study minus first dosing date plus 1. 
Last Study Date is the latest of clinic visit dates and laboratory visit dates, including all follow-up 
visits for participants who prematurely discontinued study or who completed study according to the 
Study Completion eCRF.
Duration on study (in days) will be summarized using descriptive statistics and using the number 
(i.e., cumulative counts) and percentage of participants still on study through each study visit: 
Day 1, Day 2, Day 3, Day 4, Day 7, Day 8, Day 9, Day 10, Day 11, Day 18, Day 25, and Day 39. 
For the final analysis, a ± 1 day window will be applied for the Day 39 category to allow for the 
Day 39 protocol specified visit window. 
Summaries will be provided by GS-5894 cohort (and overall) for the Safety Analysis Set. 
Exposure data for GS-5894 study drug will be listed. 


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No formal statistical testing is planned.
Biktarvy is provided as standard of care by the Sponsor during the follow-up period and 
dispensing information is recorded on the Accountability eCRF. Accountability data for Biktarvy 
will be listed.
4.3.
Protocol Deviations 
Participants who did not meet the eligibility criteria for study entry but enrolled in the study will 
be listed regardless of whether they were exempted by the sponsor or not. The listing will present 
the eligibility criterion (or criteria if more than 1 deviation) that the participant did not meet.
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations by 
deviation category (e.g., eligibility criteria, informed consent) will be summarized by GS-5894 
cohort and overall for the Safety Analysis Set. 
A by-participant listing will be provided for those participants with important protocol 
deviations.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the COVID-19 pandemic which has an impact on the study 
conduct. Some participants were unable to attend onsite visits due to shelter in place guidelines, 
site closures, or other reasons. This section describes how special situations due to COVID-19 
will be handled in the analysis.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-participant listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided if applicable. If there are no COVID-19 events, this listing will not 
be produced.
4.4.2.
Protocol Deviations Due to COVID-19
A by-participant listing will be provided for participants with important protocol deviations 
related to COVID-19 if applicable. A separate listing will be provided for participants with 
non-important protocol deviations related to COVID-19 if applicable.
4.4.3.
Missed and Virtual Visits due to COVID-19
A by-participant listing of participants with missed or virtual visits due to COVID-19 will be 
provided by participant ID number in ascending order.
Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields. A detailed 
explanation of the algorithm is given in Appendix 3.


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4.4.4.
Adverse Events Due to COVID-19
AEs of COVID-19 will be determined through a COVID-19 Standardized MedDRA Query 
(SMQ) narrow search or MedDRA Search Term (MST) and will be included in analyses of AEs 
if applicable. A by-participant listing of AEs of COVID-19 will be provided, if applicable.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (i.e., age, sex at birth, gender identity, sexual orientation, race, 
and ethnicity) and baseline characteristics (body weight [in kg], height [in cm], body mass index 
[BMI; in kg/m2]) will be summarized by GS-5894 cohort and overall using descriptive statistics 
for continuous variables and using number and percentage of participants for categorical 
variables. The summary of demographic data will be provided for the Safety Analysis Set. 
A by-participant demographic listing, including the informed consent date, will be provided by 
participant ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include HIV-1 RNA (log10 copies/mL), CD4 cell count (/μL), 
CD4 percentage (%), mode of infection (HIV risk factors), HIV disease status (AIDS, 
asymptomatic, or symptomatic HIV infection), years since HIV-1 diagnosis, years since starting 
HIV-1 treatment, resistance to any of the 4 ARV classes (yes, no) with a count of the number of 
subjects with resistance to each ARV class [NRTI, NNRTI, PI, and/or INSTI]), and ART status 
(ART-experienced or ART-naïve). These baseline characteristics will be summarized by 
GS-5894 dose group and for all GS-5894 participants using descriptive statistics for continuous 
variables and using number and percentage of participants for categorical variables. The 
summary of these baseline characteristics will be provided for the Safety Analysis Set. No 
formal statistical testing is planned.
Note: If only the month and year are collected for “date of HIV-1 diagnosis” and/or “start date of 
HIV-1 treatment”, the day will be set to ‘01’ when imputing the full date. If both the day and 
month are missing, then ‘01 July’ will be used for the day and month unless the full imputed date 
is after the first dose date of GS-5894 study drug. If HIV-1 diagnosis date or HIV-1 treatment 
start date is imputed to be after the first dose date of GS-5894 study drug, set the imputed HIV-1 
diagnosis date or treatment start date to the date of first dose of GS-5894 to avoid having a 
negative duration.
A by-participant listing of other baseline characteristics will be provided by participant 
ID number in ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will be coded using the MedDRA dictionary.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in plasma HIV-1 RNA 
(log10 copies/mL) at Day 11. 
Historical HIV-1 RNA data for placebo participants from 3 sponsor Phase 1b studies 
(GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be combined to form a single 
placebo group for the purpose of HIV-1 RNA analysis through Study Day 11. For 
Study GS-US-200-4072, HIV-1 RNA (log10 copies/mL) collected on Day 10 will be used for 
“Day 11” since HIV-1 RNA was not collected on Day 11 for this study. Each GS-5894 cohort 
will be compared to the pooled placebo group with respect to the primary efficacy endpoint, the 
change from baseline in plasma HIV-1 RNA (log10 copies/mL) at Day 11, using the 2-sided t-test 
conducted at an alpha level of 0.05. The analysis will be conducted using the FAS.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) at Day 8
The secondary efficacy endpoint change from baseline in plasma HIV-1 RNA (log10 copies/mL) 
at Day 8 will be analyzed using the same methods used for the primary endpoint. For study 
GS-US-120-0104, HIV-1 RNA (log10 copies/mL) collected on Day 7 will be used for “Day 8” 
since HIV-1 RNA was not collected at Day 8 for this study.
6.2.2.
Correlation of PK Parameter(s) and Primary Endpoint
PK/PD analysis will be described in a separate PK/PD SAP.
6.2.3.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11
The number and percentage of participants ever achieving HIV-1 RNA < 50 copies/mL 
postbaseline up to Day 11 will be summarized by GS-5894 cohort and for the placebo control 
group (using the FAS). For historical placebo control participants in study GS-US-120-0104 with 
HIV-1 RNA values analyzed using the HIV PCR Stand., 1.5 Cobas-CL assay with a LLOQ 
of 400 copies/mL, a value less than LLOQ (i.e., < 400 copies/mL) was counted as meeting the 
endpoint (HIV-1 RNA < 50 copies/mL). A Fisher’s exact test will be used to compare each 
GS-5894 cohort to the historical placebo group if at least 1 participant has HIV-1 RNA < 50 
copies./mL postbaseline up to Day 11.
6.2.4.
Percentage of Participants with Emergence of NNRTI Resistance
Percentage of participants with any emergence of resistance to the ARV class of GS-5894 
(i.e., NNRTI), will be summarized for each GS-5894 cohort by the Clinical Virology group.


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6.2.5.
Analysis of Other Efficacy Endpoints
Maximum Reduction in Plasma HIV-1 RNA Postbaseline to Day 11
The maximum postbaseline reduction in plasma HIV-1 RNA (log10 copies/mL) from Day 2 
through Day 11 will be analyzed using the same statistical methods used for the primary 
endpoint analysis. Baseline value, lowest post-baseline HIV-1 RNA value from Day 2 to Day 11, 
and the lowest change from baseline in HIV-1 RNA (log10 copies/mL) from Day 2 to Day 11 for 
each participant will be summarized by GS-5894 cohort and for the historical placebo group. 
Change from Baseline in HIV-1 RNA by Visit
Baseline value, HIV-1 RNA (log10 copies/mL), and change from baseline in HIV-1 RNA 
(log10 copies/mL) will be summarized descriptively by visit for each GS-5894 cohort and for the 
historical placebo control group through Day 11. 
Mean ± 95% confidence interval (CI) and median (Q1, Q3) of the change from baseline in 
HIV-1 RNA (log10 copies/mL) at each visit will be plotted through Day 11 using a line plot with 
a separate line displayed for each GS-5894 cohort and for the historical placebo group. Placebo 
data will be displayed for participants with a measurement collected in the analysis visit window.
Change from Baseline in CD4 by Visit
Baseline values, values at each postbaseline visit (Day 11, 18, 25, and 39), and the change from 
baseline in CD4 cell count (/μL) and CD4 percentage by visit will be summarized by GS-5894 
cohort.
Percentage of Participants with HIV-1 RNA < 50 copies/mL by Visit from Day 11 to Day 39
The number and percentage of participants with HIV-1 RNA < 50 copies/mL (split into 
categories “< 20 copies/mL” [with subcategories “< 20 copies/mL Detectable”, “< 20 copies/mL 
Not Detectable”] and “20 to < 50 copies/mL”) by visit using the Cobas 6800 assay will be 
displayed for each GS-5894 cohort and overall using the missing = excluded method at the last 
visit prior to adding SOC (Day 11) and at visits after adding SOC (Days 18, 25, and 39). 
For participants who did not meet the criteria HIV-1 RNA < 50 copies/mL at the visit, the 
number and percentage of participants with HIV-1 RNA in the following categories will be 
summarized:
•
50 to < 200 copies/mL 
•
≥ 200 copies/mL 
Missing data will be excluded in the computation of percentages (i.e., missing data points will be 
excluded from both numerator and denominator in the computation). The denominator for 
percentages at a visit is the number of participants in the FAS with nonmissing HIV-1 RNA 
value at that visit. No statistical testing is planned. 
All efficacy endpoints will include participants in the FAS.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events were graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity 
criteria specified in the protocol. A Grade 5 event indicates death. The severity grade of events 
for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings. The missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AE met the 
definition of an SAE that was specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Patient Safety 
Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date on or 
after the study drug start date. 
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
the AE onset is the same as or after the month and year (or year) of the first dosing date of study 
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An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence in Combined Severity Grade Subsets 
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided by GS-5894 cohort and overall 
for events with an onset date up to Day 11 (prior to adding SOC) and for the entire study.
•
TEAEs
•
TEAEs with Grade 3 or higher 
•
TEAEs with Grade 2 or higher
•
TE treatment-related AEs
•
TE treatment-related AEs with Grade 3 or higher 
•
TE treatment-related AEs with Grade 2 or higher
•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of study drug (only applicable for cohorts that 
were administered multiple doses)
•
TEAEs leading to premature discontinuation of study
•
TEAEs leading to death (i.e., outcome of death)
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, PT, and GS-5894 cohort (and overall):
•
TEAEs, by maximum severity
•
TEAEs up to Day 11, by maximum severity
•
TEAEs with Grade 3 or higher, by maximum severity 


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•
TE treatment-related AEs, by maximum severity
•
TE treatment-related AEs with Grade 3 or higher, by maximum severity 
•
TE SAEs
•
TE treatment-related SAEs 
•
TEAEs leading to premature discontinuation of study
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual participant during the study. 
In addition to the above summary tables, all TEAEs and TE treatment-related AEs will be 
summarized by PT only, in descending order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths
•
All AEs with severity of Grade 3 or higher
•
All AEs leading to premature discontinuation of study drug or study
7.2.
Laboratory Evaluations
Laboratory data collected during the substudy will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include all data collected after the first dose date of study drug 
unless stated otherwise. The analysis will be based on values reported in conventional units. 
When values are below the LOQ, they will be listed as such, and the closest imputed value will 
be used for the purpose of calculating summary statistics as specified in Section 3.7. 
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, coagulation, and urinalysis 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the DAIDS Toxicity Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.


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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by GS-5894 cohort (and overall) for selected laboratory 
tests specified in the study protocol as follows:
•
Baseline values 
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3
7.2.2.
Graded Laboratory Values
The DAIDS Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be used to assign toxicity grades (0 to 4) to laboratory results for analysis. 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (i.e., increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline. If the relevant baseline laboratory value 
is missing, any abnormality of at least Grade 1 observed postbaseline will be considered 
treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.


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The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test and GS-5894 cohort (and overall); 
participants will be categorized according to the most severe postbaseline abnormality grade for 
a given lab test:
•
Graded laboratory abnormalities 
•
Graded laboratory abnormalities collected up to Study Day 11 (prior to the participant 
initiating standard of care therapy on Day 11)
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with ≥ 1 nonmissing postbaseline value.
A by-participant listing of treatment-emergent laboratory abnormalities and a listing of 
treatment-emergent Grade 3 or 4 laboratory abnormalities will be provided by participant 
ID number and visit in chronological order. These listingss will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades and 
abnormal flags displayed.
7.3.
Body Weight, Height, and Vital Signs
Descriptive statistics will be provided by GS-5894 cohort (and overall) for body weight, BMI, 
and vital signs as follows:
•
Baseline value
•
Value at each postbaseline time point [visit]
•
Change from baseline at each postbaseline time point [visit]
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing if 
space permits. If not, they will be provided separately.


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7.4.
Prior and Concomitant Medications and Disease-Specific Medications
Prior and concomitant medications (i.e., non-antiretroviral [non-ARV] medications) collected at 
screening and during the study will be coded using the current version of the World Health 
Organization (WHO) Drug Dictionary. 
Disease-specific medications (i.e., nonstudy drug ARV) used prior to, during, or after the study 
(if collected) will be coded using the Gilead-modified WHO Drug Dictionary. 
7.4.1.
Prior and Disease-Specific Prior Medications
Prior and disease-specific prior medications are defined as any medications taken before a 
participant took their first dose of study drug.
A summary of prior or disease-specific prior medications will not be provided. 
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken on or after first dose date of study 
drug. Use of concomitant medications will be summarized by preferred name using the number 
and percentage of participants for each GS-5894 cohort (and overall). A participant reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of participants who received that medication. The summary will be ordered by 
preferred term in descending overall frequency. For drugs with the same frequency, sorting will 
be done alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug that continued to be taken after the first dosing date, or medications started after 
the first dosing date of study drug will be considered to be concomitant medications. 
Medications started and stopped on the same day as the first dosing date of study drug will also 
be considered concomitant. Medications with a stop date prior to the date of first dosing date of 
study drug will be excluded from the concomitant medication summary. If a partial stop date is 
entered, any medication with the month and year (if day is missing) or year (if day and month are 
missing) prior to the date of first study drug administration will be excluded from the 
concomitant medication summary. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) on or after the study 
drug start date will be included in the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. Summaries will be based on the Safety Analysis Set. No formal 
statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) and all nonstudy 
drug ARV medications will be provided in by-participant listings sorted by participant 
ID number and administration date in chronological order.


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7.5.
Electrocardiogram Results
Summaries of investigator assessment of ECG readings will be provided for the Safety Analysis 
Set for each scheduled visit. No formal statistical testing is planned.
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by GS-5894 cohort using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. If all participants have a 
baseline value then no missing category will be presented at baseline. The number and 
percentage of participants in each cross-classification group of the shift table will be presented. 
Participants with a missing value at baseline or postbaseline will not be included in the 
denominator for percentage calculation. 
No formal statistical testing is planned.
A by-participant listing for ECG assessment results will be provided by participant ID number 
and visit in chronological order.
7.6.
Other Safety Measures
A by-participant listing of subject pregnancies during the study will be provided by participant 
ID number. No additional safety measures are specified in the protocol.
Although not necessarily related to safety, a by-participant listing of all comments received 
during the study on the comments eCRF will be provided by participant ID number, and eCRF 
form for which the comment applies.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection and Analyses
Intensive PK samples are planned to be collected at several timepoints for all cohorts: predose, 
0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on respective 
days of dosing. Additional intensive PK visits may be collected for cohorts with more than 1 day 
of dosing of GS-5894. A single anytime PK collection will occur relative to study drug dosing on 
Day 1 at each postbaseline visit for all participants (on Days 2, 3, 4, 7, 8, 9, 10, 11, 18, 25, 39, or 
at early termination [if applicable]). Concentrations of GS-5894 in plasma will be determined 
using validated bioanalytical assays.
8.1.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to 0.
AUC will be calculated by the pharmacologist. The nominal time point for a key event or dosing 
interval (τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.1.2.
PK Parameters
PK parameters will be generated for all participants in the PK Analysis Set. The analyte 
presented in Table 8-1 will be evaluated if data are available.
Table 8-1.
Study Treatments and Associated Analyte
GS-5894 Cohort
Treatment
Analyte
All GS-5894 Cohorts
GS-5894
GS-5894
The analyte and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The primary PK parameters are [AUC, Cmax, and Ct] of GS-5894. The PK parameters 
to be estimated in this study are listed and defined in the PK Abbreviations section.
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Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-5894
AUClast, AUCinf, AUC0-t,%AUCexp, Cmax, Clast, Ct, Tmax, Tlast, λz, CL/F, t1/2, and Vz/F
Individual participant concentration data and individual participant PK parameters for GS-5894 
will be listed and summarized using descriptive statistics by GS-5894 cohort. Summary statistics 
(n, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented 
for both individual participant concentration data by time point and individual participant PK 
parameters by GS-5894 cohort. Moreover, the geometric mean, 95% CI, and the mean and SD of 
the natural log-transformed values will be presented for individual participant PK parameter 
data. 
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number of participants 
with concentration BLQ will be presented for each time point. For summary statistics, BLQ 
values will be treated as 0 at predose and one-half of the lower LOQ for postdose time points. If 
more than 1/3 of the concentration data for a cohort is BLQ at a PK collection timepoint then the 
mean, standard deviation, and %CV will not be calculated for that cohort and collection 
timepoint. 
Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by treatment:
•
Individual participant concentration data and summary statistics
•
Individual participant plasma PK parameters and summary statistics
The following figures may be provided for each analyte by treatment:
•
Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)
•
Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
•
Individual participant concentration data versus time (on linear and semlogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤ LOQ will not be 
displayed in the figures and remaining points connected. If more than 1/3 of the concentration 
data for a cohort is BLQ at a PK collection timepoint then the mean and SD will not be 
calculated (or plotted) for the cohort and collection timepoint.


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The following listings will be provided:
•
PK sampling details by participant, including procedures, differences in scheduled and actual 
draw times, and sample age
•
Individual data on determination of plasma half-life and corresponding regression correlation 
coefficient
8.1.3.
PK/PD Analyses
Details of the population PK/PD analysis will be provided in a stand-alone population 
PK/PD analysis plan.


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9.
REFERENCES
None.


