Clinical trial NCT01854775
Conditions: Acquired Immune Deficiency Syndrome (AIDS) HIV Infections
Keywords: Adolescents HIV-1 HIV Treatment-naive Virologically suppressed
Sponsor: Gilead Sciences
Start date: 2013-05-06; Completion date: 2025-06-18
Enrollment: 129 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of Cohort 1 are to evaluate the steady state pharmacokinetics (PK) for elvitegravir (EVG) and tenofovir alafenamide (TAF) and confirm the dose of the elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) STR (Part A) and to evaluate the safety and tolerability of E/C/F/TAF STR through Week 24 (Part B) in human immunodeficiency virus - 1 (HIV-1) infected, antiretroviral (ARV) treatment-naive adolescents.

The primary objectives of Cohort 2 are to evaluate the PK of EVG and TAF in virologically suppressed HIV-1 infected children 6 to \< 12 years of age weighing ≥ 25 kg administered E/C/F/TAF STR (Part A) and to evaluate the safety and tolerability of E/C/F/TAF STR through Week 24 in virologically suppressed HIV-1 infected children 6 to \< 12 years of age weighing ≥ 25 kg (Part B).

The primary objectives of Cohort 3 are to evaluate the PK of EVG and TAF and confirm the dose of the STR, and to evaluate the safety and tolerability of E/C/F/TAF low dose (LD) STR in virologically suppressed HIV-1 infected children ≥ 2 years of age and weighing ≥ 14 to \< 25 kg.

Detailed description:

Arms: arm 1: HIV-infected, ARV treatment-naive adolescents (12 to \< 18 years of age weighing ≥ 35 kg) will receive E/C/F/TAF (150/150/200/10 mg) fixed-dose combination (FDC) once daily for 48 weeks. Participants who complete 48 weeks of study treatment will have the option to receive E/C/F/TAF in an extension phase of the study until: a) the participant turns 18 years old and E/C/F/TAF is commercially available for adults in the country in which the participant is enrolled; b) age-appropriate E/C/F/TAF become commercially available in the country in which the participant is enrolled; or c) Gilead elects to terminate development of E/C/F/TAF in that country. arm 2: Virologically suppressed HIV-infected children (6 to \< 12 years of age weighing ≥ 25 kg) will receive E/C/F/TAF (150/150/200/10 mg) FDC once daily for 48 weeks. Participants who complete 48 weeks of study treatment will have the option to receive E/C/F/TAF in an extension phase of the study until: a) the participant turns 18 years old and E/C/F/TAF is commercially available for adults in the country in which the participant is enrolled; b) age-appropriate E/C/F/TAF become commercially available in the country in which the participant is enrolled; or c) Gilead elects to terminate development of E/C/F/TAF in that country. arm 3: Virologically suppressed HIV-infected children (≥ 2 years of age weighing ≥ 14 to \< 25 kg) will receive E/C/F/TAF (90/90/120/6 mg) FDC once daily for 48 weeks. Participants who attain a weight of ≥ 25 kg during the course of the study will switch to adult E/C/F/TAF (150/150/200/10 mg) tablets. Participants who complete 48 weeks of study treatment will have the option to receive E/C/F/TAF in an extension phase of the study until: a) the participant turns 18 years old and E/C/F/TAF is commercially available for adults in the country in which the participant is enrolled; b) age-appropriate E/C/F/TAF became commercially available in the country in which the participant is enrolled; or c) Gilead elects to terminate development of E/C/F/TAF in that country.
Interventions: intervention 1: E/C/F/TAF intervention 2: E/C/F/TAF (Low Dose)
Intervention descriptions: intervention 1: Tablets administered orally with food. intervention 2: 90/90/120/6 mg STR administered once daily orally with food.