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10.
SOFTWARE
SAS® Software Version 9.X. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version X.0. Statistical Solutions, Cork, Ireland.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Study Procedure
Screeninga
D1b
D2
D3 b
D4
D7b
D8
D9
D10
D11b
D18b
D25b
D39b
ETc
Visit Window
±1D
±1D
±1D
Written informed consent
X
Medical history and demography
X
Complete physical examination
X
X
X
X
Symptom driven physical examinationd
X
X
X
X
Height 
X
Weight 
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
HBV blood panel and HCV serologyf
X
CD4 cell countf
X
X
X
X
X
X
X
Plasma sample for HIV-1 genotyping/phenotypingf,g
X
X
X
Plasma HIV-1 RNAf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyf,h
X
X
X
X
X
X
X
X
X
Coagulation Panelf,h
X
X
X
X
X
X
Chemistryf,h
X
X
X
X
X
X
X
X
X
Urinalysisf,h
X
X
X
X
X
X
X
X
X
Serum pregnancy testf,i
X
Urine pregnancy testf,i, j
X
X
X
Serum FSHf,k
X
12-Lead ECG
X
X
X
X
X
X


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Study Procedure
Screeninga
D1b
D2
D3 b
D4
D7b
D8
D9
D10
D11b
D18b
D25b
D39b
ETc
Visit Window
±1D
±1D
±1D
Intensive plasma PKl
X
Single anytime plasma PKm
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs and concomitant medicationsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initiate study drug (GS-5894) dosingo
X
BVY dispensation
X
BVY or SOC administration
Xp
AE = adverse event; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); CLcr = creatinine clearance; D = Day; ECG = electrocardiogram; 
eCRF = electronic case report form; FSH = follicle-stimulating hormone; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetic(s); 
SAE = serious adverse event; SOC = standard of care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure after Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the evaluated compound. See section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Chemistry, Hematology, Coagulation, and Urinalysis profiles per Section 6.3.7 of the master protocol.
i
Participants assigned female at birth of childbearing potential only. 
j
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
k
Serum FSH test is required for participants assigned female at birth and are < 54 years old, not on hormonal contraception, and who have stopped menstruating for 
≥ 12 months but do not have documentation of hormonal ovarian failure.
l
Intensive PK samples should be collected at these timepoints for all cohorts: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
 on 
respective days of dosing. Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-5894.
m
Single anytime PK sampling will occur relative to study drug dosing on Day 1.
n
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7 [of substudy protocol] Adverse Events and Toxicity Management, for additional details.
o
For Cohort 1, a single 675-mg dose of GS-5894 administered on Day 1 with a high-fat meal (Section 5.2.4 of the substudy protocol). Subsequent cohort dose, dosing regimens 
(ie, single or multiple doses), meal requirements (fasted or with a low- or high-fat meal), and progression between cohorts will be adaptive and determined as summarized in 
Section 3.1.1 of the substudy protocol). 
p
Biktarvy® or Standard of Care will be initiated on Day 11. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation 
(Section 6.4.1 of master protocol).
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Appendix 2.
Details for Statistical Programming
For continuous HIV-1 RNA endpoints change from baseline at Day 11, change from baseline at 
Day 8, and maximum change from baseline from Day 2 to Day 11, p-values will be presented for 
each GS-5894 dose cohort vs. placebo.
The following SAS code can be used to get p-values for pairwise comparisons (each GS-5894 
cohort vs. placebo) for primary endpoint “change from baseline in HIV-1 RNA 
(log10 copies/mL) at Day 11” and other continuous endpoints:
**Assign treatment groups for testing**;
data trtgrp;
set trtgrp;
   if dose01p=’675 mg’  and meal=’High-Fat’ then trt=1;
    else if dose01p=’1200 mg’ and meal=’Low-Fat’  then trt=2;
    else if dose01p=’900 mg’  and meal=’High-Fat’ then trt=3;
    else if treatment=’Placebo’                   then trt=4;
run;
ods output estimates=estimate;
proc mixed data = trtgrp;
class trt ;
model chgD11  = trt / ddfm=kr;
/*least squares means*/
lsmeans trt / diff e;
/* p-values for each GS-5894 trt group and PBO for primary endpoint */
estimate 'cohort 1 vs placebo' trt  1 0 0 -1 / cl alpha=0.05;
estimate 'cohort 2 vs placebo' trt  0 1 0 -1 / cl alpha=0.05;
estimate 'cohort 3 vs placebo' trt  0 0 1 -1 / cl alpha=0.05;
run;
Toxicity Grading for Laboratory Values:
DAIDS Toxicity Grading Scale (Version 2.1) is available at the following location: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 


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Appendix 3.
Data Collection of COVID-19 Data
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
12.1.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by Clinical 
Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
12.2.
Determination of Missed and Virtual Visits
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 12-1). The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit will be assigned as follows:
i)
If COVID-19 terms are identified through NLP and the visit date is missing, then 
result is ”Missed Visit”
ii) If COVID-19 and Virtual terms are identified through NLP for a visit, then result is 
“Virtual Visit”. When there are multiple records for the same participant and the same 
visit, if one record could be categorized as “Virtual Visit”, all records associated with 
this participant and this visit will be categorized as “Virtual Visit”
iii) Otherwise result is missing
Table 12-1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits.
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-544-5905-01_SAP_15Sep2023
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
16-Sep-2023
00:58:55
Clinical Development
eSigned
19-Sep-2023
23:20:22
PPD
PPD

Prot_001.pdf: 
CLINICAL SUBSTUDY-02 PROTOCOL
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate 
Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals 
in Participants With HIV-1 Substudy-02: GS-1720
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
162030
EudraCT Number:
Not applicable
ClinicalTrials.gov 
Identifier:
NCT05585307
Indication:
HIV-1 infection
Protocol ID:
GS-US-544-5905-02
Contact Information:
The medical monitor name and contact information will be provided on 
the Key Study Team Contact List.
Protocol Version/Date:
Original:
27 February 2023
Amendment 1:
02 March 2023
Amendment 2:
05 May 2023
A high-level summary of amendment history is provided in 
Appendix 11.3.
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.
GILEAU 


GS-1720 
Protocol GS-US-544-5905 Substudy-02 
Gilead Sciences, Inc. 
Final 
Amendment2 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................................ 2 
LIST OF IN-TEXT TABLES ......................................................................................................................................... 3 
LIST OF IN-TEXT FIGURES ........................................................................................................................................ 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. .4 
SUBSTUDY PROTOCOL SYNOPSIS .......................................................................................................................... 5 
SUBSTUDY-02 STUDY SCHEMA .............................................................................................................................. 8 
SUBSTUDY-02 STUDY PROCEDURES TABLE ....................................................................................................... 9 
1. 
INTRODUCTION ................................................................................................................................................ 11 
1.1. 
Rationale for Substudy-02 ....................................................................................................................... 11 
1.2. 
Background on Study Interventions Used in Substudy-02 ...................................................................... 11 
1.2.1. 
GS-1720 ................................................................................................................................. ll 
1.3. 
Rationale for Dose Selection of Study Drng ........................................................................................... 14 
1.4. 
Benefit-Risk Assessment for the Study ................................................................................................... 15 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................................... 16 
3. 
STUDY DESIGN ................................................................................................................................................. 17 
3 .1. 
Study Design Overview ........................................................................................................................... 17 
3 .1.1. 
Dose Selection/Modification ................................................................................................. 18 
3.2. 
Duration oflnte1vention .......................................................................................................................... 18 
3 .3. 
Substudy-02 Specific Discontinuation Criteria ....................................................................................... 18 
Definitions for Time of Prima1y Endpoint and End of Study .............................................................................. 18 
4. 
PARTICIPANT POPULATION .......................................................................................................................... 19 
4.1. 
Number of Participants and Participant Selection for Substudy-02 ........................................................ 19 
4.2. 
Substudy-02-Specific Inclusion Criteria ................................................................................................. 19 
4.3. 
Substudy-02-Specific Exclusion Criteria ................................................................................................ 19 
5. 
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ........................................................... 20 
5.1. 
Enrollment and Treatment Code Access ................................................................................................. 20 
5.2. 
Description and Handling of GS-1720 and BVY .................................................................................... 20 
5.2.1. 
Fo1mulation ........................................................................................................................... 20 
5.2.2. 
Packaging and Labeling ........................................................................................................ 20 
5.2.3. 
Storage and Handling ............................................................................................................ 21 
5.2.4. 
Dosage and Ad1ninist1·ation ................................................................................................... 21 
5.3. 
Prior and Concoinitant Medications ........................................................................................................ 22 
5.4. 
Accountability for Study Drng Supplies: Study Drng and SOC ART Provided by the Sponsor 
(BVY) ...................................................................................................................................................... 22 
6. 
STUDY PROCEDURES ...................................................................................................................................... 23 
6.1. 
Instiuctions for Study Procedw·es ........................................................................................................... 23 
6.1.1. 
Phaimacokinetics ................................................................................................................... 23 
6.1.2. 
Subopti1nal Virologic Response ............................................................................................ 23 
6.1.3. 
Investigator Follow-up With Prima1y Health Care Provider ................................................ 24 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ................................................................................ 25 
7 .1. 
Toxicity Manage1nent .............................................................................................................................. 25 
7.1.1. 
Grade 1 and 2 Laborato1y Abnormalities or Clinical Events ................................................ 25 
CONFIDENTIAL 
Page2 
05 May 2023 


GS-1720 
Protocol GS-US-544-5905 Substudy-02 
Gilead Sciences, Inc. 
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Amendment2 
7.1.2. 
Grade 3 Laborato1y Abno1malities or Clinical Events .......................................................... 25 
7.1.3. 
Grade 4 Laborato1y Abno1malities or Clinical Events .......................................................... 25 
8. 
STATISTICAL CONSIDERATIONS ................................................................................................................. 27 
9. 
RESPONSIBILITIES ........................................................................................................................................... 28 
10. REFERENCES ..................................................................................................................................................... 29 
11. APPENDICES ...................................................................................................................................................... 30 
11.1. 
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements .......... 30 
11.2. 
Management of Clinical and Laborat01y Adverse Events ...................................................................... 33 
11.3. 
Amendment Histo1y ................................................................................................................................ 34 
11.3.1. 
Amend1nent 2 (05 May 2023) ............................................................................................... 34 
11.3.2. 
Amend1nent 1 (02 March 2023) ............................................................................................ 34 
11.4. 
Investigator Signatw·e Page ..................................................................................................................... 35 
Table 1. 
Table 2. 
Table 3. 
Figure 1. 
Figure 2. 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Substudy-02 Study Procedw·es Table ........................................................................................ 9 
GS-US-615-6392: Prelimina1y PK Parameters of GS-1720 Following Single-Dose 
Administration of Oral GS-1720 (N = 8 Per Coho1t) in the Fasted Condition ....................... 13 
GS-1720 Dosage by Cohoit ..................................................................................................... 21 
LIST OF IN-TEXT FIGURES 
Overview of Visits, Dosing, and Key Assessments for Substudy-02 ....................................... 8 
GS-US-615-6392: Prelimina1y Mean (SD) GS-1720 Plasma Concentrntion-Time 
Profiles Following Single-Dose Administration of Oral GS-1720 (N = 8 Per Coho1t) 
in the Fasted Condition ............................................................................................................ 13 
Page3 
05 May 2023 


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Amendment 2
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ART
antiretroviral therapy
ARV
antiretroviral
AUC0-168h
area under the plasma drug concentration versus time curve from time zero to 168 hours 
postdose
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
AUCinf
area under the plasma drug concentration versus time curve extrapolated to infinite time, 
calculated as AUClast + (Clast/z)
BVY
Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide; coformulated)
Cmax
maximum observed plasma drug concentration
EC95
95% effective concentration
ET
early termination
FIH
first in human
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
INSTI
integrase strand-transfer inhibitor
IQ
inhibitory quotient
LA
long acting
paEC95
protein-adjusted 95% effective concentration
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PTM
placebo to match
PWH
people with HIV-1
RNA
ribonucleic acid
SAE
serious adverse event
SD
standard deviation
SOC
standard of care
SRT
safety review team
t1/2
terminal elimination half-life 
Tmax
observed time point of Cmax
US, USA
United States, United States of America


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Gilead Sciences, Inc. 
Amendment 2
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SUBSTUDY PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, 
Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1 
Substudy-02: GS-1720 
Regulatory Agency Identifier Numbers:
IND Number: 162030
EudraCT Number: Not Applicable
ClinicalTrials.gov Identifier: NCT05585307
Study Centers Planned
See master protocol synopsis for study centers planned.
Objectives and Endpoints:
See master protocol synopsis for objectives and endpoints.
Study Design: See master protocol synopsis for the overview of this substudy design.
Substudy-02 is an open-label, Phase 1b, single/multiple-dose, multicohort study to evaluate the 
safety, pharmacokinetics (PK), and antiviral activity of GS-1720 given as monotherapy in 
people with HIV-1 who are either treatment-naive or treatment-experienced but naive to the 
study drug class, and have not received any antiretroviral therapy (ART) within 12 weeks of 
screening, including medications received for preexposure prophylaxis or postexposure 
prophylaxis. Any current or prior receipt of long-acting parenteral antiretrovirals, such as 
monoclonal antibodies targeting HIV-1, injectable lenacapavir or cabotegravir, or injectable 
rilpivirine, is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11, or upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or an 
alternative standard-of-care (SOC) ART regimen selected by the investigator. If participants 
are switching to BVY, a sufficient supply will be given to provide coverage for the remainder 
of the study. Participants will be required to return to the clinic for follow-up visits on 
Days 25, 39, and 60. 
Following study completion, the participant’s care will transfer to a primary health care 
provider who will determine the participant’s HIV long-term treatment plan. For participants 


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Amendment 2
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who complete the study, 6 and 12 months (± 1 month) after enrollment the investigator 
(or delegate) will contact the participant’s primary health care provider to request and record 
all available plasma HIV-1 RNA and resistance testing results and, if applicable, changes in 
HIV treatment regimen with date of change. 
This substudy will enroll up to 5 cohorts, with at least 6 participants in each cohort. Initial 
participants will be enrolled in Cohort 1, with dosing in subsequent cohorts proceeding after 
safety review team review of emerging data from Cohort 1.
The doses and dosing regimen for GS-1720 in each cohort will be selected based on a review 
of available PK, cumulative safety, and HIV-1 RNA data through the primary endpoint 
(Day 11) and/or relevant and available safety and PK data from the ongoing Phase 1a 
first-in-human study of GS-1720.
Number of Participants Planned: Up to 40 participants
Target Population: See master protocol synopsis for the target population.
Duration of Intervention: Approximately 60 days
Diagnosis and Main Eligibility Criteria: See master protocol for diagnosis and main 
eligibility criteria. For inclusion in this substudy, participants must also be willing to initiate 
BVY provided by the sponsor, or an alternative SOC ART regimen selected by the 
investigator, on Day 11 or upon ET, and be willing and able to comply with meal requirements 
on dosing days.
Study Procedures/Frequency
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11, or upon ET, participants will institute a regimen of BVY provided by the sponsor or 
an alternative SOC ART regimen selected by the investigator. Participants will be required to 
return to the clinic for follow-up visits on Days 25, 39, and 60. For participants who complete 
the study, 6 and 12 months (± 1 month) after enrollment the investigator (or delegate) will 
contact the participant’s primary health care provider to request and record all available 
plasma HIV-1 RNA and resistance testing results and, if applicable, changes in HIV treatment 
regimen with date of change.
The detailed schedule of procedures for Substudy-02 is provided in Table 1.


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Test Product, Dose, and Mode of Administration: 
Single or multiple doses of GS-1720 will be administered starting on Day 1. The dose, dose 
regimen, and meal requirements for administration of GS-1720 in Cohort 1 are provided 
below. Subsequent cohort dosing, dosing regimen (ie, single or multiple doses), meal 
requirements (fasted, or with a low-fat or high-fat meal), and progression between cohorts will 
be adaptive. Doses in subsequent cohorts will not exceed the doses indicated below.
Single or multiple doses of GS-1720 will be administered orally by site staff, at approximately 
the same time each day, with or without regard to food (as appropriate). The GS-1720 dose 
used in any cohort will not be higher than those previously evaluated in the Phase 1a study 
GS-US-615-6392.
•
Cohort 1: Single dose of GS-1720 450 mg administered on both Day 1 and Day 2 in the 
fasted condition 
•
Cohort 2: Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
•
Cohort 3: Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
•
Cohort 4: Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
•
Cohort 5: Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Reference Therapy, Dose, and Mode of Administration: Not applicable.
Statistical Methods: See master protocol for statistical methods.


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SUBSTUDY-02 STUDY SCHEMA
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-02
ART = antiretroviral therapy; BVY = bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®); 
PK = pharmacokinetic; SOC = standard of care
a
After assessments on Day 11 or upon early termination, participants will initiate a regimen of BVY provided by the sponsor 
or an alternative SOC ART regimen selected by the investigator. 
b
Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-1720.
For Cohort 1, a single 450-mg dose of GS-1720 will be administered on both Day 1 and Day 2 in the fasted condition. The doses, 
dosing regimen (single or multiple doses), and meal requirements for GS-1720 in each subsequent cohort will be selected based 
on a review of available PK, cumulative safety, and HIV-1 RNA data through the primary endpoint (Day 11), and/or relevant and 
available safety and PK data from the ongoing Phase 1a first-in-human study of GS-1720 (Section 3.1.1). 
Day 
Treatment 
PK 
GS-1720 Treatment 
f f f f 
T f 
-28 
2 
3 
4 
7 
• 
* 
• 
Clinic visit 
• 
Initiate GS-1720 dosing (single or multiple doses) 
V Primary endpoint 
Initiate BVY (B/F/TAF) or SOC 
* Intensive PKb 
Single anytime plasma PK 
T 
I BVY or SOC ART Treatmenta > 
V 
f f 
T 
T 
T 
10 
11 
25 
39 
60 


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SUBSTUDY-02 STUDY PROCEDURES TABLE
Table 1.
Substudy-02 Study Procedures Table
Study Procedure
Screeninga
D1b
D2
D3b
D4
D7b
D8
D9
D10
D11b
D25b
D39b
D60b
ETc
Visit Window
± 2D
± 2D
± 2D
Written informed consent
X
Medical history and demography
X
Complete physical examination
X
X
X
X
Symptom-driven physical examinationd
X
X
X
X
Height 
X
Weight 
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
HBV blood panel and HCV serologyf
X
CD4 cell countf
X
X
X
X
X
X
X
Plasma sample for HIV-1 
genotyping/phenotypingf,g
X
X
X
Plasma HIV-1 RNAf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyf
X
X
X
X
X
X
X
X
X
Coagulation panelf
X
X
X
X
X
X
Chemistryf
X
X
X
X
X
X
X
X
X
Urinalysisf
X
X
X
X
X
X
X
X
X
Serum pregnancy testf,h
X
Urine pregnancy testf,h,i
X
X
X
X
Serum FSHf,j
X
12-Lead ECG
X
X
X
X
X
X
Intensive plasma PKk,l
X


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Single anytime plasma PKm
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs and concomitant medicationsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initiate study drug (GS-1720) dosingo
X
BVY dispensation
X
BVY or SOC self-administration
Xp
Investigator (or delegate) follow-up with 
primary health care provider
For participants who complete the study, 6 and 12 months (± 1 month) after enrollment the investigator (or delegate) will 
contact the participant’s primary health care provider to request and record all available plasma HIV-1 RNA and resistance 
testing results and, if applicable, changes in HIV treatment regimen with date of change.
AE = adverse event; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); D = Day; ECG = electrocardiogram; eCRF = electronic case report form; 
ET = early termination; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetic(s); SAE = serious adverse event; 
SOC = standard of care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom-driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure after Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the evaluated compound. See Section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Participants assigned female at birth of childbearing potential only. 
i
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
j
Serum FSH test is required for participants assigned female at birth and < 54 years old, not on hormonal contraception, and who have stopped menstruating for ≥ 12 months 
but do not have documentation of hormonal ovarian failure.
k
Intensive PK samples should be collected at these time points for all cohorts: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on 
respective days of dosing. Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-1720.
l
For Cohort 1, intensive PK visits will be required for Day 1 and Day 2.
m
Single anytime PK sampling will occur relative to study drug dosing on Day 1. Single anytime PK sampling will not be done if drug dosing and intensive PK sampling are 
performed on the same day.
n
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.
o
For Cohort 1, a single 450-mg dose of GS-1720 will be administered on both Day 1 and Day 2 in the fasted condition (Section 5.2.4). Subsequent cohort dose, dosing regimen 
(ie, single or multiple dose), meal requirements (fasted or with a low-fat or high-fat meal), and progression between cohorts will be adaptive and determined as summarized in 
Section 3.1.1. 
p
BVY or SOC will be initiated on Day 11. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation (Section 6.4.1 of 
master protocol).
CCI
" 


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1.
INTRODUCTION
Substudy-02, conducted under the GS-US-544-5905 master protocol, will evaluate the safety, 
pharmacokinetics (PK), and antiviral activity of GS-1720 given as monotherapy in people with 
HIV-1 (PWH) who are either treatment-naive or treatment-experienced but naive to the integrase 
strand-transfer inhibitor (INSTI) class, and have not received any antiretroviral (ARV) therapy 
(ART) within 12 weeks of screening (full population details provided in Section 4).
1.1.
Rationale for Substudy-02
An overall rationale for the development of long-acting (LA) ARV agents is provided in the 
GS-US-544-5905 master protocol.
A rationale for the development of GS-1720 is provided below in Section 1.2.1.
1.2.
Background on Study Interventions Used in Substudy-02
1.2.1.
GS-1720
1.2.1.1.
General Information
Integrase strand-transfer inhibitors play an ever-growing role in HIV-1 treatment, and are a key 
component of combination ARV therapies. Currently, there are 5 INSTIs approved for the 
treatment of HIV infection. As a class, INSTIs exhibit strong antiviral activity and excellent 
clinical tolerability. Notably, all approved oral INSTIs require once or twice daily dosing. 
Therefore, developing novel INSTIs with optimal oral LA PK that can be combined with other 
LA oral ARVs would fulfill an unmet medical need; ie, the availability of regimens that can be 
administered less frequently. GS-1720 is a novel potent and selective LA INSTI, engineered to 
have a long t1/2 (projected to be approximately 240 hours), with a favorable nonclinical 
pharmacology profile that supports clinical development as a once weekly, oral ARV agent for 
the treatment of HIV infection.
For further information, refer to the current investigator’s brochure (IB), including the following:
1. Nonclinical PK
2. Nonclinical pharmacodynamics (PD)
3. Nonclinical toxicology
1.2.1.2.
Nonclinical Pharmacology and Toxicology
Nonclinical pharmacology and toxicology studies are provided in the IB.


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1.2.1.3.
Clinical Studies of GS-1720
1.2.1.3.1.
GS-US-615-6392
Study GS-US-615-6392 is an ongoing, first-in-human (FIH), Phase 1a study in healthy 
participants to evaluate the safety, tolerability, and PK of single and multiple ascending oral 
doses of GS-1720 up to 1350 mg. The study is planned to include up to 9 cohorts, each 
comprising at least 9 participants. Currently, participants have been enrolled in single ascending 
dose Cohorts 1 to 3 (n = 10/cohort) and received GS-1720 50-, 150-, and 450-mg doses 
(with Cohort 4 scheduled to receive GS-1720 1350 mg by 01 March 2023) (or placebo to match 
[PTM]), respectively, and multiple ascending dose Cohorts 5 and 6 (n = 9/cohort) and received, 
or are receiving, GS-1720 150- and 450-mg doses (or PTM), respectively, once weekly for 
6 doses. 
Preliminary PK Summary
Preliminary GS-1720 plasma concentration-time profiles and preliminary PK parameters after 
administration of single oral doses of 50 mg (Cohort 1), 150 mg (Cohort 2), and 450 mg 
(Cohort 3) GS-1720 in the fasted condition are presented in Figure 2 and Table 2, based on PK 
data available on 03 February 2023.
Median time to Tmax of GS-1720 occurred between 3.5 and 4.0 hours. A 9-fold increase in dose 
(from 50 to 150 to 450 mg) resulted in a 3.5-fold higher Cmax and 3.6-fold higher AUC0-168h. Less 
than dose-proportional increases observed in Cmax and AUC0-168h suggest that GS-1720 exhibits 
nonlinearity in dose-exposure relationship due to solubility-limited absorption.


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Figure 2.
GS-US-615-6392: Preliminary Mean (SD) GS-1720 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of 
Oral GS-1720 (N = 8 Per Cohort) in the Fasted Condition
IQ1, IQ5 = inhibitory quotient 1- or 5-fold higher than the protein-adjusted 95% effective concentration against wild-type HIV-1 
virus (paEC95: 1938 ng/mL)
Table 2.
GS-US-615-6392: Preliminary PK Parameters of GS-1720 Following 
Single-Dose Administration of Oral GS-1720 (N = 8 Per Cohort) in the 
Fasted Condition
Parameter
Cohort 1
(50 mg, Fasted)
Cohort 2
(150 mg, Fasted)
Cohort 3
(450 mg, Fasted)
Cmax (ng/mL)
4300 (28.3)
6860 (28.1)
15,000 (21.5)
Tmax (h)
3.50 (2.25, 5.50)
4.00 (2.25, 5.50)
4.00 (3.00, 4.00)
AUC0-168h (h•ng/mL)
370,000 (35.5)
636,000 (33.0)
1,340,000 (22.2)
AUCinf (h•ng/mL)
944,000 (46.1)
1,680,000 (41.1)
3,490,000 (29.4)
%AUCexp
0.74 (24.5)
8.17 (70.4)
40.3 (14.2)
t1/2 (h) [days]
227 (206, 239) [9.47]
225 (206, 271) [9.37]
235 (218, 248) [9.77]
%CV = percentage coefficient of variation; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile.
PK parameters presented to 3 significant figures as mean (%CV), except for Tmax, and t1/2, which are presented as median 
(Q1, Q3) hours, with [median days] for t1/2. Note: Preliminary analysis was conducted using nominal time points.
,,...., 
....J 
-€ 
OJ) 
s:: 
'-' 
100000 
s:: 
10000 
0 
·.;:; 
C<l 
.):::; 
s:: 
<I.) u § 
1000 
u 
C<l 
E 
r/l 
e<:S 
0::: 
100 
0 
N 
r---
I 
ifJ 
0 
0 
--
Coho11 1: 50 mg: Fasted (N=S) 
---
Coh01t 2: 150 mg; Fasted (N=S) 
_._ Coho1t 3: 450 mg; Fasted (N=S) 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • IQ5 (9690 ng/mL) 
240 
480 
720 
960 
1200 
1440 
1680 
Time (hr) 


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Safety Summary
In a preliminary blinded review of available safety data for 39 participants, as of 
14 February 2023, no deaths, serious adverse events (SAEs), Grade 3 or higher adverse events 
(AEs), or discontinuations due to AEs were reported. Study drug (GS-1720 or PTM)-related AEs 
were reported for 3 participants; headache and vertigo were reported for 1 participant each in 
Cohort 3 (GS-1720 450 mg or PTM, single dose), and decreased appetite and paresthesia of the 
right foot were reported for 1 participant in Cohort 5 (GS-1720 150 mg or PTM, once weekly 
dose). None of these study drug-related AEs was serious.
There were no clinically relevant changes from predose in values for hematology, clinical 
chemistry, urinalysis, or coagulation parameters in this preliminary review. Three participants, 
all in Cohort 2 (GS-1720 150 mg or PTM, single dose), had Grade 3 laboratory abnormalities; 
1 participant had glycosuria and a decrease in creatinine clearance, 1 participant had increased 
direct bilirubin (with no other signs or symptoms of hepatotoxicity), and 1 participant had an 
increase in creatine kinase. None of these Grade 3 laboratory abnormalities was considered 
clinically relevant. No Grade 4 laboratory abnormalities were reported.
No notable changes from predose were observed in vital signs (systolic and diastolic blood 
pressure, pulse, temperature, and weight).
1.3.
Rationale for Dose Selection of Study Drug
Selection of GS-1720 doses for this study takes into consideration the available safety, 
tolerability, and PK data for GS-1720 from the ongoing FIH study with oral single and multiple 
ascending doses in healthy volunteers (Study GS-US-615-6392), as well as emerging preliminary 
safety and antiviral data in this substudy.
As of 14 February 2023, 30 participants (24 active and 6 placebo) had received a single oral dose 
of GS-1720 (50 to 450 mg) or PTM, and 9 participants (6 active and 3 placebo) had received 
multiple oral doses of GS-1720 (150 mg) or PTM. In a preliminary blinded review of available 
safety data from 39 participants, as of 14 February 2023, GS-1720 was generally well tolerated. 
No deaths, SAEs, Grade 3 or higher AEs, or discontinuations due to AEs were reported. Three 
participants had Grade 3 laboratory abnormalities, none of which was considered clinically 
relevant. No Grade 4 laboratory abnormalities were reported.
As of 17 February 2023, available preliminary PK data from Study GS-US-615-6392 showed 
less than dose-proportional PK of GS-1720 following single doses of 50, 150, and 450 mg 
(Figure 2 and Table 2). Based on modeling and simulation, a 450-mg dose of GS-1720 given on 
both Day 1 and Day 2 is expected to result in a GS-1720 plasma concentration at Day 11 
(ie, 240 h from the first dose) that is approximately 5-fold the inhibitory quotient (IQ), defined as 
the in vitro-derived protein-adjusted 95% effective concentration against the wild-type HIV-1 
virus (paEC95: 1938 ng/mL), and is selected for evaluation in Cohort 1 of this substudy. GS-1720 
exposures projected for Cohort 1 (450 mg on Day 1 and 450 mg on Day 2, taken approximately 
24 h apart) are expected to be well covered by exposures in multiple ascending dose Cohort 6 in 
the FIH study. Preliminary clinical safety and PK data from Cohort 6, in which participants are 


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given a 450-mg dose of GS-1720 once weekly for 6 weeks (initial dosing completed on 
23 February 2023), will be reviewed by the safety review team [SRT]. Higher and/or lower doses 
will be evaluated in subsequent cohorts to target a range of IQ values that characterize the 
PK-PD relationship between GS-1720 PK and changes from baseline in HIV-1 viral load. Doses 
in Cohorts 2 to 5 will be determined by the SRT based on cumulative safety, PK, and virologic 
data from Cohort 1, as well as safety and available PK data from the FIH study (Study 
GS-US-615-6392). Doses selected for Cohorts 2 to 5 will be adaptive and have projected 
exposures within the range of observed exposures in the FIH study.
1.4.
Benefit-Risk Assessment for the Study
Potential risks to participants may include prolonged exposure (several weeks) to subtherapeutic 
concentrations of study drug. This could lead to the development of resistance to the study drug 
and, potentially, the study drug class, which could limit future treatment options. Strategies to 
mitigate this risk, and additional benefit-risk assessments applicable to Substudy-02 and 
GS-1720, are described in Section 1.4 of the master protocol.


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2.
OBJECTIVES AND ENDPOINTS
Objectives and endpoints are described in Section 2 of the master protocol.


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3.
STUDY DESIGN
3.1.
Study Design Overview
This substudy is being conducted as part of an umbrella study, as described in the master 
protocol.
Substudy-02 is an open-label, Phase 1b, single/multiple-dose, multicohort study to evaluate the 
safety, PK, and antiviral activity of GS-1720 given as monotherapy in PWH who are either 
treatment-naive or treatment-experienced but naive to the study drug class and have not received 
any ART within 12 weeks of screening, including medications received for preexposure 
prophylaxis or postexposure prophylaxis. Any current or prior receipt of LA parenteral ARVs, 
such as monoclonal antibodies targeting HIV-1, injectable lenacapavir or cabotegravir, or 
injectable rilpivirine, is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant (Figure 1). Participants will be required to return to the clinic for 
visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11, or upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or an alternative 
standard-of-care (SOC) ART regimen selected by the investigator. If participants are switching 
to BVY, a sufficient supply will be given to provide coverage for the remainder of the study. 
Participants will be required to return to the clinic for follow-up visits on Days 25, 39, and 60. 
Overnight fasting (≥ 6 hours) is required for laboratory analyses prior to visits on Days 1, 3, 7, 
11, 25, 39, and 60.
Following study completion, the participant’s care will transfer to a primary health care provider 
who will determine the participant’s HIV long-term treatment plan. For participants who 
complete the study, 6 and 12 months (± 1 month) after enrollment the investigator (or delegate) 
will contact the participant’s primary health care provider to request and record all available 
plasma HIV-1 RNA and resistance testing results and, if applicable, changes in HIV treatment 
regimen with date of change.
The selection of doses and dosing regimens for GS-1720 is described in Section 3.1.1.
This substudy will enroll up to 5 cohorts, with at least 6 participants in each cohort. Initial 
participants will be enrolled in Cohort 1, with dosing in subsequent cohorts proceeding after SRT 
review of emerging data from Cohort 1, as described in Section 3.1.1.
Sequential enrollment in cohorts, and order of assignment to substudies, are described in 
Section 5.1.1 of the master protocol.
The sponsor may elect to hold dosing, stop/pause substudy enrollment, or stop the study (or 
substudy, or specific cohort) at any time based on review of preliminary safety, efficacy, and PK 
data (see master protocol Section 5.1.1).


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3.1.1.
Dose Selection/Modification
Enrollment and dosing with GS-1720 will begin with Cohort 1. The dose and regimen of 
GS-1720 for Cohort 1 is defined in Section 5.2.4.
A summary of SRT reviews, dose decisions, and cohort progression applicable to this substudy is 
included in Section 3.1.1 of the master protocol.
3.2.
Duration of Intervention
Participants will be under evaluation in Substudy-02 for 60 days.
Participants will receive single or multiple doses of GS-1720, starting on Day 1. Participants will 
then initiate a BVY or alternative SOC regimen following study assessments on Day 11 for the 
remainder of the study. Participants will be required to return to the clinic for follow-up visits on 
Days 25, 39, and 60.
3.3.
Substudy-02 Specific Discontinuation Criteria
Criteria for early discontinuation from the substudy for individual participants are described in 
Section 3.3.1 of the master protocol.
3.4.
Definitions for Time of Primary Endpoint and End of Study
Definitions for the time of the primary endpoint and end of study for each substudy are described 
in Section 3.4 of the master protocol.


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection for Substudy-02
In Substudy-02, up to 5 cohorts, each containing at least 6 participants, will be enrolled. 
Participant replacement is described in Section 4.1.1 of the master protocol.
4.2.
Substudy-02-Specific Inclusion Criteria
Inclusion criteria applicable to all substudies are provided in Section 4.2 of the master protocol. 
In addition to meeting the inclusion criteria in the master protocol, participants must also meet 
the following inclusion criteria to be eligible for participation in this substudy: 
S02-1. Willing to initiate an SOC ART regimen on Day 11 or upon ET as stated in Section 4.2 in 
the master protocol. For this substudy, willing to initiate BVY provided by the sponsor or an 
alternative SOC ART regimen selected by the investigator on Day 11 or upon ET.
S02-2. Willing and able to comply with meal requirements on dosing days.
4.3.
Substudy-02-Specific Exclusion Criteria
Exclusion criteria applicable to all substudies are provided in Section 4.3 of the master protocol. 
In addition to not meeting any of the exclusion criteria in the master protocol, participants must 
not meet the following exclusion criterion to be eligible for participation in this substudy:
S02-1. Requirement for ongoing therapy with any prohibited medication listed in Section 5.3.


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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Enrollment and Treatment Code Access
Participant enrollment procedures are described in Section 5.1 of the master protocol.
5.2.
Description and Handling of GS-1720 and BVY 
BVY will be provided by the sponsor for use during the study, as applicable.
5.2.1.
Formulation
GS-1720 tablets are available in strengths of 10, 50, and 250 mg. GS-1720 10- and 50-mg tablets 
are round, plain-faced, film-coated, beige tablets. GS-1720 250-mg tablets are capsule-shaped, 
plain-faced, film-coated, beige tablets. In addition to the active ingredient, GS-1720 tablets also 
contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, 
iron oxide red, iron oxide yellow, and ferrosoferric oxide.
BVY tablets (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) are 
capsule-shaped, film-coated, purplish-brown, debossed with “GSI” on one side of the tablet and 
“9883” on the other side of the tablet. Each tablet core contains 50 mg of bictegravir (equivalent 
to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide 
(equivalent to 28 mg of tenofovir alafenamide fumarate). In addition to the active ingredients, the 
BVY tablets contain croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. 
The tablet cores are film-coated with iron oxide red, iron oxide black, polyethylene glycol, 
polyvinyl alcohol, talc, and titanium dioxide. Additional details are provided in local prescribing 
information for BVY product.
5.2.2.
Packaging and Labeling
GS-1720 tablets are packaged in white, high-density polyethylene bottles containing silica gel 
desiccant and polyester packing material. Each bottle is sealed with a white, continuous-thread, 
child-resistant, polypropylene screw cap with an induction-sealed, aluminum-faced liner.
BVY tablets are packaged in white, high-density polyethylene bottles. Each bottle contains 
30 tablets, silica gel desiccant, and polyester packing material. Each bottle is enclosed with a 
white, continuous-thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner.
Study drug to be distributed to centers in the United States (US) and other participating countries 
will be labeled to meet applicable requirements of the US Food and Drug Administration and/or 
other local regulations as applicable.


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5.2.3.
Storage and Handling
GS-1720 tablets should be stored below 30 °C. BVY should be stored according to the storage 
conditions specified on the label. 
GS-1720 and BVY should be stored in a securely locked area, accessible only to authorized site 
personnel. To ensure the stability of GS-1720 and BVY and proper identification, the drug 
products should not be stored in a container other than that in which they are supplied. 
5.2.4.
Dosage and Administration 
Single or multiple doses of GS-1720 will be administered starting on Day 1. The dose, dosing 
regimen, and meal requirements for administration of GS-1720 in Cohort 1 are provided in 
Table 3. Subsequent cohort doses, dosing regimens (ie, single or multiple doses), meal 
requirements (fasted, or with a low-fat or high-fat meal), and progression between cohorts will 
be adaptive, as described in Section 3.1.1. Doses in subsequent cohorts will not exceed those 
indicated in Table 3.
Single or multiple doses of GS-1720 will be administered orally by site staff, at approximately 
the same time each day (in the case of multiple dose regimens), with or without regard to food 
(as appropriate). The GS-1720 dose used in any cohort will not be higher than those previously 
evaluated in the Phase 1a Study GS-US-615-6392.
A low-fat/moderate calorie breakfast (400-500 calories; 100-125 calories from fat) or a 
high-fat/high-calorie breakfast (800-1000 calories; 500-600 calories from fat) may be initiated 
30 minutes prior to study drug administration. Participants may be administered GS-1720 at or 
within 5 minutes of participants consuming the meal.
Table 3.
GS-1720 Dosage by Cohort
Cohort
Treatment
Cohort 1
A single dose of GS-1720 450 mg will be administered on both Day 1 and Day 2 
in the fasted condition
Cohort 2
Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 3
Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 4
Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 5
Single or multiple doses of GS-1720 up to 1350 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
If BVY is initiated after assessments on Day 11, or upon ET, it will be administered orally, once 
daily, without regard to food.


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5.3.
Prior and Concomitant Medications
See Section 5.3 of the master protocol for information on prior or concomitant medication rules 
applicable to this substudy, including restricted medications through Day 11. The investigator 
should reach out to the sponsor for guidance prior to the use of any concomitant medication from 
Day 11 through the end of the study.
From Day 11 through the last visit, the investigator should follow local prescribing information 
for BVY or other ART taken as SOC by an individual participant. 
5.4.
Accountability for Study Drug Supplies: Study Drug and SOC ART 
Provided by the Sponsor (BVY)
Guidance related to accountability, return, and disposal for study drug supplies (study drug 
[GS-1720 for this substudy] and SOC ART provided by the sponsor [BVY for this substudy]) is 
provided in Section 5.4 of the master protocol.


GS-1720 
Protocol GS-US-544-5905 Substudy-02 
Gilead Sciences, Inc. 
6_ 
STUDY PROCEDURES 
Final 
Amendment2 
Study procedures applicable to all studies are listed in Section 6 of the master protocol. Study 
procedures specific to Substudy-02 are listed in the sections below. The time points for study 
procedures are specified in Table 1. A substudy-specific infonned consent fo1m will be required 
for Substudy-02. 
6.1. 
6.1.1. 
Instructions for Study Procedures 
Pharmacokinetics 
Blood samples will be collected to detennine GS-1720 PK ( and metabolites, if appropriate) in 
plasma as indicated in Table 1. 
6.1.2. 
Suboptimal Virologic Response 
Management of suboptimal virologic response is described in Section 6.3 .9 .1.3 of the master 
protocol. 
6.1.2.1. 
Management ofVirologic Rebound 
Management ofvirologic rebound is described in Section 6.3.9.1.3 of the master protocol. 
6.1.2.2. 
Resistance Analysis at Paiiicipant's Last Visit 
Resistance analysis at a paiiicipant's last visit is described in Section 6.3.9.1.3 of the master 
protocol. 
CONFIDENTIAL 
Page 23 
05 May 2023 


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6.1.3.
Investigator Follow-up With Primary Health Care Provider 
For participants who complete the study, 6 and 12 months (± 1 month) after enrollment the 
investigator (or delegate) will contact the participant’s primary health care provider to request 
and record all available plasma HIV-1 RNA and resistance testing results and, if applicable, 
changes in HIV treatment regimen with date of change. At each time point, the investigator 
(or delegate) should make and document at least 3 attempts of contact over a period of 4 weeks.
These data are derived from secondary use data (previously collected for other purposes), 
therefore collection and submission of AEs are not required. 


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Adverse events are specified in Section 7 of the master protocol. Information regarding toxicity 
management that is specific to GS-1720 is described below, and included in Appendix 11.2. 
Pregnancy precautions, definition of female of childbearing potential, and contraceptive 
requirements specific to GS-1720 are included in Appendix 11.1.
7.1.
Toxicity Management 
All clinically significant laboratory toxicities will be managed according to uniform guidelines 
detailed in Appendix 11.2 and as outlined below.
•
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 multiple-dose 
cohorts for a clinically insignificant Grade 3 or 4 laboratory abnormality (eg, creatine kinase 
elevation after strenuous exercise, or triglyceride elevation that is nonfasting or can be 
medically managed). Recurrences of laboratory abnormalities considered unrelated to study 
drug may not require permanent discontinuation.
•
Grade 3 or 4 clinical events, if considered unrelated to study drug, may not require dose 
interruption; continuation of study drug for multiple-dose cohorts is at the discretion of the 
investigator.
7.1.1.
Grade 1 and 2 Laboratory Abnormalities or Clinical Events
•
Continue study drug at the discretion of the investigator for multiple-dose cohorts, as 
applicable.
7.1.2.
Grade 3 Laboratory Abnormalities or Clinical Events
•
For a Grade 3 clinically significant laboratory abnormality confirmed by repeat testing that is 
considered related to study drug, the study drug should be withheld in multiple-dose cohorts 
and the medical monitor consulted.
7.1.3.
Grade 4 Laboratory Abnormalities or Clinical Events
•
For a Grade 4 clinical event or clinically significant laboratory abnormality confirmed by 
repeat testing considered related to study drug, the study drug should be permanently 
discontinued in multiple-dose cohorts 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 comes first. A clinically 
significant Grade 4 laboratory abnormality that is not confirmed by repeat testing should be 
managed according to the algorithm for the new toxicity grade.


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Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the sponsor’s medical monitor, and the appropriate course of action will be discussed and 
decided. Whether or not considered treatment-related, all participants experiencing an AE must 
be monitored periodically until symptoms subside, any abnormal laboratory values have resolved 
or returned to baseline levels or are considered irreversible, or until there is a satisfactory 
explanation for the changes observed.
Any questions regarding toxicity management should be directed to the sponsor’s medical 
monitor.


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8.
STATISTICAL CONSIDERATIONS
Details of statistical methods will be provided in the statistical analysis plan for this substudy, 
including any deviations from the original statistical analyses planned. Statistical considerations 
for this substudy are described in Section 8 of the master protocol.


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9.
RESPONSIBILITIES
Details regarding responsibilities are specified in Section 9 of the master protocol.


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10.
REFERENCES
None


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11.
APPENDICES
11.1.
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 of age with amenorrhea of at least 12 months may also 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.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female participant 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 Participants Assigned Female at Birth
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-1720 is contraindicated in pregnancy as any malformative effect is unknown. There is no 
suspicion of human teratogenicity based on class effects or genotoxic potential. GS-1720 has 
insufficient data to exclude the possibility of a clinically relevant interaction with hormonal 
contraception that results in reduced contraception efficacy. Therefore, hormonal contraception 
is not recommended as a contraceptive method either solely or as a part of a contraceptive 
regimen. Refer to the latest version of the investigator’s brochure (IB) for additional information.
b.
Contraception Requirements for Participants Assigned Female at Birth of 
Childbearing Potential
The inclusion of participants assigned female at birth 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 hormone-containing contraceptives as a form of birth control during the study. 
They must have a negative serum pregnancy test at screening and a negative urine pregnancy test 
at the Day 1 visit before enrollment. Pregnancy tests will be performed at monthly intervals 
thereafter until the end of contraception requirement.