Protocol documents:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, 
and Antiviral Activity of the 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) Single Tablet Regimen (STR) in HIV-1 Infected 
Antiretroviral Treatment-Naive Adolescents and Virologically 
Suppressed Children
Name of Test Drug:
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) STR
Study Number:
GS-US-292-0106
Protocol Version:
Amendment 6
Protocol Date:
21 February 2020
Analysis Type:
Interim 6 Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
25 November 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives of Cohort 3...................................................................................................................7
1.2.
Study Design of Cohort 3.........................................................................................................................7
1.2.1.
Design Configuration .............................................................................................................7
1.2.2.
Subject Population..................................................................................................................8
1.2.3.
Treatment Group ....................................................................................................................8
1.2.4.
Study Schema (Main Phase)...................................................................................................8
1.2.5.
Key Eligibility Criteria...........................................................................................................8
1.2.6.
Study Periods/Phases and Duration........................................................................................8
1.2.7.
Pharmacokinetic Evaluation...................................................................................................9
1.2.9.
Schedule of Assessments........................................................................................................9
1.3.
Sample Size and Power of Cohort 3.........................................................................................................9
2.
PLANNED ANALYSES FOR COHORT 3 .......................................................................................................10
2.1.
Cohort 3 Week 24 Independent Data Monitoring Committee Analysis.................................................10
2.2.
Interim 5 Analysis..................................................................................................................................10
2.3.
Interim 6 Analysis..................................................................................................................................10
2.4.
Final Analysis ........................................................................................................................................10
2.5.
Changes from Protocol-Specified Analysis............................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .............................................................................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...............................................................................................................11
3.1.4.
DXA Analysis Set ................................................................................................................11
3.1.5.
PK Analysis Sets ..................................................................................................................12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates..............................................................................................................................12
3.4.
Multiple Comparisons............................................................................................................................12
3.5.
Missing Data and Outliers......................................................................................................................12
3.5.1.
Missing Data ........................................................................................................................12
3.5.2.
Outliers.................................................................................................................................13
3.6.
Data Handling Conventions and Transformed Data...............................................................................13
3.7.
Visit Windows........................................................................................................................................14
3.7.1.
Key Definitions ....................................................................................................................14
3.7.2.
Analysis Windows................................................................................................................15
3.7.3.
Selection of Data in the Event of Multiple Records in a Window .......................................16
4.
SUBJECT DISPOSITION ..................................................................................................................................18
4.1.
Subject Enrollment.................................................................................................................................18
4.2.
Disposition of Subjects ..........................................................................................................................18
4.3.
Extent of Exposure.................................................................................................................................19
4.3.1.
Duration of Exposure to Study Drug....................................................................................19
4.3.2.
Adherence with Study Drug.................................................................................................19
4.4.
Protocol Deviations................................................................................................................................20
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5.
BASELINE CHARACTERISTICS....................................................................................................................21
5.1.