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Duration of required contraception for female participants in this clinical study should start from 
the screening visit until the end of the protocol-defined follow-up period.
Participants assigned female at birth and of childbearing potential must agree to one 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 any of the following methods of birth control listed below:
•
Nonhormonal intrauterine device
•
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 during treatment and until the end of contraception 
requirement.
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 the 
end of the protocol-defined follow-up period. If the partner assigned female at birth and of 
childbearing potential is not pregnant, additional contraception recommendations should also be 
considered.
Participants assigned male at birth must also refrain from sperm donation and cryopreservation 
of germ cells 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), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.


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5)
Procedures to be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from the start of the study until the end of the 
protocol-defined follow-up period.
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study until the end of the protocol-defined follow-up period must also 
report the information to the investigator. Instructions for reporting pregnancy, partner 
pregnancy, and pregnancy outcome are outlined in Section 7.4.2.3 of the master protocol.


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11.2.
Management of Clinical and Laboratory Adverse Events
Grade 1 
___ 
G_r_a_d_e_2 __ _.I I 
Grade 3 
I I 
Grade 4 
r 
Continue study 
drug dosing at 
the discretion of 
the inve~tigator 
l 
Repeat lab to confirm 
toxicity grade 
l 
If confirmed, and possibly or probably rel<1ted 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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11.3.
Amendment History
High-level summaries of the history of this study’s amendments are provided in tabular form in 
the subsections below (from most recent amendment to oldest), with changes listed in order of 
importance. Minor changes such as the correction of typographic errors, grammar, or formatting 
are not detailed. 
A separate tracked change (red-lined) document comparing protocol amendment 1 to this 
amendment will be made available upon the publication of this protocol.
11.3.1.
Amendment 2 (05 May 2023)
Rationale for Key Changes Included in Amendment 2
Affected Sections
Per Food and Drug Administration (FDA) request, additional language included 
noting following study completion, the participant’s care will transfer to a primary 
health care provider who will determine the participant’s HIV long-term treatment 
plan. For those participants who complete the study, 6 and 12 months after 
enrollment the investigator (or delegate) will contact the participant’s primary 
health care provider to request and record all available plasma HIV-1 RNA and 
resistance testing results and, if applicable, changes in HIV regimen with date of 
change. 
Synopsis, Table 1, 
Sections 3.1 and 6.1.3
Minor changes included to correct typographic errors.
Throughout, as required
11.3.2.
Amendment 1 (02 March 2023)
Rationale for Key Changes Included in Amendment 1
Affected Sections
References to the United States prescribing information for Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) removed as sites outside 
of the United States will be involved; replaced with reference to local prescribing 
information. Added details on BVY formulations, packaging, labeling, storage 
conditions, and administration.
Sections 5.2, 5.2.1, 5.2.2, 
5.2.3, 5.2.4, and 5.3 


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11.4.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
STUDY ACKNOWLEDGMENT
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, 
and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1 Substudy-02: 
GS-1720
Amendment 2, 05 May 2023
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval.
Name (Printed)
Signature
Director, Clinical Development
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


Prot GS-US-544-5905-02 amd-2
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Development
eSigned
05-May-2023
15:21:22
PPD

Prot_000.pdf: 
CLINICAL SUBSTUDY-01 PROTOCOL
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate 
Safety, Pharmacokinetics, and Antiviral Activity of Novel 
Antiretrovirals in Participants With HIV-1 Substudy-01: GS-5894 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
162030
EudraCT Number:
Not Applicable
ClinicalTrials.gov 
Identifier:
Not Available
Indication:
HIV-1 infection
Protocol ID:
GS-US–544–5905-01
Contact Information:
The medical monitor name and contact information will be 
provided in the Key Study Team Contact List.
Protocol 
Version/Date:
Original:
03 August 2022
Amendment 1:
27 September 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.
GILEAU 


CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in 
the protocol. You will not disclose any of the information to others without written 
authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered.


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TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................................3
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF IN-TEXT FIGURES........................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................................................5
SUBSTUDY PROTOCOL SYNOPSIS..........................................................................................................................7
SUBSTUDY-01 STUDY SCHEMA ............................................................................................................................10
SUBSTUDY-01 STUDY PROCEDURES TABLE.....................................................................................................11
1.
INTRODUCTION................................................................................................................................................13
1.1.
Rationale for Substudy-01.......................................................................................................................13
1.2.
Background on Study Interventions Used in Substudy-01......................................................................13
1.2.1.
GS–5894................................................................................................................................13
1.3.
Rationale for Dose Selection of Study Drug ...........................................................................................18
1.4.
Risk/Benefit Assessment for Substudy-01 ..............................................................................................19
2.
OBJECTIVES AND ENDPOINTS......................................................................................................................20
3.
STUDY DESIGN.................................................................................................................................................21
3.1.
Study Design Overview...........................................................................................................................21
3.1.1.
Dose Selection/Modification.................................................................................................21
3.2.
Duration of Intervention..........................................................................................................................22
3.3.
Substudy-01-Specific Discontinuation Criteria.......................................................................................22
3.4.
Definitions for Time of Primary Endpoint and End of Study .................................................................22
4.
PARTICIPANT POPULATION..........................................................................................................................23
4.1.
Number of Participants and Participant Selection for Substudy-01........................................................23
4.2.
Substudy-01-Specific Inclusion Criteria .................................................................................................23
4.3.
Substudy-01-Specific Exclusion Criteria ................................................................................................23
5.
STUDY INTERVENTIONS AND CONCOMITANT MEDICATIONS ...........................................................24
5.1.
Enrollment and Treatment Code Access .................................................................................................24
5.2.
Description and Handling of GS-5894 and Commercially Available BVY ...........................................24
5.2.1.
Formulation ...........................................................................................................................24
5.2.2.
Packaging and Labeling ........................................................................................................24
5.2.3.
Storage and Handling ............................................................................................................24
5.2.4.
Dosage and Administration ...................................................................................................25
5.3.
Prior and Concomitant Medications........................................................................................................25
5.4.
Accountability for Study Drug Supplies: Study Drug and SOC ART provided by Sponsor 
(BVY)......................................................................................................................................................26
6.
STUDY PROCEDURES......................................................................................................................................27
6.1.
Instructions for Study Procedures ...........................................................................................................27
6.1.1.
Pharmacokinetics...................................................................................................................27
6.1.2.
Suboptimal Virologic Response............................................................................................27
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT................................................................................28
7.1.
Toxicity Management..............................................................................................................................28
7.1.1.
Grade 1 and 2 Laboratory Abnormalities or Clinical Events................................................28
7.1.2.
Grade 3 Laboratory Abnormalities or Clinical Events..........................................................28


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7.1.3.
Grade 4 Laboratory Abnormalities or Clinical Events..........................................................28
8.
STATISTICAL CONSIDERATIONS.................................................................................................................30
9.
RESPONSIBILITIES...........................................................................................................................................31
10.
REFERENCES.....................................................................................................................................................32
11.
APPENDICES......................................................................................................................................................33
11.1.
Pregnancy Precautions, Definition of Childbearing Potential, and Contraceptive Requirements ..........33
11.2.
Management of Clinical and Laboratory Adverse Events ......................................................................36
11.3.
Investigator Signature Page.....................................................................................................................37
LIST OF IN-TEXT TABLES
Table 1.
Substudy-01 Study Procedures Table......................................................................................11
Table 2.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 Following 
Single-Dose Administration of Oral GS-5894 (N = 6 per Cohort) in the Fasted 
Condition .................................................................................................................................17
Table 3.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 Following 
Single-Dose Administration of Oral GS-5894 675 mg in the Fasted Condition as 
well as with a Low-Fat or High-Fat Meal ...............................................................................17
Table 4.
GS-5894 Dosage by Cohort.....................................................................................................25
Table 5.
Examples of Medications Prohibited From Day 11 Through Day 39 Because of the 
Potential for Pharmacokinetic Drug-Drug Interaction With GS-5894a...................................26
LIST OF IN-TEXT FIGURES
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-01 .....................................10
Figure 2.
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma Concentration-Time 
Profiles Following Single-Dose Administration of Oral GS-5894 (N = 6 per Cohort) 
in the Fasted Condition............................................................................................................15
Figure 3.
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma Concentration-Time 
Profiles Following Single-Dose Administration of Oral GS-5894 675 mg in the 
Fasted Condition as well as with a Low-Fat or High-Fat Meal...............................................16


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
%CV 
percentage coefficient of variation
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ART
antiretroviral therapy
ARV
antiretroviral
AUC
area under the concentration versus time curve
AUC0-168 h 
partial area under the concentration versus time curve from time “0” to time “168 h”
BVY
bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®)
Clast
last observed quantifiable concentration of the drug
Cmax
maximum observed concentration of drug
Ct
concentration at specified time “t”
CYP
cytochrome P450 enzyme
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
Gilead
Gilead Sciences/Gilead Sciences, Inc.
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
IB
investigator’s brochure
IND
investigational new drug
INSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
mAbs
monoclonal antibodies
LA
long-acting
NNRTI
nonnucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
PD
pharmacodynamic
PEP
postexposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PrEP
pre-exposure prophylaxis
PWH
people with HIV
RNA
ribonucleic acid


GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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27 September 2022
SAE
serious adverse event
SOC
standard of care
SRT
safety review team
t1/2 
terminal elimination half-life
Tlast 
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
US
United States


GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
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Amendment 1
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SUBSTUDY PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, 
Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1 
Substudy-01: GS-5894
IND Number: 162030 
EudraCT Number: Not applicable
ClinicalTrials.gov Identifier: Not available
Study Centers Planned:
See master protocol synopsis for study centers planned.
Objectives and Endpoints:
See master protocol synopsis for objectives and endpoints.
Study Design: See master protocol synopsis for the overview of this substudy design.
Substudy-01 is an open-label, Phase 1b, single-dose/multiple-dose, multicohort study to 
evaluate the safety, pharmacokinetics (PK), and antiviral activity of GS-5894 given as 
monotherapy in people with HIV-1 (PWH) who are either treatment-naive or 
treatment-experienced but naive to the study drug class and have not received any 
antiretroviral therapy (ART) within 12 weeks of screening, including medications received for 
pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior 
receipt of long-acting parenteral ARVs such as monoclonal antibodies (mAbs) targeting 
HIV-1, injectable cabotegravir, or injectable rilpivirine is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon early termination (ET), participants will initiate a regimen of Biktarvy® 
(bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or another 
nonnucleoside reverse transcriptase inhibitor (NNRTI)-based standard of care (SOC) ART 
regimen selected by the investigator. If participants are switching to BVY, a 30-day supply 
will be given to provide coverage for up to 5 half-lives of GS-5894. Participants will be 
required to return to the clinic for follow-up visits on Days 18, 25, and 39.


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Protocol GS-US–544–5905 Substudy-01
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This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data.
The doses and dosing regimen for GS-5894 in each cohort will be selected based on a review 
of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint 
(Day 11), and/or relevant and available safety and PK data from the ongoing Phase 1a 
first-in-human (FIH) study of GS-5894.
Number of Participants Planned: Up to 30 participants
Target Population: See master protocol synopsis for the target population. 
Duration of Intervention: Up to 39 days
Diagnosis and Main Eligibility Criteria: See master protocol for diagnosis and main 
eligibility criteria. For inclusion in this substudy, participants must also be willing to initiate 
BVY provided by the sponsor, or a non-NNRTI-based SOC ART regimen selected by the 
investigator, on Day 11 or upon ET, and be willing and able to comply with meal requirements 
on dosing days.
Study Procedures/Frequency:
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 
in the clinic for each participant. Participants will be required to return to the clinic for visits 
on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon ET, participants will initiate a regimen of BVY provided by the sponsor or 
another non-NNRTI-based SOC ART regimen selected by the investigator. Participants will 
be required to return to the clinic for visits on Days 18, 25, and 39. 
The detailed schedule of procedures for Substudy-01 is provided in Table 1.
Test Product, Dose, and Mode of Administration: 
Single or multiple doses of GS-5894 will be administered starting on Day 1. The dose, dose 
regimen, and meal requirements for administration of GS-5894 in Cohort 1 are provided 
below. Subsequent cohort dosing, dosing regimens (ie, single or multiple doses), meal 
requirements (fasted or with a low-fat or high-fat meal), and progression between cohorts will 
be adaptive. Doses in subsequent cohorts will not exceed the doses indicated below.
Doses of GS-5894 will be administered orally at the clinic under observation by site staff in 
the morning at approximately the same time each day (in the case of multiple-dose regimens).
Single or multiple doses of study drug (GS-5894) will be administered orally in the morning 
with or without regard to food (as appropriate).

Cohort 1: Single dose of GS-5894 675 mg administered on Day 1 with a high-fat meal


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
Cohort 2: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 3: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 4: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)

Cohort 5: Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Reference Therapy, Dose, and Mode of Administration: Not applicable
Statistical Methods: See master protocol for statistical methods. 


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Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
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SUBSTUDY-01 STUDY SCHEMA
Figure 1.
Overview of Visits, Dosing, and Key Assessments for Substudy-01
ART = antiretroviral therapy; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); 
FIH = first in human; PK = pharmacokinetic; SOC = standard of care
a
After assessments on Day 11 or upon early termination, participants will initiate a regimen of BVY provided by the sponsor 
or another non-NNRTI based SOC ART regimen selected by the investigator. 
b
Additional intensive PK visits may be required for cohorts with more than one day of dosing of GS-5894.
For Cohort 1, a single dose of 675 mg dose of GS-5894 will be administered on Day 1 with a high fat meal. The doses, 
dosing regimen (single or multiple doses), and meal requirements for GS-5894 in each subsequent cohort will be selected based 
on a review of available PK, cumulative safety and HIV-1 RNA data through the primary endpoint (Day 11), and/or relevant and 
available safety and PK data from the ongoing Phase 1a FIH study of GS-5894 (Section 3.1.1).
Day 
Treatment 
PK 
GS-5894 Treatment 
1 T T T T T 
-28 
1 
2 
3 
4 
7 
8 
.. 
* 
• 
Clinic visit 
A Initiate GS-5894 dosing (single or multiple doses) 
V Primary endpoint 
Initiate BVY (B/F/TAF) or SOC 
* Intensive PKb 
Single anytime plasma PK 
T 
9 
BVY or SOC ART Treatmenta 
V 
T T 
T 
T 
T 
10 
11 
18 
25 
39 


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Protocol GS-US–544–5905 Substudy-01
Final
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Amendment 1
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SUBSTUDY-01 STUDY PROCEDURES TABLE
Table 1.
Substudy-01 Study Procedures Table
Study Procedure
Screeninga
D1b
D2
D3 b
D4
D7b
D8
D9
D10
D11b
D18b
D25b
D39b
ETc
Visit Window
±1D
±1D
±1D
Written informed consent
X
Medical history and demography
X
Complete physical examination
X
X
X
X
Symptom driven physical examinationd
X
X
X
X
Height 
X
Weight 
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
X
HBV blood panel and HCV serologyf
X
CD4 cell countf
X
X
X
X
X
X
X
Plasma sample for HIV-1 
genotyping/phenotypingf,g
X
X
X
Plasma HIV-1 RNAf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyf,h
X
X
X
X
X
X
X
X
X
Coagulation panelf,h
X
X
X
X
X
X
Chemistryf,h
X
X
X
X
X
X
X
X
X
Urinalysisf,h
X
X
X
X
X
X
X
X
X
Serum pregnancy testf,i
X
Urine pregnancy testf,i, j
X
X
X
Serum FSHf,k
X
12-Lead ECG
X
X
X
X
X
X
Intensive plasma PKl
X
Single anytime plasma PKm
X
X
X
X
X
X
X
X
X
X
X
X
Review AEs and concomitant medicationsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initiate study drug (GS-5894) dosingo
X
BVY dispensation
X
BVY or SOC administration
          Xp


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Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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AE = adverse event; BVY = bictegravir/emtricitabine/tenofovir alafenamide (coformulated; Biktarvy®); CLcr = creatinine clearance; D = Day; ECG = electrocardiogram; 
eCRF = electronic case report form; FSH = follicle-stimulating hormone; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; PK = pharmacokinetic(s); 
SAE = serious adverse event; SOC = standard of care
a
Prospective participants should be screened no more than 28 days prior to administration of the first dose of study drug.
b
Overnight fasting (≥ 6 hours) is required.
c
ET assessments will be performed within 72 hours of prematurely discontinuing from the study or study drug, as applicable.
d
Symptom driven physical examinations will be performed as needed, based on reported signs and symptoms.
e
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained.
f
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol.
g
Participants who meet the criteria for virologic failure after Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the evaluated compound. See section 6.3.9.1.3 of the master protocol for management of virologic failure.
h
Chemistry, hematology, coagulation, and urinalysis profiles per Section 6.3.7 of the master protocol.
i
Participants assigned female at birth of childbearing potential only. 
j
A negative urine pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a serum test.
k
Serum FSH test is required for participants assigned female at birth and are < 54 years old, not on hormonal contraception, and who have stopped menstruating for 
≥ 12 months but do not have documentation of hormonal ovarian failure.
l
Intensive PK samples should be collected at these timepoints for all cohorts: predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose 
) on 
respective days of dosing. Additional intensive PK visits may be required for cohorts with more than 1 day of dosing of GS-5894.
m
Single anytime PK sampling will occur relative to study drug dosing on Day 1.
n
From the time of obtaining informed consent through the first administration of study drug, record all SAEs, as well as any nonserious AEs related to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details.
o
For Cohort 1, a single 675-mg dose of GS-5894 administered on Day 1 with a high-fat meal (Section 5.2.4). Subsequent cohort dose, dosing regimens (ie, single or multiple 
doses), meal requirements (fasted or with a low- or high-fat meal), and progression between cohorts will be adaptive and determined as summarized in Section 3.1.1). 
p
BVY or SOC will be initiated on Day 11. Participants who discontinue study drug before Day 11 should start this regimen at the time of discontinuation (Section 6.4.1 of 
master protocol).
CCI


GS–5894
Protocol GS-US–544–5905 Substudy-01
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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1.
INTRODUCTION
Substudy-01 will evaluate the safety, pharmacokinetics (PK), and antiviral activity of GS-5894 
given as monotherapy in people with HIV-1 (PWH), who are either treatment-naive or 
treatment-experienced but naive to nonnucleoside reverse transcriptase inhibitor (NNRTI) class 
and have not received any antiretroviral (ARV) therapy (ART) within 12 weeks of screening 
(full population details provided in Section 4). This is a substudy being conducted as part of the 
GS-US-544-5905 master protocol.
1.1.
Rationale for Substudy-01
Current first-line ART regimens consist of 2 or 3 ARV drugs, often coformulated, allowing a 
one-pill, once-daily oral treatment regimen; these regimens result in virologic suppression in 
more than 80% of PWH {Department of Health and Human Services (DHHS) 2018}, {Gunthard 
2016}, {European Aids Clinical Society (EACS) 2021}, {World Health Organization (WHO) 
2016}. A major factor preventing more widespread success of oral treatment is suboptimal 
adherence, a primary cause of incomplete viral suppression. There are multiple barriers to 
adherence, such as inconvenience, side effects, stigma, and discrimination {Enriquez 2011}.
Long-acting (LA) ARV regimens with less frequent dosing, for example LA injectable or oral 
weekly regimens, have the potential to address challenges with suboptimal adherence and 
treatment fatigue associated with daily oral therapy and improve success rates while also helping 
to prevent transmission of HIV.
An oral weekly regimen could benefit individuals who desire an oral regimen but prefer a 
regimen that can be taken less frequently than daily.
Based on the available PK data (as of 22 June 2022) from the ongoing Phase 1a first-in-human 
(FIH) study GS-US-544-5906, the median terminal elimination half-life (t1/2) of GS-5894 was 
between 4.77 and 7.96 days. GS-5894 also exhibited high metabolic stability and a slow rate of 
metabolism in human hepatocytes. With these supporting data, GS-5894 has the potential to be 
administered orally once weekly and to be combined with other LA agents as part of a 
combination regimen for the treatment of HIV-1 infection.
1.2.
Background on Study Interventions Used in Substudy-01
1.2.1.
GS–5894
1.2.1.1.
General Information
GS-5894 is a novel NNRTI being developed as a once-weekly oral treatment for HIV-1 
infection. In vitro antiviral testing has demonstrated that GS-5894 is a potent and selective 
nonnucleoside inhibitor of HIV-1 replication, showing strong antiviral activity against clinical 
isolates from all major HIV-1 subtypes. GS-5894 maintains full antiviral activity against a broad 
spectrum of HIV-1 mutants resistant to nucleoside reverse transcriptase inhibitors (NRTIs), 


GS–5894
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Amendment 1
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protease inhibitors (PIs), and integrase strand-transfer inhibitors (INSTIs). 
In addition, reverse transcriptase (RT) mutant viruses that are resistant to the NNRTIs nevirapine 
and efavirenz remain largely sensitive to GS-5894. With the human t1/2, GS-5894 has the 
potential to be administered orally once weekly and to be combined with other LA agents as part 
of a combination regimen for the treatment of HIV-1 infection.
For further information on GS–5894, refer to the current investigator’s brochure (IB), including 
the following:
1. Nonclinical PK
2. Nonclinical pharmacodynamics (PD)
3. Nonclinical toxicology
1.2.1.2.
Nonclinical Pharmacology and Toxicology
Nonclinical pharmacology and toxicology studies are provided in the IB.
1.2.1.3.
Clinical Studies of GS-5894 
1.2.1.3.1.
GS-US-544-5906
Study GS-US-544-5906 is an ongoing, Phase 1a study in healthy volunteers evaluating the 
safety, tolerability, and PK of single and multiple ascending oral doses of a GS-5894. 
Twenty-four unique participants across 3 dosing cohorts have received either GS-5894 or 
placebo (3:1 ratio). Administration of single oral doses of GS-5894 225 mg (Cohort 1), 675 mg 
(Cohort 2), and 2025 mg (Cohort 3) is complete. In addition, 19 participants completed dosing in 
the food-effect Cohort 5. Pharmacokinetic sampling for Cohorts 1, 2, and 3, and Cohort 5 
(through at least Day 7) is complete. Pharmacokinetic data available as of 22 June 2022 are 
summarized below.
Preliminary PK Summary:
Preliminary GS-5894 plasma concentration-time profiles and preliminary PK parameters after 
administration of single oral doses of 225 mg (Cohort 1), 675 mg (Cohort 2), and 2025 mg 
(Cohort 3) in the fasted condition, as well as 675 mg with a low- or high-fat meal (Cohort 5) are 
presented in Figure 2, Figure 3, and Table 2 and Table 3. Median time to maximal plasma 
concentrations of GS-5894 (Cmax) occurred between 3.5 and 5.5 hours (median Tmax). A 9-fold 
increase in dose (from 225 mg to 675 mg and then 2025 mg) resulted in only 2.8-fold higher 
Cmax and 3.2-fold higher AUC0-168h. The increases in Cmax and AUC0-168h were less than dose 
proportional, suggesting GS-5894 exhibits solubility-limited absorption. GS-5894 showed a 
positive food effect; Cmax and AUC0-168h following a 675 mg dose with a low-fat meal were 
3-fold higher and 3.6-fold higher compared with a 675 mg dose in the fasted condition. 
Similarly, Cmax and AUC0-168h following a 675 mg dose with a high-fat meal were 6.1-fold higher 
and 7.7-fold higher compared to a 675 mg dose in the fasted condition.


GS- 5894 
Protocol GS-US- 544-5905 Substudy-01 
Gilead Sciences, Inc. 
Final 
Amendment 1 
Figure 2. 
1000 
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of 
Oral GS-5894 (N = 6 per Cohort) in the Fasted Condition 
-+- Cohort 2 675 mg; Fasted (N=6) 
---e- Cohort 3: 2025 mg; Fasted (N=6) 
---+- Cohort 1: 225 mg; Fasted (N=6) 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • IQS (254 ng/mL) 
• • · • .. · · • .... • .... • .... • .... • .... • · · • .... • .... • .... • .... • .... • · · • .. · · • .... • .... • .... • .... • · · .. • · · • IQl (50.8 ng/mL) 
Time (h) 
IQl, 5 = inhibito1y quotient 1- or 5-fold higher than the protein adjusted EC95 against wild type HIV-1 virus (paEC95; 
50.8 ng/mL) 
CONFIDENTIAL 
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27 September 2022 


GS- 5894 
Protocol GS-US- 544-5905 Substudy-01 
Gilead Sciences, Inc. 
Final 
Amendment 1 
Figure 3. 
1 
l 1000 
.._, 
i:: 
0 'i 
8 
i:: 
0 u 
"' E 100 
i:i: s 
(I) 
+ I 
;j 
10 
00 
tr) 
rh 
c., 
GS-US-544-5906: Preliminary Mean (SD) GS-5894 Plasma 
Concentration-Time Profiles Following Single-Dose Administration of 
Oral GS-5894 675 mg in the Fasted Condition as well as with a 
Low-Fat or High-Fat Meal 
-+- Cohort 2: 675 mg; Fasted (N=6) 
---e- Cohort 5B: 675 mg; High-fat meal (N=9) 
---+- Cohort 5A: 675 mg; Low-fat meal (N=10) 
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • IQS (254 ng/mL) 
• .. • .... • .... • .... • .... • .... • .. • .... • .... • .... • .... • .... • .... • .. • IQl (50.8 ng/mL) 
Time (h) 
IQl, 5 = inhibito1y quotient 1- or 5-fold higher than the protein adjusted EC95 against wild type HIV-1 virus (paEC95; 
50.8 ng/mL) 
CONFIDENTIAL 
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Table 2.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 
Following Single-Dose Administration of Oral GS-5894 
(N = 6 per Cohort) in the Fasted Condition
Parameter
Cohort 1 
(225 mg, Fasted)
Cohort 2 
(675 mg, Fasted)
Cohort 3
(2025 mg, Fasted)
Cmax (ng/mL)
123 (38.9)
179 (51.3)
349 (19.3)
Tmax (h)
5.00 (3.00, 5.00)
3.50 (2.75, 4.25)
4.50 (4.00, 5.25)
Clast (ng/mL)
8.98 (36.6)
6.73 (10.0)
40.3 (30.3)
Tlast (h)
288 (240, 336)
660 (318, 720)
168 (168, 168)
AUC0-168 h (h•ng/mL)
4080 (33.3)
6520 (57.5)
12900 (22.9)
AUCInf (h•ng/mL)
8350 (50.4)
14200 (53.4)
20200 (25.8)
AUCExtrap (%)
29.8 (36.7)
19.0 (60.2)
35.0 (18.6)
t1/2 (d)
6.68 (5.30, 10.4)
7.96 (6.28, 12.7)
4.77 (4.20, 6.31)
d = days; h = hour; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile. PK parameters presented to 
3 significant figures as mean (%CV) except t1/2, Tlast and Tmax which are presented as median (Q1, Q3).
Note: Analysis was conducted using nominal timepoints.
Table 3.
GS-US-544-5906: Preliminary Plasma PK Parameters of GS-5894 
Following Single-Dose Administration of Oral GS-5894 675 mg in the 
Fasted Condition as well as with a Low-Fat or High-Fat Meal
Parameter
Cohort 2 
(225 mg, Fasted)
Cohort 5A 
(675 mg With Low-fat 
Meal)
Cohort 5B
(675 mg With High-fat 
Meal)
Cmax (ng/mL)
179 (51.3)
534 (38.1)
1090 (39.3)
Tmax (h)
3.50 (2.75, 4.25)
5.50 (4.00, 7.50)
5.00 (5.00, 9.00)
Clast (ng/mL)
6.73 (10.0)
39.3 (75.8)
80.4 (46.5)
Tlast (h)
660 (318, 720)
336 (336, 336)
336 (336, 336)
AUC0-168 h (h•ng/mL)
6520 (57.5)
23700 (68.4)
50200 (37.6)
AUCInf (h•ng/mL)
14200 (53.4)
43200 (69.4)
88200 (40.0)
AUCExtrap (%)
19.0 (60.2)
21.3 (36.8)
19.7 (35.1)
t1/2 (d)
7.96 (6.28, 12.7)
6.52 (5.31, 8.35)
5.62 (4.89, 7.31)
d = days; h = hour; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile. PK parameters presented to 
3 significant figures as mean (%CV) except t1/2, Tlast and Tmax which are presented as median (Q1, Q3).
Note: Analysis was conducted using nominal timepoints.


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Safety Summary:
In a preliminary blinded review of safety data as of 28 June 2022 (n = 43), no deaths, 
serious adverse events (SAEs), Grade 2 or higher adverse events (AEs), or discontinuations due 
to AEs have been reported to date. Two participants experienced AEs related to study drug; one 
in Cohort 2 (675 mg GS-5894) with proteinuria at Day 2 (resolved at Day 7) and one in Cohort 5 
(675 mg GS-5894, low-fat/moderate-calorie breakfast) with nausea, diarrhea, and vomiting at 
Day 1 (all resolved on same day). 
Grade 3 laboratory abnormalities were reported for 3 participants and were not clinically relevant 
(creatinine clearance: 2 participants; low-density lipoprotein cholesterol: 1 participant).
No notable changes from predose in white bloods cells, eosinophils, or vital signs (systolic blood 
pressure, diastolic blood pressure, pulse, temperature, and respiration rate) have been observed in 
the study. No clinically significant electrocardiogram (ECG) abnormalities have been reported.
1.3.
Rationale for Dose Selection of Study Drug
Selection of the GS-5894 doses for this study takes into consideration the available safety, 
tolerability, and PK data for GS-5894 from the ongoing FIH study with oral single and multiple 
ascending doses in healthy volunteers (Study GS-US-544-5906), as well as emerging preliminary 
safety and antiviral activity data in this substudy.
As of 28 June 2022, 43 participants (37 active and 6 placebo) have received a single oral dose of 
GS-5894 (225 to 2025 mg) or placebo-to-match. All participants have completed at least 7 days 
of follow up. As of the data cut-off date (28 June 2022), there were no deaths, SAEs, Grade 2 or 
higher AEs, or discontinuations due to AEs. GS-5894 was generally well-tolerated.
Available PK data from Study GS-US-544-5906 (as of 22 June 2022), as shown in Figure 2 and 
Figure 3, as well as in Table 2 and Table 3, demonstrates that the highest Cmax and AUC0-168h 
were observed following a 675-mg dose with a high-fat meal (Cohort 5B). Exposure margins 
based on observed data following 675 mg with a high-fat meal (Cohort 5B) were 14-fold and 
11-fold for AUC0-168h and 5-fold and 7-fold for Cmax compared with the dog and mouse 
NOAELs, respectively. Following a 675 mg dose with a high-fat meal, mean GS-5894 
concentrations achieved target IQ5 (that is 5-fold higher than the protein adjusted EC95 against 
wild type HIV-1 virus [paEC95; 50.8 ng/mL]) rapidly, and concentrations were maintained 
(> IQ5) through 72 hours postdose; mean GS-5894 concentrations at Day 8 and Day 12 were 
173.5 ng/mL (maintained above IQ3) and 115.5 ng/mL (maintained above IQ2), respectively. 
Based on these results, 675 mg with a high-fat meal was selected for evaluation in Cohort 1 of 
this substudy. Higher/lower doses (compared to Cohort 1 dose) may be evaluated in subsequent 
cohorts to target a range of IQ values to characterize the PK/PD relationship between GS-5894 
PK parameters and changes in HIV-1 viral load.


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1.4.
Risk/Benefit Assessment for Substudy-01
Potential risks to participants could include prolonged exposure for several weeks to 
subtherapeutic concentrations of the study drug, which can lead to HIV-1 developing resistance 
to the study drug and potentially to the study drug class and could limit future treatment options. 
Strategies to mitigate this risk and additional risk/benefit assessments applicable to Substudy-01 
and GS-5894 are described in Section 1.4 of the master protocol.


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2.
OBJECTIVES AND ENDPOINTS
Objectives and endpoints are described in Section 2 of the master protocol.


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3.
STUDY DESIGN
3.1.
Study Design Overview
This substudy is being conducted as part of an umbrella study as described in the master 
protocol.
Substudy-01 is an open-label, Phase 1b, single/multiple-dose, multicohort study to evaluate the 
safety, PK, and antiviral activity of GS-5894 given as monotherapy in PWH who are either 
treatment-naive or treatment experienced but naive to the study drug class and have not received 
any ART within 12 weeks of screening, including medications received for pre-exposure 
prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior receipt of long-
acting parenteral ARVs such as monoclonal antibodies (mAbs) targeting HIV-1, injectable 
cabotegravir, or injectable rilpivirine is exclusionary.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant (Figure 1). Participants will be required to return to the clinic for 
visits on Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). After assessments on 
Day 11 or upon early termination (ET), participants will initiate a regimen of 
Biktarvy® (bictegravir [BIC, B]/emtricitabine [FTC, F]/tenofovir alafenamide [TAF]; BVY) 
provided by the sponsor, or other non-NNRTI based standard of care (SOC) ART regimen 
selected by the investigator. If participants are switching to BVY, a 30-day supply will be given 
to provide coverage for up to 5 half-lives of GS-5894. Participants will be required to return to 
the clinic for follow-up visits on Days 18, 25, and 39. Overnight fasting (≥ 6 hours) is required 
for laboratory analyses prior to visit on Days 1, 3, 7, 11, 18, 25, and 39.
The selection of doses and dosing regimen for GS-5894 is described in Section 3.1.1.
This substudy will enroll up to approximately 5 cohorts with at least 6 participants in each 
cohort. Participants will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts 
will proceed after safety review team (SRT) review of emerging data as described in 
Section 3.1.1.
Sequential enrollment in cohorts and order of assignment to substudies is described in 
Section 5.1.1 of the master protocol.
The sponsor may elect to hold dosing, stop/pause substudy enrollment, or stop the study 
(or substudy, or specific cohort) at any time based on review of preliminary safety, efficacy, and 
PK data (see master protocol Section 5.1.1).
3.1.1.
Dose Selection/Modification
Enrollment and dosing with GS-5894 will begin with Cohort 1. The dose and regimen of 
GS-5894 for Cohort 1 is defined in Section 5.2.4. 


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A summary of SRT reviews, dose decisions and cohort progression applicable to this substudy is 
included in Section 3.1.1 of the master protocol.
3.2.
Duration of Intervention
Participants will be under evaluation in this Substudy-01 for 39 days.
Participants will receive single or multiple doses of GS-5894 starting on Day 1. Participants will 
then initiate a BVY or another non-NNRTI-based SOC ART regimen on Day 11 following study 
assessments to provide coverage for up to 5 half-lives of GS-5894. Participants will be required 
to return to the clinic for follow-up visits on Days 18, 25, and 39.
3.3.
Substudy-01-Specific Discontinuation Criteria
Substudy criteria for early discontinuation for the individual participants are described in 
Section 3.3.1 of the master protocol.
3.4.
Definitions for Time of Primary Endpoint and End of Study
The definitions for time of primary endpoint and end of study for each substudy are described 
Section 3.4 of the master protocol.


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4.
PARTICIPANT POPULATION
4.1.
Number of Participants and Participant Selection for Substudy-01
In Substudy-01, up to approximately 5 cohorts of at least 6 participants each will be enrolled. 
Participant replacement is described in Section 4.1.1 of the master protocol.
4.2.
Substudy-01-Specific Inclusion Criteria
Inclusion criteria applicable to all substudies is provided in Section 4.2 of the master protocol. In 
addition to meeting the inclusion criteria in the master protocol, participants must also meet the 
following inclusion criteria to be eligible for participation in this substudy:
S01-1. Willing to initiate an SOC ART regimen on Day 11 or upon ET as stated in Section 4.2 in 
the master protocol. For this substudy, willing to initiate BVY provided by the sponsor or 
a non-NNRTI-based SOC ART regimen selected by the investigator on Day 11 or upon 
ET.
S01-2. Willing and able to comply with meal requirements on dosing days.
4.3.
Substudy-01-Specific Exclusion Criteria
Exclusion criteria applicable to all substudies are provided in Section 4.3 of the master protocol. 
In addition to not meeting any of the exclusion criteria in the master protocol, participants must 
not meet the following exclusion criterion to be eligible for participation in this substudy:
S01-1. Requirement for ongoing therapy with any prohibited medications listed in Section 5.3.


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5.
STUDY INTERVENTIONS AND CONCOMITANT 
MEDICATIONS
5.1.
Enrollment and Treatment Code Access
Participant enrolment procedures are described in Section 5.1 of the master protocol.
5.2.
Description and Handling of GS-5894 and Commercially Available BVY
Commercially available BVY will be provided by the sponsor for use during the study as 
applicable. Further information regarding storage and handling are available in the prescribing 
information for the commercial BVY product.
The description and handling of GS-5894 is described below.
5.2.1.
Formulation
GS-5894 tablets are available in strengths of 75 and 600 mg. GS-5894 tablets, 75 mg, are round, 
plain-faced, film-coated, gray-colored tablets. GS-5894 tablets, 600 mg, are oval, plain-faced, 
film-coated, gray-colored tablets. In addition to the active ingredient, GS-5894 tablets, 75 mg 
and 600 mg, also contain microcrystalline cellulose, crospovidone, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and ferrosoferric oxide.
5.2.2.
Packaging and Labeling
GS-5894 tablets are packaged in white, high-density polyethylene bottles containing silica gel 
desiccant and polyester coil packing material. Each bottle is enclosed with a white 
continuous-thread, child-resistant, polypropylene screw cap with an induction-sealed, 
aluminum-faced liner.
Study drugs to be distributed to centers in the United States (US) will be labeled to meet 
applicable requirements of the US Food and Drug Administration (FDA) and/or other local 
regulations as applicable.
5.2.3.
Storage and Handling
GS-5894 tablets should be stored below 30 C. Storage conditions are specified on the label. 
GS-5894 should be stored in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability of GS-5894 and proper identification, the drug product should not be 
stored in a container other than the container in which it is supplied.


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5.2.4.
Dosage and Administration
Single or multiple doses of GS-5894 will be administered starting on Day 1. The dose, 
dose regimen, and meal requirements for administration of GS-5894 in Cohort 1 are provided in 
Table 4. Subsequent cohort dose, dosing regimens (ie, single or multiple doses), meal 
requirements (fasted or with a low- or high-fat meal), and progression between cohorts will be 
adaptive as described in Section 3.1.1. Doses in subsequent cohorts will not exceed the doses 
indicated in Table 4.
Doses of GS-5894 will be administered orally at the clinic under observation by site staff in the 
morning at approximately the same time each day (in the case of multiple-dose regimens).
A low-fat/moderate-calorie breakfast (400-500 calories, 100-125 calories from fat) or a 
high-fat/high-calorie breakfast (800-1000 calories, 500-600 calories from fat) will be initiated 
30 minutes prior to study drug administration, respectively. Participants will be administered 
GS-5894 at or within 5 minutes of participants consuming the meal.
Table 4.
GS-5894 Dosage by Cohort
Cohort
Treatment
Cohort 1
Single 675 mg dose administered on Day 1 with a high-fat meal
Cohort 2
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 3
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 4
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
Cohort 5
Single or multiple doses of GS-5894 up to 2025 mg administered in the fasted 
condition or with food (low-fat or high-fat meal)
5.3.
Prior and Concomitant Medications
See Section 5.3 of the master protocol for information on prior and concomitant medication rules 
applicable to all substudies including restricted medications through Day 11.
Medications prohibited from after the last dose of study drug on Day 11 through Day 39 in this 
substudy are presented in Table 5. Metabolism of GS-5894 was detectable with 
cytochrome P450 enzyme (CYP)3A in-vitro. Concomitant use of GS-5894 with some 
medications or herbal/natural supplements that are inhibitors of CYP3A may result in increased 
exposure of GS-5894. On the other hand, concomitant use of GS-5894 with some medications or 
herbal/natural supplements that are inducers of CYP3A may result in decreased exposure of 
GS-5894. Representative strong CYP3A inhibitors and strong/moderate CYP3A inducers listed 
in Table 5 are recommended to be excluded while participating in this substudy (Day 11 through 
Day 39). This table is not exhaustive and if there are medications not included in Table 5, 


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the investigator should reach out to the sponsor for guidance to use any concomitant medication 
while participants are on the substudy.
Table 5.
Examples of Medications Prohibited From Day 11 Through Day 39 
Because of the Potential for Pharmacokinetic Drug-Drug Interaction 
With GS-5894a
Medication Class
Prohibited Medications
ARVs 
Amprenavir, lopinavir, ritonavir, indinavir, 
saquinavir, nelfinavir, ritonavir- or cobicistat-
containing regimens, boceprevir, telaprevir, 
efavirenz, etravirine, and nevirapine
Antiandrogens
Apalutamide, enzalutamide
Antibiotics 
Clarithromycin, rifampin, rifapentine, telithromycin, 
troleandomycin
Antifungals 
Itraconazole, ketoconazole, voriconazole, 
posaconazole
Herbal Medications
St. John’s wort
ARVs = antiretrovirals 
a
This table represents examples of the most common concomitant medications and is not meant to be exhaustive. If the 
investigator is unsure if a medication is allowed per protocol, he/she should consult with the sponsor.
From Day 11 through the last visit, the investigator should follow the current United States 
Prescribing Information to inform the use of concomitant/prohibited medications for 
BVY {BIKTARVY 2021} or other ART taken as the SOC by the individual participant.
5.4.
Accountability for Study Drug Supplies: Study Drug and SOC ART 
provided by Sponsor (BVY)
Guidance related to accountability, return, and disposal for study drug supplies (study drug 
[GS-5894 for this study] and SOC ART provided by the sponsor [BVY for this substudy]) is 
provided in Section 5.4 of the master protocol.