Demographics and Baseline Characteristics ..........................................................................................21
5.2.
Medical History......................................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22
6.1.
Definition of the Efficacy Endpoints......................................................................................................22
6.1.1.
Efficacy Endpoints ...............................................................................................................22
6.1.2.
US FDA-Defined Snapshot Algorithm ................................................................................22
6.1.3.
Missing = Failure and Missing = Excluded Analyses ..........................................................23
6.2.
Analysis Methods for Efficacy Endpoints..............................................................................................23
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................24
7.
SAFETY ANALYSES........................................................................................................................................25
7.1.
Adverse Events.......................................................................................................................................25
7.1.1.
Adverse Event Dictionary ....................................................................................................25
7.1.2.
Adverse Event Severity........................................................................................................25
7.1.3.
Relationship of AEs to Study Drug......................................................................................25
7.1.4.
Relationship of AEs to Study Procedure..............................................................................25
7.1.5.
Serious AEs..........................................................................................................................25
7.1.6.
Treatment Emergent AEs .....................................................................................................25
7.1.7.
Summaries of AEs and Deaths.............................................................................................26
7.1.8.
Category C Events................................................................................................................27
7.2.
Laboratory Evaluations ..........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................27
7.2.2.
Graded Laboratory Values ...................................................................................................28
7.3.
Bone Safety Analyses ............................................................................................................................29
7.3.1.
Bone Mineral Density ..........................................................................................................29
7.3.2.
Bone Safety Assessments.....................................................................................................30
7.3.3.
Fracture Events.....................................................................................................................30
7.4.
Renal Safety Analyses............................................................................................................................31
7.4.1.
Serum Creatinine..................................................................................................................31
7.4.2.
Estimated Glomerular Filtration Rate ..................................................................................31
7.4.3.
Urine Retinol Binding Protein to Creatinine Ratio and 
Beta-2-Microglobulin to Creatinine Ratio............................................................................31
7.4.4.
Proteinuria by Quantitative Assessment...............................................................................31
7.5.
Tanner Stage Assessment.......................................................................................................................31
7.6.
Palatability/Acceptability Assessment ...................................................................................................32
7.7.
Body Weight, Height, and Vital Signs...................................................................................................32
7.8.
Nonstudy-Drug Antiretroviral Medications ...........................................................................................32
7.9.
Concomitant Non-ARV Medications.....................................................................................................33
7.10.
Electrocardiogram Results .....................................................................................................................33
7.11.
Other Safety Measures ...........................................................................................................................33
7.12.
Missed and Virtual Visits due to COVID-19 .........................................................................................33
7.13.
Changes from Protocol-Specified Safety Analysis ................................................................................33
8.
PHARMACOKINETICS ANALYSIS ...............................................................................................................34
8.1.
Analysis Methods for Trough PK ..........................................................................................................34
8.2.
Statistical Analysis Methods for Intensive PK.......................................................................................34
8.3.
Estimation of PK Parameters .................................................................................................................34
8.4.
Statistical Analysis Methods ..................................................................................................................35
8.4.1.
General Considerations for Statistical Analyses ..................................................................35
8.4.2.
Statistical Comparative Analysis..........................................................................................36
8.5.
Changes from Protocol-Specified PK Analysis .....................................................................................37