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6_ 
STUDY PROCEDURES 
Final 
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Study procedures applicable to all studies are listed in Section 6 of the master protocol. 
Study procedures specific to Substudy-01 are listed in the sections below. The timepoints for 
study procedures are specified in Table 1. Substudy-specific ICFs will be required for 
Substudy-01. 
6.1. 
6.1.1. 
Instructions for Study Procedures 
Pharmacokinetics 
Blood samples will be collected to detennine GS-5894 PK (and metabolites, if appropriate) in 
plasma as indicated in Table 1. 
6.1.2. 
Suboptimal Virologic Response 
Management of suboptimal virologic response is described in Section 6.3 .9 .1.3 of the master 
protocol. 
6.1.2.1. 
Management of Virologic Rebound 
Management ofvirologic rebound is described in Section 6.3.9.1.3 of the master protocol. 
6.1.2.2. 
Resistance Analysis at Paiiicipant's Last Visit 
Resistance analysis at the pa1iicipant's last visit is described in Section 6.3.9.1.3 of the master 
protocol. 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
Adverse events are specified in Section 7 of the master protocol. Information regarding toxicity 
management that is specific to GS-5894 is described below and included in Appendix 11.2. 
Pregnancy precautions, definition of female of childbearing potential, and contraceptive 
requirements specific to GS-5894 are included in Appendix 11.1.
7.1.
Toxicity Management
All clinically significant laboratory toxicities will be managed according to uniform guidelines 
detailed in Appendix 11.2 and as outlined below.

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 multiple 
dose cohorts for a clinically insignificant Grade 3 and 4 laboratory 
abnormality (eg, creatine kinase [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 
interruption; continuation of the investigational product for multiple dose cohorts is at the 
discretion of the investigator.
7.1.1.
Grade 1 and 2 Laboratory Abnormalities or Clinical Events

Continue study drug at the discretion of the investigator for multiple dose cohorts, as 
applicable.
7.1.2.
Grade 3 Laboratory Abnormalities or Clinical Events

For a Grade 3 clinically significant laboratory abnormality confirmed by repeat testing that is 
considered to be related to the study drug, the study drug should be withheld in multiple dose 
cohorts and the medical monitor consulted.
7.1.3.
Grade 4 Laboratory Abnormalities or Clinical Events

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 in multiple dose cohorts 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.


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Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the sponsor’s 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 sponsor’s 
medical monitor.


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8.
STATISTICAL CONSIDERATIONS
Details of statistical methods will be provided in the statistical analysis plan for this substudy, 
including any deviations from the original statistical analyses planned. Statistical considerations 
for this substudy are described in Section 8 of the master protocol.


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9.
RESPONSIBILITIES
Details regarding responsibilities are specified in Section 9 of the master protocol.


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10.
REFERENCES
BIKTARVY, Gilead Science Inc. BIKTARVY® bicteoravir 50mo/emtricitabine 20Dmo/ 
tenofovir alafenamide 25mg tablets, U. S. Prescribinig Information. Revised: 
February.  2021:
Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral 
Agents in Adults and Adolescents Living with HIV.  2018:298. 
Enriquez M, McKinsey DS. Strategies to improve HIV treatment adherence in developed 
countries: clinical management at the individual level. HIV AIDS (Auckl) 
2011;3:45-51.
European Aids Clinical Society (EACS). EACS Guidelines, Version 11.0.  2021:
Gunthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al. Antiretroviral Drugs 
for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations 
of the International Antiviral Society-USA Panel. JAMA 2016;316 (2):191-210.
World Health Organization (WHO). Consolidated Guidelines On The Use Of Antiretroviral 
Drugs For Treating And Preventing HIV Infection: Recommendations For A 
Public Health Approach. Second Edition.  2016.


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11.
APPENDICES
11.1.
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 of age with amenorrhea of at least 12 months may also be considered postmenopausal if 
their follicle-stimulating hormone (FSH) level is in the postmenopausal range and they are not 
using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female participant 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 Participants Assigned Female at Birth
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-5894 is contraindicated in pregnancy as a malformative effect is unknown. There is no 
suspicion of human teratogenicity based on class effects or genotoxic potential. GS-5894 has 
insufficient data to exclude the possibility of a clinically relevant interaction with hormonal 
contraception that results in reduced contraception efficacy. Therefore, hormonal contraception 
is not recommended as a contraceptive method either solely or as a part of a contraceptive 
regimen. Refer to the latest version of the IB for additional information.
b.
Contraception Requirements for Participants Assigned Female at Birth of 
Childbearing Potential
The inclusion of participants assigned female at birth 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 hormone-containing contraceptives 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 


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the 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 female participants in this clinical study should start from 
the screening visit until 39 days after the last study drug dose.
Participants assigned female at birth and of childbearing potential must agree to one 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 during treatment and until the end of contraception 
requirement.
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 
39 days after the last study drug dose. If the partner assigned female at birth and of childbearing 
potential is not pregnant, additional contraception recommendations should also be considered.
Participants assigned male at birth must also refrain from sperm donation and cryopreservation 
of germ cells during treatment and until the end of contraception requirement.


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4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method. A female condom and a male condom should not be used 
together.
5)
Procedures to be Followed in the Event of Pregnancy
Participants assigned female at birth will be instructed to notify the investigator if they become 
pregnant or suspect they are pregnant at any time from the start of the study until 39 days after 
the last study drug dose.
Participants assigned male at birth whose partner has become pregnant or suspects they are 
pregnant from start of study until 39 days after the last study drug dose must also report the 
information to the investigator. Instructions for reporting pregnancy, partner pregnancy, and 
pregnancy outcome are outlined in Section 7.4.2.3 of the master protocol.


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11.2.
Management of Clinical and Laboratory Adverse Events
G de 1 
... I __ 
G_ra_de_ 2 _ _.I I 
Grade, 3 I 1 .. I __ 
G_r_a_d_e_4_1 __ I 
l 
Continue study 
drug dosing at 
the discretion of 
the i nve!i.lis at Or 
Repe t I b to confirm 
to k1ty gr de 
lrf confirm · d, 
d pos ibl:Y or pro. bly r • ·1 t d lo 
dy 
drug(s), disco,nt nue studv(s} do:s.i g permane 1tly, 
d 
mana e subject accord·n to loca1 pr.actice. Subject 
hould 
- fo low du clini lly "nd1c 
dun i th 
I bora ory bnormal ty ret rns to ba,sellne, or 1s 
o herwise expla'ined 


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11.3.
Investigator Signature Page
GILEAD SCIENCES, INC.
333 LAKESIDE DRIVE
FOSTER CITY, CA 94404
USA
STUDY ACKNOWLEDGMENT
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, 
and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1.
27 September 2022 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed)
Exec Director, Clinical Development
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-


Prot GS-US-544-5905-01 amd-1
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 27-Sep-2022
21:43:49
PPD

SAP_005.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
An Umbrella Phase 1b, Open-label, Multi-Cohort Study to 
Evaluate Safety, Pharmacokinetics, and Antiviral Activity of 
Novel Antiretrovirals in Participants With HIV-1 Sub study 03: 
GS-6212
Name of Test Drug:
GS-6212
Study Number:
GS-US-544-5905-03
Master Protocol Version 
(Date):
Original 
(03 August 2022)
Amendment 1 (27 September 2022)
Amendment 2 (24 February 2023)
Substudy Protocol Version 
(Date):
Original (08 June 2023)
Amendment 1 (18 August 2023)
Analysis Type:
Final Analysis (Substudy 03)
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
27 Aug 2024
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
GILEAU 


GS-6212 
Study GS-US-544-5905 Substudy 03
Statistical Analysis Plan – Final Analysis
Version 1.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF APPENDICES.................................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................7
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................8
1.2.
Study Design .............................................................................................................................................8
1.3.
Sample Size and Power .............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................11
2.1.
Interim Analysis ......................................................................................................................................11
2.2.
Dose Escalation Analysis ........................................................................................................................11
2.3.
Final Analysis..........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................12
3.1.
Analysis Sets ...........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set ......................................................................................................12
3.1.2.
Full Analysis Set....................................................................................................................12
3.1.3.
Safety Analysis Set................................................................................................................13
3.1.4.
Pharmacokinetic Analysis Set ...............................................................................................13
3.2.
Participant Grouping ...............................................................................................................................13
3.3.
Strata and Covariates...............................................................................................................................13
3.4.
Examination of Participant Subgroups....................................................................................................13
3.5.
Multiple Comparisons .............................................................................................................................13
3.6.
Missing Data and Outliers.......................................................................................................................13
3.6.1.
Missing Data..........................................................................................................................13
3.6.2.
Outliers ..................................................................................................................................14
3.7.
Data Handling Conventions and Transformations ..................................................................................14
3.8.
Analysis Visit Windows..........................................................................................................................16
3.8.1.
Definition of Predose, Postdose, Study Day .........................................................................16
3.8.2.
Analysis Visit Windows........................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................18
4.
PARTICIPANT DISPOSITION ..........................................................................................................................19
4.1.
Participant Enrollment and Disposition...................................................................................................19
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................20
4.2.1.
Study Drug Exposure and Duration on Study .......................................................................20
4.3.
Protocol Deviations .................................................................................................................................21
5.
BASELINE CHARACTERISTICS .....................................................................................................................22
5.1.
Demographics and Baseline Characteristics ...........................................................................................22
5.2.
Other Baseline Characteristics ................................................................................................................22
5.3.
Medical History.......................................................................................................................................22
6.
EFFICACY ANALYSES.....................................................................................................................................23


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6.1.
Primary Efficacy Endpoint......................................................................................................................23
6.2.
Secondary Efficacy Endpoints ................................................................................................................23
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) on Day 8.........................23
6.2.2.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11 .....................................................................................................23
6.3.
Other Efficacy Endpoints ........................................................................................................................23
6.4.
Sensitivity Analyses ................................................................................................................................24
7.
SAFETY ANALYSES.........................................................................................................................................26
7.1.
Adverse Events and Deaths.....................................................................................................................26
7.1.1.
Adverse Event Dictionary .....................................................................................................26
7.1.2.
Adverse Event Severity .........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug.....................................................................26
7.1.4.
Relationship of Adverse Events to Study Procedure.............................................................26
7.1.5.
Serious Adverse Events.........................................................................................................26
7.1.6.
Treatment-Emergent Adverse Events....................................................................................27
7.1.6.1.
Definition of Treatment-Emergent Adverse Events........................................27
7.1.6.2.
Incomplete Dates .............................................................................................27
7.1.7.
Summaries of Adverse Events and Deaths............................................................................27
7.1.7.1.
Summaries of AE Incidence in Combined Severity Grade 
Subsets .............................................................................................................27
7.2.
Laboratory Evaluations ...........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................29
7.2.2.
Graded Laboratory Values ....................................................................................................30
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities .............................................30
7.2.2.2.
Summaries of Laboratory Abnormalities ........................................................30
7.3.
Body Weight, Height, and Vital Signs ....................................................................................................31
7.4.
Prior and Concomitant Medications and Disease Specific Medications.................................................31
7.4.1.
Prior and Disease-Specific Prior Medications.......................................................................31
7.4.2.
Concomitant Medications......................................................................................................31
7.5.
Electrocardiogram Results.......................................................................................................................32
7.5.1.
Investigator Electrocardiogram Assessment .........................................................................32
7.6.
Other Safety Measures ............................................................................................................................33
7.7.
Changes From Protocol-Specified Safety Analyses................................................................................33
8.
PHARMACOKINETIC (PK) ANALYSES.........................................................................................................34
8.1.
PK Sample Collection and Analyses.......................................................................................................34
8.1.1.
Estimation of PK Parameters.................................................................................................34
8.1.2.
PK Parameters .......................................................................................................................34
8.2.
Statistical Analysis Methods ...................................................................................................................35
8.2.1.
General considerations ..........................................................................................................35
8.2.2.
PK Analyses ..........................................................................................................................35
8.2.3.
PK/PD Analyses ....................................................................................................................37
8.3.
Sensitivity Analysis.................................................................................................................................37
9.
REFERENCES.....................................................................................................................................................38
10.
SOFTWARE.........................................................................................................................................................39
11.
SAP REVISION...................................................................................................................................................40
12.
APPENDICES......................................................................................................................................................41


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HIV-1 RNA................................................................................16
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including Thyrotropin), 
Urinalysis and eGFRCG............................................................................................................17
Table 3-3.
Analysis Visit Windows for Vital Signs and Weight..............................................................17
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests .....................................................17
Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage ................................................18
Table 8-1. 
Study Treatments and Associated Analyte..............................................................................34
Table 8-2.
PK Parameters for Each Analyte.............................................................................................35
Table 8-3.
Analytes and PK Parameters for Estimation of Accumulation Ratios ....................................36
LIST OF APPENDICES
Appendix 1.
Study Procedures Table...........................................................................................................41
Appendix 2.
Details for Statistical Programming ........................................................................................43


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LIST OF ABBREVIATIONS
AE
adverse event
ART
antiretroviral therapy
ARV
antiretroviral
BLQ
below the limit of quantitation
BMI
body mass index
BVY
Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide)
CCG
eCRF completion guidelines
CD4
cluster of differentiation type 4
CI
confidence interval
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
eGFRCG
estimated glomerular filtration rate (Cockcroft Gault formula)
ET
early termination
FAS
full analysis set
FIH
first-in-human
Hb
hemoglobin
HIV-1
human immunodeficiency virus type 1
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
INSTI
integrase strand-transfer inhibitor
LLT
lower-level term
LOQ
limit of quantitation
mAbs
monoclonal antibodies
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA search term
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase inhibitors
PD
pharmacodynamic
PEP
post-exposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic
PrEP
pre-exposure prophylaxis
PT
preferred term
PWH
people with HIV
Q1, Q3
first quartile, third quartile
RNA
ribonucleic acid


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SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
SRT
safety review team
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
%CV
coefficient of variation, defined as ratio of standard deviation to the mean


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PHARMACOKINETIC ABBREVIATIONS
AUC
area under the plasma/serum concentration versus time curve
AUC0-t
partial area under the concentration versus time curve from time “0” to time “t”
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
AUCinf
area under the concentration versus time curve from time zero to infinity
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ct
concentration at time t
Ctau
observed drug concentration at the end of the dosing interval
Ctrough
concentration at the end of the dosing interval 
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Vz/F
apparent volume of distribution of the drug
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for study GS-US-544-5905-03 (Master Protocol GS-US-544-5905, Substudy 03). This SAP is 
based on the study GS-US-544-5905 master protocol Amendment 2 dated 24 February 2023, 
substudy GS-US-544-5905-03 protocol Amendment 1 dated 18 August 2023, and the electronic 
case report form (eCRF) for study GS-US-544-5905-03. The SAP will be finalized before study 
GS-US-544-5905-03 database finalization. Any changes made after the finalization of the SAP 
will be documented in the study GS-US-544-5905-03 CSR.
1.1.
Study Objectives
The primary objective of this substudy is to evaluate the short-term antiviral activity of GS-6212 
with respect to the change from baseline in plasma HIV-1 RNA (log10 copies/mL) on Day 11 in 
people with HIV-1 (PWH) who are antiretroviral (ARV) treatment naive or treatment 
experienced but naive to the integrase strand-transfer inhibitor (INSTI) class, and have not 
received any antiretroviral therapy (ART) within 12 weeks of screening including medications 
received for pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP).
The secondary objectives of this substudy are as follows:
•
To evaluate the short-term antiviral activity of GS-6212 in reducing plasma HIV-1 RNA 
(log10 copies/mL)
•
To investigate the safety and tolerability of GS-6212 by dose cohort
•
To characterize the plasma pharmacokinetics (PK) of GS-6212 
•
To characterize the PK/pharmacodynamic (PD) relationship between the exposure of 
GS-6212 and the viral dynamics of HIV-1
•
To determine the number and percentage of participants who achieve HIV-1 RNA 
< 50 copies/mL of the HIV-1 RNA assay by Day 11 at each dose level
•
To examine the emergence of resistance to the INSTI drug class
1.2.
Study Design
This is an open-label Phase 1b, multiple dose, multicohort, substudy to an umbrella study 
designed to evaluate safety, PK, and antiviral activity of GS-6212 given as monotherapy in PWH 
who are either treatment-naive or treatment experienced but naive to the study drug class, and 
have not received any ART within 12 weeks of screening, including medications received for 
preexposure prophylaxis (PrEP) or postexposure prophylaxis (PEP). Any current or prior receipt 
of long-acting parenteral ARVs including: monoclonal antibodies (mAbs) targeting HIV-1, 
injectable cabotegravir, or injectable rilpivirine, is exclusionary.


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This umbrella study will consist of a master protocol describing information relevant to all 
substudies; and each novel compound will have its own substudy. GS-US-544-5905-03 will be 
the third substudy with GS-6212 as the compound. This flexible clinical study design allows for 
opening new substudies as new agents become available and closing substudies with study drugs 
that demonstrate minimal clinical activity and/or unacceptable toxicity.
After screening and meeting all eligibility criteria, study drug dosing will be initiated on Day 1 in 
the clinic for each participant. Participants will be required to return to the clinic for visits on 
Days 2, 3, 4, 7, 8, 9, 10, and 11 (primary endpoint assessment). Doses of GS-6212 will be 
administered orally at the clinic under observation by site staff on clinic visit days/times and at 
home by the participant on nonclinic visit days/times at approximately the same time each day. 
In cohorts where GS-6212 is administered more than once daily, in-clinic observation of dosing 
will be conducted for the morning dose only. Participants will record at-home dosing details in a 
dosing log.
After assessments on Day 11 or upon early termination (ET), participants will initiate a regimen 
of Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide; BVY) provided by the sponsor or 
an alternative standard-of-care (SOC) ART regimen selected by the investigator. If participants 
are switching to BVY, a sufficient supply will be given to provide coverage for the remainder of 
the study. Participants will be required to return to the clinic for a follow-up visit on Day 25.
Overnight fasting (≥ 6 hours prior to dosing) is required for laboratory and/or PK analyses on 
Days 1 and 11 (see Section 5.3). On all other days (Days 2 through 10), the AM doses should be 
taken on an empty stomach.
Following study completion, the participant’s care will be transferred to a primary health care 
provider who will determine the participant’s HIV long-term treatment plan. 
This substudy will enroll up to 5 cohorts with at least 6 participants in each cohort. Participants 
will be enrolled in Cohort 1 initially and then dosing in subsequent cohorts will proceed as 
appropriate after safety review team (SRT) review of emerging data from Cohort 1 and available 
data from the Phase 1a SAD/MAD Study GS-US-469-6401.
The dose level and dosing regimen for study drug in each cohort will be selected based on a 
review of available PK, cumulative safety, and HIV-1 RNA data through the primary endpoint 
(Day 11) for this substudy, and/or relevant and available safety and PK data from the ongoing 
Phase 1a first-in-human (FIH) study for GS-6212.
Assessments will be conducted per the schedule of assessment table (see Schedule of 
Assessments, Appendix 1).
1.3.
Sample Size and Power
A sample size of 6 to 8 participants in each dose cohort will provide 83% to 94% power to detect 
a treatment difference of 1.0 log10 copies/mL in change from baseline in HIV-1 RNA on Day 11 
between at least one of the study drug dose groups and the historical placebo group (N = 21). In 
this power analysis, it is assumed that a standard deviation (SD) for the change from baseline in 


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HIV-1 RNA on Day 11 is 0.662 log10 copies/mL for each study drug dose group and 
0.359 log10 copies/mL for the placebo group, and a 2-sided t-test is conducted at an alpha level 
of 0.05. Standard deviations were estimated from historical Phase 1b studies conducted by the 
sponsor (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072). The maximum SD from 
treatment groups was used for the study drug dose group and SD from the pooled placebo group 
was used for the placebo group.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
Before the final analysis, interim analyses may be conducted and the analyses may be submitted 
to regulatory agencies to seek guidance for the overall clinical development program of 
GS-6212.
2.2.
Dose Escalation Analysis
A safety review team (SRT) will review the data from this substudy after all participants from 
Cohort 1 complete their Day 11 visit. The SRT review will include cumulative safety and HIV-1 
RNA data through the primary endpoint (Day 11) and available PK data from Cohort 1 of this 
substudy; and/or relevant and available safety and PK data from the Phase 1a FIH study for 
GS-6212 (as appropriate). This initial SRT review will facilitate decision-making for dose level, 
dosing regimen (including whether GS-6212 study drug will be taken in a fasted state, or with a 
low-fat or high-fat meal) and timing of dosing for Cohorts 2 to 5. Following SRT review of 
Cohort 1, no additional cohorts were required. Cohorts 2-5 were not enrolled. 
2.3.
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. The analysis of the primary endpoint (change from baseline in HIV-1 RNA 
[log10  copies/mL] on Day 11) will be conducted at the time of the final analysis and will be 
tested at the 0.05 significance level (2-sided test).


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of participants in each category will be presented; for continuous 
variables, the number of participants (n), mean, SD or standard error (SE), median, first quartile 
(Q1), third quartile (Q3), minimum (Min), and maximum (Max) will be presented.
All statistical tests will be 2-sided and performed at the 5% significance level unless otherwise 
specified.
By-participant listings will be presented for all participants in the All Enrolled Analysis Set and 
will be sorted by participant identification (ID) number, visit date, and time (if applicable), 
unless otherwise specified. Data collected on log forms, such as AEs, will be presented in 
chronological order within participants. The treatment group to which participants were initially 
assigned will be used in the listings. Age, sex at birth, race, and ethnicity will be included in the 
listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the participants to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
For each analysis set, the number and percentage of participants eligible for inclusion as well as 
the number and percentage of participants who were excluded and the reasons for their exclusion 
will be summarized in the disposition table as detailed in Section 4. A listing of reasons for 
exclusion from analysis sets will be provided by participant.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all participants who received a study participant ID number in 
the study after screening.
All Enrolled Analysis Set is the primary analysis set for by-participant listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all participants who were enrolled and received at least one 
dose of GS-6212 study drug in this substudy. Participants will be grouped according to the 
GS-6212 cohort assigned at enrollment.
Participants who were randomized and assigned to receive placebo from 3 historical Gilead 
Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be used as a 
historical control through Study Day 11 for only the HIV-1 RNA endpoints.
The Full Analysis Set will be the primary analysis set for efficacy analyses.


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3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all participants who took at least 1 dose of GS-6212 in this 
study. Participants who received treatment other than that assigned at enrollment will be 
analyzed according to the treatment that they received.
All data collected on/after first dose date of GS-6212 during the study will be included in the 
safety summaries.
The Safety Analysis Set is the primary analysis set for safety analyses.
3.1.4.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all participants who were enrolled in the study, received any dose 
of GS-6212 in this study, and have at least 1 nonmissing post baseline concentration value for 
GS-6212.
The PK Analysis Set is the primary analysis set for all PK analyses.
3.2.
Participant Grouping
For analyses based on the FAS, participants will be grouped according to the GS-6212 cohort to 
which they were enrolled. Data from participants who were randomized and assigned to receive 
placebo from 3 historical Gilead Phase 1b studies (GS-US-120-0104, GS-US-141-1219, and 
GS-US-200-4072) will be pooled to form a historical placebo group for HIV-1 RNA endpoints 
through Day 11. For all other analyses, participants will be grouped according to the actual 
GS-6212 treatment received in this study.
3.3.
Strata and Covariates
No covariates will be included in efficacy analyses.
3.4.
Examination of Participant Subgroups
There are no prespecified participant subgroups for efficacy or safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made in this proof-of-concept study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for 
prior and concomitant medications in Section 7.4.


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3.6.2.
Outliers
Outliers of non-PK will be identified during the data management and data analysis process, but 
no sensitivity analyses will be conducted. All data will be included in the data analysis.
Outliers of PK data may be identified during review of data by the PK scientist, and if necessary, 
appropriate sensitivity analyses may be conducted.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.
In general, age collected on Day 1 (in years) will be used for analyses and presented in listings. If 
age on Day 1 is not available for a participant, then age derived based on date of birth and the 
Day 1 visit date will be used instead. If an enrolled participant was not dosed with any study 
drug, the enrollment date will be used instead of the Day 1 visit date. For participant without an 
enrollment date the first informed consent was signed will be used for the age derivation. Age 
required for longitudinal and temporal calculations and analyses (eg, estimates of creatinine 
clearance, age at date of AE) will be based on age derived from date of birth and the date of the 
measurement or event, unless otherwise specified.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:
•
A value that is 1 unit less than the lower LOQ at the same precision level of the originally 
reported value will be used to calculate descriptive statistics if the datum is reported in the 
form of “ x” (where x is considered the lower LOQ). For example, if the values are reported 
as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to calculate summary 
statistics. An exception to this rule is any value reported as < 1 or < 0.1, etc. For values 
reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to calculate 
summary statistics.
•
A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the upper LOQ). Values 
with decimal points will follow the same logic as above.
•
The lower or upper LOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of “≤ x” or “≥ x” (where x is considered the lower or upper LOQ, 
respectively).


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If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data (eg, change from baseline in HIV-1 RNA will 
be performed on the log10 transformed data) or nonparametric analysis methods may be used, as 
appropriate.
Data Handling for PK Summaries
Natural logarithm transformation will be used for analyzing non-BLQ concentrations and PK 
parameters in intensive PK samples. Concentration values that are below the limit of quantitation 
(BLQ) will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be 
treated as 0 at predose and postdose time points for summary purposes. The number of samples 
will be summarized to reflect the actual number of samples assessed at that time point
At predose, if all concentration values are BLQ, then the mean, and order statistics (minimum, 
Q1, median, Q3, and maximum) will be displayed as 0 and the rest of the summary statistics (ie, 
SD and CV) will be missing. If any values are non-BLQ, then the number of samples, order 
statistics, and all summary statistics will be displayed.
At any given postdose time point, if more than one-third of the participants have a concentration 
value of BLQ, then only the number of samples and order statistics will be displayed; otherwise, 
order statistics and summary statistics will be displayed.
The following conventions will be used for the presentation of order statistics for intensive PK 
concentrations:
•
If at least 1 participant has a concentration value of BLQ for the time point, the minimum 
value will be displayed as “BLQ.”
•
If more than 25% of the participants have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”
•
If more than 50% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”
•
If more than 75% of the participants have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”
•
If all participants have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
Concentration related PK parameters (eg, Clast, Cmax, and Ctau) that are BLQ will be excluded 
before log transformation or statistical model fitting and displayed as described above.


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Predose, Postdose, Study Day
Study day will be calculated from the first dosing date of study drug (or first dose date of placebo 
for placebo historical control group [HIV-1 RNA data only]) and derived as follows:
•
For postdose study days: Assessment Date – First Dosing Date + 1
•
For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of first dose of study drug administration.
Baseline is defined as the last available value collected on or prior to the first dose date 
(and time, where applicable) of study drug (ie, prior to taking first dose of study drug). 
Postbaseline is defined as any value collected after the first dose of study drug. Last Study Date 
is the latest of clinic visit dates and laboratory visit dates, including all follow-up visits for 
participants who prematurely discontinued study or who completed study according to the Study 
Completion eCRF.
3.8.2.
Analysis Visit Windows
Participant visits might not occur on protocol-specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows.
The analysis windows for HIV-1 RNA are provided in Table 3-1; for hematology, chemistry, 
urinalysis, and eGFRCG in Table 3-2; for vital signs and weight in Table 3-3; for ECGs and 
coagulation in Table 3-4; and CD4 cell count and percentage in Table 3-5.
Table 3-1.
Analysis Visit Windows for HIV-1 RNA
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2
2
2
2
Day 3
3
3
3
Day 4
4
4
5
Day 7
7
6
7
Day 8
8
8
8
Day 9
9
9
9
Day 10
10
10
10
Day 11
11
11
11
Day 25
25
12
(none)


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Cohort GS-6212 will be compared to the historical placebo control group through Study Day 11.
The percentage of participants with HIV-1 RNA < 50 copies/mL will be displayed on Day 11 
(last value prior to starting standard of care) and on Days 25.
Table 3-2.
Analysis Visit Windows for Hematology, Chemistry (including 
Thyrotropin), Urinalysis and eGFRCG 
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 3
3
2
5
Day 7
7
6
9
Day 11
11
10
11
Day 25
25
12
(none)
Table 3-3.
Analysis Visit Windows for Vital Signs and Weight
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 2*
2
2
2
Day 3
3
3
3
Day 4*
4
4
5
Day 7
7
6
9
Day 11
11
10
11
Day 25
25
12
(none)
*Weight is not scheduled to be collected on Day 2 and Day 4 per protocol, so any weight collected on Day 2 will be considered 
for Day 3, any weight collected during Day 4 period will be considered for Day 7.
Table 3-4.
Analysis Visit Windows for ECGs and Coagulation Tests
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 7
7
2
9
Day 11
11
10
11
Day 25
25
12
(none)


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Table 3-5.
Analysis Visit Windows for CD4 Cell Count and Percentage
Visit Window Study Day
Nominal Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 11
11
2
11
Day 25
25
12
(none)
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value.
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:
•
For baseline, the last nonmissing value on or prior to the first dose of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no 
time recorded on the same day, the baseline value will be the average of the measurements 
for continuous data (except for HIV-1 RNA, see below), or the measurement with the lowest 
severity (ie, normal will be selected over abnormal for safety ECG findings) for categorical 
data.
•
For postbaseline values:
The record closest to the nominal day for that visit will be selected (with the exception of 
CD4+ cell count and CD4% in which the latest record will be selected and HIV-1 RNA 
level [see below]).
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data (except for HIV-1 RNA, see below) and the worst severity will be taken 
for categorical data, unless otherwise specified.
•
For baseline and postbaseline HIV-1 RNA, the latest (considering both date and time) 
record(s) in the window will be selected. If both “Roche COBAS 6800” and 
“Roche COBAS 6800 Repeat” (ie, the HIV-1 RNA result obtained from an additional aliquot 
of the original sample) are available with the same collection time, the results from the 
“Roche COBAS 6800 Repeat” will be selected for analysis purposes; otherwise, if there are 
multiple “Roche COBAS 6800” records with the same collection time, the geometric mean 
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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment and Disposition
A summary of key study dates will present the dates for: 1) first participant screened 2) first 
participant enrolled 3) last participant enrolled 4) last participant last visit for primary endpoint 
[Day 11], and 5) last participant last visit for clinical study report.
A summary of participant enrollment in this substudy will be provided for each country, and 
investigator within country. This summary will present the number and percentage of 
participants enrolled. For each column, the denominator for the percentage calculation will be 
the total number of participants enrolled for that column.
A summary of participant disposition will present the number of participants screened for this 
substudy (denoted by an “C” contained within the participant screening number under the master 
protocol) and the number of participants who met all eligibility criteria but were not enrolled 
with the reasons that participants were not enrolled. An additional summary of participant 
disposition for participants in the All Enrolled Analysis Set will be provided. The number and 
percentage of participants in each of the categories listed below will be summarized:
•
All Enrolled Analysis Set
•
Safety Analysis Set
•
Full Analysis Set
•
PK Analysis Set
•
Completed study drug
•
Did not complete study drug with reasons for premature discontinuation of study drug
•
Completed study
•
Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of participants in each category will be provided. The denominator for 
the percentage calculation will be the total number of participants in the Safety Analysis Set 
corresponding to that column.
In addition, the total number of participants who were enrolled, and the number of participants in 
each of the disposition categories listed above will be displayed in a flowchart.
The randomization schedules used for the study will be provided as an appendix to the CSR.


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The following by-participant listings will be provided by participant ID number in ascending 
order to support the above summary tables:
•
Reasons for premature study drug or study discontinuation 
•
Reasons for screen failure (will be provided by screening ID number in ascending order)
•
Analysis set status (participants excluded from any of the analysis sets)
4.2.
Extent of Study Drug Exposure and Adherence
A participant’s extent of exposure to study drug data will be examined by assessing the total 
duration of exposure to study drug. Study drug administration was performed at the study site; 
adherence will not be summarized.
4.2.1.
Study Drug Exposure and Duration on Study
Dose of GS-6212 will be 
 on Days 1 
through 10 for Cohort 1. Cohorts 2-5 were not initiated. The first AM dose (on Day 1) should be 
taken following overnight fasting (≥ 6 hours). All other AM doses (on Days 2 through 10) should 
be taken around the same time every morning on an empty stomach (fasting for ≥ 2 hours). Each 
PM dose should be taken around the same time every evening with or without food. Participants 
are required to keep the pattern of study drug intake consistent throughout the 10 days of dosing 
as much as possible. Study drug exposure will be summarized based on data collected on the 
Study Drug Administration eCRF.
Duration on sponsor-provided Biktarvy® (BVY) as standard of care or alternative SOC will be 
summarized using descriptive statistics, and will be calculated as: (last dose date BVY or 
alternative SOC – first dose date of BVY or alternative SOC) + 1. The start and stop dates for 
BVY administered as standard of care are collected on the ARV eCRF with subcategory of 
“CURRENT”. Records with a BVY or alternative SOC start date on or after the last date in study 
will be excluded from calculations.
The number (ie, cumulative counts) and percentage of participants on BVY or alternative SOC 
for at least the following number of days will be summarized: 7 days, 14 days. For the final 
analysis, a ± 2 day window will be applied for the 14 days category (allows for the Day 25 [on 
Study] protocol specified visit window and participants starting BVY or alternative SOC on 
Day 11).
Duration on study (in days) will be defined as last date in study minus first dosing date plus 1. 
Last Study Date is the latest of clinic visit dates and laboratory visit dates, including all follow-up 
visits for participants who prematurely discontinued study or who completed study according to the 
Study Completion eCRF.
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Duration on study (in days) will be summarized using descriptive statistics and using the number 
(ie, cumulative counts) and percentage of participants still on study through each study 
visit: ≥ 1 day, ≥ 2 days, ≥ 3 days, ≥ 4 days, ≥ 7 days, ≥ 8 days, ≥ 9 days, ≥ 10 days, ≥ 11 days, 
and ≥ 25 days. For the final analysis, a ± 2 day window will be applied for the ≥ 25 days 
category to allow for the Day 25 protocol specified visit window.
Summaries will be provided for the Safety Analysis Set. Exposure data for GS-6212 study drug 
will be listed.
No formal statistical testing is planned.
BVY will be provided as standard of care by the Sponsor during the follow-up period and 
dispensing information will be recorded on the Accountability eCRF. 
Drug accountability data for study drug, BVY will be listed. Drug accountability data of 
alternative standard of care is not available.
4.3.
Protocol Deviations
A by participant listing will be provided for those participants who did not meet at least 1 
eligibility (inclusion or exclusion) criteria. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that the participant did not meet and related comments, if 
collected.
Important protocol deviations occurring after participants entered the study are documented 
during routine monitoring. Any important deviation identified will be included in a by-
participant listing. The number and percentage of participants with important protocol deviations 
by deviation category (eg, eligibility criteria, informed consent) will be summarized for the 
Safety Analysis Set.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized 
using descriptive statistics for continuous variables and using number and percentage of 
participants for categorical variables. The summary of demographic data will be provided for the 
Safety Analysis Set.
A by-participant demographic listing, including the informed consent date, will be provided by 
participant ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include HIV-1 RNA (log10 copies/mL), CD4 cell count (/μL), 
CD4 percentage (%), mode of infection (HIV risk factors), HIV disease status (AIDS, 
asymptomatic, or symptomatic HIV infection), years since HIV-1 diagnosis, years since starting 
HIV-1 treatment, resistance to any of the 4 ARV classes (yes, no) with a count of the number of 
subjects with resistance to each ARV class [NRTI, NNRTI, PI, and/or INSTI]), and ART status 
(ART-experienced or ART-naïve). These baseline characteristics will be summarized and for all 
GS-6212 participants using descriptive statistics for continuous variables, and using number and 
percentage of participants for categorical variables. The summary of these baseline 
characteristics will be provided for the Safety Analysis Set. No formal statistical testing is 
planned.
Note: If only the month and year are collected for “date of HIV-1 diagnosis” and/or “start date of 
HIV-1 treatment”, the day will be set to ‘01’ when imputing the full date. If both the day and 
month are missing, then ‘01 July’ will be used for the day and month unless the full imputed date 
is after the first dose date of GS-6212 study drug. If HIV-1 diagnosis date or HIV-1 treatment 
start date is imputed to be after the first dose date of GS-6212 study drug, set the imputed HIV-1 
diagnosis date or treatment start date to the date of first dose of GS-6212 to avoid having a 
negative duration.
A by-participant listing of other baseline characteristics will be provided by participant 
ID number in ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will be coded using the MedDRA dictionary.
A by-participant listing of general medical history will be provided by participant ID number in 
ascending order. The listing will include relevant medical condition or procedure reported term, 
onset date, ongoing status, and resolution date (if applicable).


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in plasma HIV-1 RNA 
(log10 copies/mL) on Day 11.
Historical HIV-1 RNA data for placebo participants from 3 sponsor Phase 1b studies 
(GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) will be combined to form a single 
placebo group for the purpose of HIV-1 RNA analysis through Study Day 11. For 
Study GS-US-200-4072, HIV-1 RNA (log10 copies/mL) collected on Day 10 will be used for 
“Day 11” since HIV-1 RNA was not collected on Day 11 for this study. GS-6212 cohort will be 
compared to the pooled placebo group with respect to the primary efficacy endpoint, the change 
from baseline in plasma HIV-1 RNA (log10 copies/mL) on Day 11, using the 2-sided t-test 
conducted at an alpha level of 0.05. The analysis will be conducted using the FAS.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) on Day 8
The secondary efficacy endpoint change from baseline in plasma HIV-1 RNA (log10 copies/mL) 
on Day 8 will be analyzed using the same methods used for the primary endpoint. For study 
GS-US-120-0104, HIV-1 RNA (log10 copies/mL) collected on Day 7 will be used for “Day 8” 
since HIV-1 RNA was not collected on Day 8 for this study.
6.2.2.
Percentage of Participants Ever Achieving HIV-1 RNA < 50 copies/mL 
Postbaseline up to Day 11
The number and percentage of participants ever achieving HIV-1 RNA < 50 copies/mL 
postbaseline up to Day 11 will be summarized by GS-6212 cohort and for the placebo control 
group (using the FAS). For historical placebo control participants in study GS-US-120-0104 with 
HIV-1 RNA values analyzed using the HIV PCR Stand, 1.5 Cobas-CL assay with a LLOQ 
of 400 copies/mL, a value less than LLOQ (ie, < 400 copies/mL) was counted as meeting the 
endpoint (HIV-1 RNA < 50 copies/mL). A Fisher’s exact test will be used to compare each 
GS-6212 cohort to the historical placebo group if at least 1 participant has HIV-1 RNA 
< 50 copies/mL postbaseline up to Day 11.
6.3.
Other Efficacy Endpoints
Maximum Reduction in Plasma HIV-1 RNA Postbaseline to Day 11
The maximum postbaseline reduction in plasma HIV-1 RNA (log10 copies/mL) from Day 2 
through Day 11 will be analyzed using the same statistical methods used for the primary 
endpoint analysis. Baseline value, lowest post-baseline HIV-1 RNA value from Day 2 to Day 11, 
and the lowest change from baseline in HIV-1 RNA (log10 copies/mL) from Day 2 to Day 11 for 
each participant will be summarized for GS-6212 cohort and for the historical placebo group.


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Change from Baseline in HIV-1 RNA by Visit
Baseline value, HIV-1 RNA (log10 copies/mL), and change from baseline in HIV-1 RNA 
(log10 copies/mL) will be summarized descriptively by visit for GS-6212 cohort and for the 
historical placebo control group through Day 11.
Mean ± 95% confidence interval (CI) and median (Q1, Q3) of the change from baseline in 
HIV-1 RNA (log10 copies/mL) at each visit will be plotted through Day 11 using a line plot with 
a separate line displayed for GS-6212 cohort and for the historical placebo group. Placebo data 
will be displayed for participants with a measurement collected in the analysis visit window.
Change from Baseline in CD4 by Visit
Baseline values, values at postbaseline visit Day 11 and Day 25), and the change from baseline 
in CD4 cell count (/μL) and CD4 percentage by visit will be summarized.
Percentage of Participants with HIV-1 RNA < 50 copies/mL by Visit from Day 11 to Day 25
The number and percentage of participants with HIV1 RNA < 50 copies/mL (split into categories 
“< 20 copies/mL” [with subcategories “< 20 copies/mL Detectable”, “< 20 copies/mL Not 
Detectable”] and “20 to < 50 copies/mL”) by visit using the Cobas 6800 assay will be displayed 
for GS-6212 cohort and overall using the missing = excluded method at the last visit prior to 
adding SOC (Day 11) and at visits after adding SOC (Days 25).
For participants who did not meet the criteria HIV-1 RNA < 50 copies/mL at the visit, the 
number and percentage of participants with HIV-1 RNA in the following categories will be 
summarized:
•
50 to < 200 copies/mL
•
≥ 200 copies/mL
Missing data will be excluded in the computation of percentages (ie, missing data points will be 
excluded from both numerator and denominator in the computation). The denominator for 
percentages at a visit is the number of participants in the FAS with nonmissing HIV-1 RNA 
value at that visit. No statistical testing is planned.
All efficacy endpoints will include participants in the FAS.
6.4.
Sensitivity Analyses
Sensitivity analyses will be performed among participants who took the study drug with correct 
amount of dose at each intake and completed the study drug as planned per protocol. Participants 
who were under dosed, or early terminated study drug will be excluded from the sensitivity 
analyses. Sensitivity analyses will include following analyses:


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•
Change from baseline in plasma HIV-1 RNA (log10 copies/mL) on Day 11 using the same 
statistical methods used for the primary endpoint analysis; 
•
Maximum postbaseline reduction in plasma HIV-1 RNA (log10 copies/mL) from Day 2 
through Day 11 using the same statistical methods used for the primary endpoint 
analysis; 
•
Change from baseline in HIV-1 RNA (log10 copies/mL) by visit. 


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA version 27.0. System organ class (SOC), high-level group term (HLGT), high-level 
term (HLT), preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events were graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity 
criteria specified in the protocol. A Grade 5 event indicates death. The severity grade of events 
for which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings. The missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-participant data listings will show the relationship as missing.
7.1.4.
Relationship of Adverse Events to Study Procedure
Study procedure related AEs are those for which the investigator selected “Yes” on the AE CRF 
to the question of “Related to Study Procedures.” Relatedness will always default to the 
investigator’s choice, not that of the medical monitor. Events for which the investigator did not 
record relationships to study procedure will be considered related to study procedure for 
summary purposes. However, by-participant data listings will show the relationship as missing 
from that captured on the CRF.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AE met the 
definition of an SAE that was specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with those in the Gilead Patient Safety database before data 
finalization.


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7.1.6.
Treatment-Emergent Adverse Events
7.1.6.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date on or 
after the study drug start date. If the AE onset date is the same as the date of study drug start date 
then the AE onset time must be on or after the study drug start time. If the AE onset time is 
missing when the start dates are the same the AE will be considered treatment emergent.
7.1.6.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
the AE onset is the same as or after the month and year (or year) of the first dosing date of study 
drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.7.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.7.1.
Summaries of AE Incidence in Combined Severity Grade Subsets
A brief, high-level summary of the number and percentage of participants who experienced at 
least 1 TEAE in the categories described below will be provided for events with an onset date up 
to Day 11 (prior to adding SOC) and for the entire study.
•
TEAEs
•
TEAEs with Grade 3 or higher
•
TEAEs with Grade 2 or higher
•
TE treatment-related AEs
•
TE procedure-related AEs
•
TE treatment-related AEs with Grade 3 or higher
•
TE treatment-related AEs with Grade 2 or higher


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•
TE SAEs
•
TE treatment-related SAEs
•
TEAEs leading to premature discontinuation of study drug
•
TEAEs leading to premature discontinuation of study
•
TEAEs leading to death (ie, outcome of death)
The number and percentage of participants who experienced at least 1 TEAE will be provided 
and summarized by SOC, PT:
•
TEAEs, by maximum severity
•
TEAEs up to Day 11, by maximum severity
•
TEAEs with Grade 3 or higher, by maximum severity
•
TE treatment-related AEs, by maximum severity
•
TE procedure-related AEs, by maximum severity
•
TE treatment-related AEs with Grade 3 or higher, by maximum severity
•
TE SAEs
•
TE treatment-related SAEs
•
TEAEs leading to premature discontinuation of study
Multiple events will be counted only once per participant in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual participant during the study.
In addition to the above summary tables, all TEAEs and TE treatment-related AEs will be 
summarized by PT only, in descending order of total frequency.
In addition, data listings will be provided for the following:
•
All AEs, indicating whether the event is treatment emergent
•
All SAEs
•
All Deaths


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•
All AEs with severity of Grade 3 or higher
•
All AEs leading to premature discontinuation of study drug or study
7.2.
Laboratory Evaluations
Laboratory data collected during the substudy will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include all data collected after the first dose date of study drug 
unless stated otherwise. The analysis will be based on values reported in conventional units. 
When values are below the LOQ, they will be listed as such, and the closest imputed value will 
be used for the purpose of calculating summary statistics as specified in Section 3.7.
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, coagulation, and urinalysis 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the DAIDS Toxicity Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities will be flagged in the data listings, as appropriate. 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.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided for selected laboratory tests specified in the study protocol 
as follows:
•
Baseline values
•
Values at each postbaseline visit
•
Change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3


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7.2.2.
Graded Laboratory Values
The DAIDS Toxicity Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be used to assign toxicity grades (0 to 4) to laboratory results for analysis. 
Grade 0 includes all values that do not meet the criteria for an abnormality of at least Grade 1. 
For laboratory tests with criteria for both increased and decreased levels, analyses for each 
direction (ie, increased, decreased) will be presented separately.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any time postbaseline. If the relevant baseline laboratory value 
is missing, any abnormality of at least Grade 1 observed postbaseline will be considered 
treatment emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
participants in the study with the given response at baseline and each scheduled postbaseline 
visit.
The following summaries (number and percentage of participants) for treatment-emergent 
laboratory abnormalities will be provided by lab test; participants will be categorized according 
to the most severe postbaseline abnormality grade for a given lab test:
•
Graded laboratory abnormalities
•
Graded laboratory abnormalities collected up to Study Day 11 (prior to the participant 
initiating standard of care therapy on Day 11)
•
Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with ≥ 1 nonmissing postbaseline value.
A by-participant listing of treatment-emergent laboratory abnormalities and a listing of 
treatment-emergent Grade 3 or 4 laboratory abnormalities will be provided by participant 
ID number and visit in chronological order. These listings will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades and 
abnormal flags displayed.


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7.3.
Body Weight, Height, and Vital Signs
Descriptive statistics will be provided for body weight, BMI, and vital signs as follows:
•
Baseline value
•
Value at each postbaseline time point [visit]
•
Change from baseline at each postbaseline time point [visit]
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-participant listing of vital signs will be provided by participant ID number and visit in 
chronological order. Body weight, height, and BMI will be included in the vital signs listing if 
space permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications and Disease Specific Medications
Prior and concomitant medications (ie, non-antiretroviral [non-ARV] medications) collected at 
screening and during the study will be coded using the current version of the World Health 
Organization (WHO) Drug Dictionary.
Disease-specific medications (ie, nonstudy drug ARV) used prior to, during, or after the study 
(if collected) will be coded using the Gilead-modified WHO Drug Dictionary.
7.4.1.
Prior and Disease-Specific Prior Medications
Prior and disease-specific prior medications are defined as any medications taken before a 
participant took their first dose of study drug.
A summary of prior or disease-specific prior medications will not be provided.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken on or after first dose date of study 
drug. Use of concomitant medications will be summarized by preferred name using the number 
and percentage of participants for GS-6212 cohort. A participant reporting the same medication 
more than once will be counted only once when calculating the number and percentage of 
participants who received that medication. The summary will be ordered by preferred term in 
descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.


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For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug that continued to be taken after the first dosing date, or medications started after 
the first dosing date of study drug will be considered to be concomitant medications. 
Medications started and stopped on the same day as the first dosing date of study drug will also 
be considered concomitant. Medications with a stop date prior to the date of first dosing date of 
study drug will be excluded from the concomitant medication summary. If a partial stop date is 
entered, any medication with the month and year (if day is missing) or year (if day and month are 
missing) prior to the date of first study drug administration will be excluded from the 
concomitant medication summary. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) on or after the study 
drug start date will be included in the concomitant medication summary. Medications with 
completely missing start and stop dates will be included in the concomitant medication summary, 
unless otherwise specified. Summaries will be based on the Safety Analysis Set. No formal 
statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) and all nonstudy 
drug ARV medications will be provided in by-participant listings sorted by participant 
ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
Summaries of investigator assessment of ECG readings will be provided for the Safety Analysis 
Set for each scheduled visit. No formal statistical testing is planned.
7.5.1.
Investigator Electrocardiogram Assessment
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented using the following categories: normal; abnormal, not clinically 
significant; abnormal, clinically significant; or missing. If all participants have a baseline value 
then no missing category will be presented at baseline. The number and percentage of 
participants in each cross-classification group of the shift table will be presented. Participants 
with a missing value at baseline or postbaseline will not be included in the denominator for 
percentage calculation.
No formal statistical testing is planned.
A by-participant listing for ECG assessment results will be provided by participant ID number 
and visit in chronological order.


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7.6.
Other Safety Measures
A by-participant listing of subject pregnancies during the study will be provided by participant 
ID number if applicable. No additional safety measures are specified in the protocol.
Although not necessarily related to safety, a by-participant listing of all comments received 
during the study on the comments eCRF will be provided by participant ID number, and eCRF 
form for which the comment applies.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection and Analyses
Intensive PK samples are planned to be collected on Study Day 1 and Day 10 at the following 
timepoints for all cohorts (as applicable): predose (≤ 30 minutes before dose), 0.25, 0.5, 1, 2, 3, 
4, 6, 8, and 12 hours postdose (12 hour postdose sample is optional) on respective days of 
dosing. Additionally, single trough PK samples will be drawn prior to AM drug dosing on Study 
Days 2, 3, 4, 7, 8, 9, and 11. Concentrations of GS-6212 in plasma will be determined using 
validated bioanalytical assays.
8.1.1.
Estimation of PK Parameters
PK parameters will be estimated by leveraging relevant PK data (ie, intensive PK data) using 
Phoenix WinNonlin® software (version 8.2.0) with standard noncompartmental methods. The 
linear up/log down rule will be used in conjunction with the appropriate noncompartmental 
model, with input values for dose level, dosing time, plasma concentration, and corresponding 
real-time values, based on drug dosing times whenever possible. If the PK scientist identifies that 
another method is more appropriate, the reasons for this decision should be documented.
All predose sample times before time-zero will be converted to 0.
Area under the curve (AUC) will be calculated, as appropriate, by the PK scientist. For AUC 
calculation, samples that are BLQ occurring prior to the achievement of the first quantifiable 
concentration will be assigned a concentration value of zero to prevent overestimation of the 
initial AUC. Samples that are BLQ at all other time points will be treated as missing data in 
WinNonlin®. The nominal time point for a key event or dosing interval (τ) may be used to permit 
direct calculation of AUC over specific time intervals. The appropriateness of this approach will 
be assessed by the PK scientist on a profile-by-profile basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 (as applicable) are dependent on an 
accurate estimation of the terminal elimination phase of drug. The appropriateness of calculating 
these parameters will be evaluated upon inspection of PK data on a profile-by-profile basis by 
the PK scientist.
8.1.2.
PK Parameters
PK parameters will be generated for all participants for whom parameters can be derived in the 
PK Analysis Set. The analyte presented in Table 8-1 will be evaluated if data are available.
Table 8-1. 
Study Treatments and Associated Analyte
GS-6212 Cohort
Treatment
Analyte
All GS-6212 Cohorts
GS-6212 
GS-6212 


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The analyte and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study, as appropriate. The PK parameters to be estimated in this study are listed and defined 
in the PK Abbreviations section.
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-6212
For intensive PK sampling up to 12 hours postdose on Day 1 and Day 10, following 
parameters will be calculated (as applicable): AUC0-t, AUClast, AUCtau, Cmax, Ct, Clast, Ctau, 
Cavg, Tmax, Tlast, and additionally λz, CL/F, t1/2, and Vz/F if applicable; accumulation ratio 
(Day 10 / Day 1) for Ct, Cmax, AUC0-t, and AUClast; Ctrough on Day 11; Ctrough,avg (average 
Ctrough based on all predose trough sampling done across several days- D2, D3, D4, D7, D8, 
D9, D10, and D11)
8.2.
Statistical Analysis Methods
8.2.1.
General considerations
Individual participant concentration data and individual participant PK parameters for GS-6212 
will be listed and summarized using descriptive statistics. Summary statistics (number of 
participants, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and Q3) will be 
presented for both individual participant concentration data by visit/time point and individual 
participant PK parameters (as applicable). Moreover, the geometric mean, 95% CI, %Geometric 
CV [%GCV], and the mean and SD of the natural log-transformed values will be presented for 
individual participant PK parameter data.
Individual concentration data listings and summaries will include all participants with 
concentration data. The sample size for each time point will be based on the number of 
participants with nonmissing concentration data at that time point. The number and percentage of 
participants with concentration BLQ, as well as an indicator if more than one-third of the 
participants are BLQ will be presented for each time point. For summary statistics, BLQ values 
will be treated as zero at predose and postdose time points. If more than one-third of the values at 
a postdose time point are BLQ then the mean and SD will not be presented at that time point 
Concentration values will be presented as received from the bioanalytical lab and summary 
statistics will be presented to three significant digits.
8.2.2.
PK Analyses
Individual PK parameter data listings and summaries will include all participants for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of participants with nonmissing data for that PK parameter. Data and summary statistics will be 
presented to three significant digits.


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The following tables will be provided for GS-6212:
•
Individual estimates and summary statistics of plasma pharmacokinetic parameters on Day 1 
and Day 10
•
Individual data and summary statistics of plasma concentration (ng/mL) at protocol-specified 
sampling times
•
Statistical comparisons of plasma pharmacokinetic parameter estimates on Day 10 vs Day 1 
for the accumulation analysis
Accumulation analysis of analyte GS-6212 will be evaluated by comparing the relevant Day 10 
PK parameters to Day 1 PK parameters within cohort 1. The analytes and parameters are 
presented in Table 8-3.
A mixed effects model with the natural log-transformed PK parameter as the dependent variable, 
a fixed effect for day, and a random effect for participant, will be used to estimate the difference 
between Day 10 and Day 1. A 90% CI for the true difference on the log-scale across all 
participants will be estimated. The estimate and associated 90% CI will be exponentiated to 
obtain an estimate of the GLSM ratio and its associated 90% CI. 
The following SAS® PROC MIXED code will provide assessment for accumulation ratio for 
natural-log transformed parameters.
proc mixed;
where analyte=‘GS-6212 and paramcd =‘parameter’;
class subjid day; 
random subjid;
model lnest = day / ddfm=kr;
lsmeans day / diff cl alpha = 0.1;
estimate ‘Test (Day 10) versus Reference (Day 1)’ day -1 1 / cl alpha = 0.10;
ods output Estimates = LS_Diffs LSMeans = LS_Means CovParms = MSE;
run;
Table 8-3.
Analytes and PK Parameters for Estimation of Accumulation Ratios 
Analytes
PK Parameters on Day 1
PK Parameters on Day 10
GS-6212
AUC0-8h, AUClast, C8h, Cmax
AUC0-8h, AUClast, C8h, Cmax
The following figures will be provided for GS-6212:
•
Mean (± SD) concentration data on Day 1 (on linear and semilogarithmic scales). 
•
Mean (± SD) concentration data on Day 10 (on linear and semilogarithmic scales). 


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•
Mean (± SD) concentration data from Day 1 through Day 11 (on linear and semilogarithmic 
scales). 
If more than one-third of the values at a postdose time point are BLQ, then the mean and SD will 
not be presented at that time point and remaining points connected. If lower error bar (mean-SD) 
is < 0 at a timepoint then it will not be presented at that timepoint.
•
Median (Q1, Q3) concentration data on Day 1 (on linear and semilogarithmic scales). 
•
Median (Q1, Q3) concentration data on Day 10 (on linear and semilogarithmic scales).
•
Median (Q1, Q3) concentration data Day 1 through Day 11 (on linear and semilogarithmic 
scales).
If more than one-third of the values at a postdose time point are BLQ then the median, Q1 and 
Q3 will not be presented at that time point and remaining points connected. If lower error bar 
(Q1) is BLQ at a timepoint then it will be presented as LLOQ at that timepoint.
•
Individual participant concentration data versus time (on linear and semilogarithmic scales). 
Values of BLQ will be displayed as 0 on the linear scale and missing on the semi-logarithmic 
scale.
The following listings may be provided, as applicable:
•
Plasma PK sampling details by participant, including procedures, differences in scheduled 
and actual draw times, and sample age
8.2.3.
PK/PD Analyses
No formal PK/PD analysis is planned due to small number of participants in this study.
8.3.
Sensitivity Analysis
Sensitivity analysis may be conducted for the key PK analyses if the PK scientist identifies PK 
data as questionable. The sensitivity analysis will exclude specific data from analyses, if 
appropriate. If a sensitivity analysis is deemed necessary, a listing of the PK parameter(s) data 
being excluded, with associated reason(s) provided by the PK scientist, will be generated.


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9.
REFERENCES
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Version 2.1), July 2017, 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf


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10.
SOFTWARE
SAS® Software, SAS Institute Inc., Cary, NC, USA.
nQuery, Statsols, Cork, Ireland.
Phoenix WinNonlin® software, Certara, Radnor, PA, USA


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Study Prol'l'dm·p 
SUl'l'Iling" 
Dlb 
D2 
D3 
D4 
D 
D8 
D9 
D10 
Dllb 
D25 
ET' 
Visit Window 
±2D 
Written informed consent 
X 
Medical history and demography 
X 
Complete physical examination 
X 
X 
X 
X 
Symptom-driven physical examinationd 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Vital signs• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV blood panel and HCV serology' 
X 
CD4 cell countf 
X 
X 
X 
X 
X 
Plasma sample for HIV-1 
X 
X 
X 
genotyping/phenotyping4 
Plasma HIV-1 RNAf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology1 
X 
X 
X 
X 
X 
X 
X 
Coagulation panelf 
X 
X 
X 
X 
X 
X 
C.'b.emistryf 
X 
X 
X 
X 
X 
X 
X 
UrinaJysisf 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testfh 
X 
Urine pregnancy test!.b.i 
X 
X 
X 
SerumFSHf.i 
X 
12-LeadECG 
X 
X 
X 
X 
X 
X 
Intensive plasma PKk 
X 
X 
Single trough plasma PK1 
X 
X 
X 
X 
X 
X 
X 
X 
Review AEs and concomitant medications"' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug (GS-6212) dispensation° 
X 
Study drug (GS-6212) dosing" P 
X 
X 
X 
X 
X 
X 
X 
X 
BVY dispensation, as applicable 
X 


GS-6212 
Study GS-US-544-5905 Substudy 03 
Statistical Analysis Plan - Final Analysis 
Study ProcNlure 
Screening" 
\"isit Windoll" 
BVY or an alternative SOC administration 
D1b 
D2 
D3 
D4 
D7 
Version 1.0 
D8 
D9 
D10 
Dllb 
D25 
I.T< 
±2D 
X4 
AE = adverse e\·ent; AM = before noon; BVY = bictegravir/emtricitabi.ne/tenofovir alafenamide (B/F/TAF; coformulated; Bilctarvy~; CD4 = clusters of differentiation 4; 
D = Day; ECG = electrocardiogram; eCRF = electronic case report form; ET = early tenni.nation: FSH = follicle-stimulating hormone; HBV = hepatitis B Yirus: 
HCV = hepatitis C virus; HIV-I= human inununodeficiency virus type l; PK = pharmacokinetic(s); RNA = ribonucleic acid; SAE = serious adverse event; SOC = standard of 
care 
a 
Prospective participants should be screened no more than 28 days prior to administration of the first dose of snidy drug. 
b 
Overnight fasting (:! 6 hours prior to dosing) is required. 
c 
ET assessments will be performed within 72 hours of preinaturely discontinuing from the study or study drug, as applicable. 
d 
Symptom-driven physical examinations will be performed as needed, based on reported signs and symptoms. 
e 
Vital signs include blood pressure. heart rate, respiration rate, and body temperature. Participants should be sitting down for 5 minutes before vital sign measurements are 
obtained. 
f 
See detailed list of laboratory assessments in Section 6.3.7 of the master protocol 
g 
Participants who meet the criteria for virologic failure at Day 11 will be tested for the potential development of resistance against all components of the treatment regimen, 
including the snidy drug. See Section 6.3.9. 1.3 of the master protocol for management ofvirologic failure. 
h 
Participants assigned female at birth and of childbearing potential only. 
A negative uru1e pregnancy test is required prior to study drug dosing on Day 1. Positive urine pregnancy tests will be confirmed with a senun test. 
J 
A serum FSH test is required for participants assigned female at birth who are younger than 54 years. not on hormonal contraception, and who have stopped menstruatmg for 
:! 12 months but do not have documentation of ovarian hormonal failure. 
k 
Intensive PK samples should be collected at these ti.me points for all cohorts (relative to AM dosing): predose ($ 30 minutes before dose), 0.25. 0.5. 1, 2. 3, 4. 6, 8, and 
12 hours 
on respectiYe days of dosing (ie, Days 1 and 1 0). Please note that the 12-hour postdose sample (if collected) on 
Days 1 and 10 should be sampled prior to the administration of the PM dose, as applicable. 
Single trough PK sample should be drawn prior to AM drug dosing (as applicable) on the indicated dosing days (ie, Days 2, 3, 4, 7, 8, 9, and 11). 
m 
From the ti.me of obtainlllg infonned consent through the first administration of snidy drug, record all SAEs, as well as a11y nonserious AEs relat.ed to protocol-mandated 
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 
captured on the medical history eCRF. See Section 7, Adverse Events and Toxicity Management, for additional details. 
n 
Srudy drug bottles ofGS-6212 will be dispensed on Day 1 (see Section 5.2.4). 
o 
For Cohort 1, a 100-mg dose ofGS-6212 will be administered twice daily (ie, once every 12 hours= 1 hour) Oil Days 1 through 10 (for further details 011 dosing a11d meal 
requiren1ents. see Section 5.2.4). Subsequent cohort doses. dosing regimens. meal requirements (fasted or fed), and progression between cohorts will be adaptive and 
determined as s\unmarized in Section 3 .1.1. 
p 
Participants will take their study drug doses at home Oil Days 5 and 6. 
q 
After assessments on Day 11 or upon ET, participants will initiate a regimen of BVY provided by the sponsor or an alternative SOC ART regimen selected by the 
investigator. Participants who discontinue study drug before Day 11 should start this regimen at the time of disconti.tmation (see Section 6.4.1 of the master protocol). 
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Appendix 2.
Details for Statistical Programming
For continuous HIV-1 RNA endpoints change from baseline on Day 11, and maximum change 
from Day 2 to Day 11, pairwise comparisons between GS-6212 cohort and historical placebo 
group will be performed and p-values will be presented.
The following SAS code will be used to generate p-values:
**Assign treatment groups for testing**;
data trtgrp;
set trtgrp;
    if dose =’100 mg’ and meal=’Fasted’ then trt=1;
    else if treatment=’Placebo’ then trt2;
run;
ods output estimates=estimate;
proc mixed data = trtgrp;
class trt;
model chg  = trt / ddfm=kr;
/*least squares means*/
lsmeans trt / diff e;
/* p-values */
estimate 'Cohort 1 vs Placebo' trt  1 -1 / cl alpha=0.05;
run;


GS-US-544-5905-03_SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
28-Aug-2024
03:56:43
Project Team
Leader eSigned
28-Aug-2024
16:23:03
Clinical Pharmacology
eSigned
28-Aug-2024
16:42:19
PPD
PPD
PPD