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9.
REFERENCES ...................................................................................................................................................38
10.
SOFTWARE.......................................................................................................................................................39
11.
SAP REVISION..................................................................................................................................................40
12.
APPENDICES ....................................................................................................................................................41
Appendix 1.
PK Parameters ........................................................................................................................42
Appendix 2.
Study Procedures Table..........................................................................................................43
Appendix 3.
Flowchart of US FDA-Defined Snapshot Algorithm .............................................................47
Appendix 4.
Fracture Events.......................................................................................................................48
Appendix 5.
COVID-19 and Suspected COVID-19 Infections ..................................................................51
Appendix 6.
Determining Missing and Virtual Visits Due to COVID-19 ..................................................52
Appendix 7.
Programming Specifications...................................................................................................55
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for Vital Signs, Weight, Height, and Laboratory Testsa..........................15
Table 3-2.
Analysis Windows for Metabolic Assessmentsa.....................................................................15
Table 3-3.
Analysis Windows for Fasting Glucose, Urine Chemistry, and Urine Renal 
Chemistry ...............................................................................................................................16
Table 3-4.
Analysis Windows for Tanner Stage and BMD Assessments................................................16
Table 3-5.
Analysis Windows for Bone Safety Assessmentsa .................................................................16


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LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
ARV 
antiretroviral 
BLQ
below limit of quantitation
BMD
bone mineral density
BMI
body mass index
BSA
body surface area
CDER
Center for Drug Evaluation and Research
CI
confidence interval 
COBI
cobicistat (GS-9350)
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CRF
case report form
CV
coefficient of variation
DC
study drug discontinuation
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EVG
elvitegravir
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (coformulated; 
Genvoya®)
FDA
Food and Drug Administration
FEPO4
urine fractional excretion of phosphate
FTC
emtricitabine (Emtriva®)
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
HIV-1
human immunodeficiency virus (type 1) 
HLGT
high-level group term
IDMC
independent data monitoring committee
LD
low dose
MedDRA
Medical Dictionary for Regulatory Activities
NCEP
National Cholesterol Education Program
PBMC
peripheral blood mononuclear cell
PT
preferred term
PK
pharmacokinetic(s)
PR
pulse rate
PVF
pure virologic failure
Q
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QD
once daily
RNA
ribonucleic acid
SAP
statistical analysis plan
SD
standard deviation
SMQ
Standardized MedDRA query
SOC
system organ class
STB
Stribild® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; 
coformulated)
STR
single-tablet regimen
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate (Viread®)
TFL
tables, figures, and listings
TFV
tenofovir
WHO
World Health Organization


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1.
INTRODUCTION
Study GS-US-292-0106 is a Phase 2/3, open-label, multicenter, multicohort, single-arm study of 
the pharmacokinetics (PK), safety, tolerability, and antiviral activity of the 
elvitegravir/cobicistat/ emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen
(STR) in HIV-1 infected, antiretroviral (ARV) treatment-naive adolescents and virologically 
suppressed children. 
This document describes the statistical analysis methods and data presentations to be used in the
summary and analysis of data for Study GS-US-292-0106 Interim 6 Analysis. This analysis will 
only include data collected from Cohort 3 (virologically suppressed HIV-1 infected children 
≥2 years of age weighing ≥14 to < 25 kg), and will be conducted after all Cohort 3 subjects 
have completed their Week 48 visit or prematurely discontinued from the study.
1.1.
Study Objectives of Cohort 3
The primary objectives are: 

To evaluate the PK of EVG and TAF and confirm the dose of the STR in virologically 
suppressed HIV-1 infected children ≥2 years of age weighing ≥ 14 to < 25 kg administered 
E/C/F/TAF low dose (LD) (90/90/120/6 mg) STR

To evaluate the safety and tolerability of E/C/F/TAF LD STR through Week 24 in 
virologically suppressed HIV-1 infected children ≥2 years of age weighing ≥ 14 to < 25 kg
The secondary objectives are:

To evaluate the antiviral activity of switching to E/C/F/TAF LD STR through Week 48 in 
virologically suppressed HIV-1 infected children ≥2 years of age weighing ≥ 14 to < 25 kg

To evaluate the safety and tolerability of E/C/F/TAF LD STR through Week 48 in 
virologically suppressed HIV-1 infected children ≥2 years of age weighing ≥ 14 to < 25 kg
1.2.
Study Design of Cohort 3
1.2.1.
Design Configuration
For subjects in Cohort 3, there are 2 study phases, a main phase 
. 
The “main phase” refers to the safety and efficacy evaluation phase through Week 48. 
Approximately 25 HIV-1 infected, virologically suppressed children will be enrolled in the main 
phase to receive the E/C/F/TAF LD STR once daily with food.
All enrolled subjects will participate in an intensive PK evaluation at Week 2 to evaluate EVG 
and TAF plasma PK and confirm the dose of EVG and TAF.
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1.2.2.
Subject Population
Virologically suppressed, HIV-1 infected children (≥2 years of age and screening weight ≥14 to 
< 25 kg) of either sex with plasma HIV-1 RNA levels < 50 copies/mL) for 
≥6 consecutive months prior to screening on a stable ARV regimen, with no prior history of 
resistance to any component of the E/C/F/TAF LD STR.
1.2.3.
Treatment Group
This is an open-label, single-arm study. All Cohort 3 subjects will be enrolled and treated with 
the E/C/F/TAF LD STR.
1.2.4.
Study Schema (Main Phase)
1.2.5.
Key Eligibility Criteria
HIV-1 infected subjects who meet the following criteria:

Age at Baseline: ≥2 years old

Weight at Screening: ≥14 kg (31 lbs) to < 25 kg (55 lbs)

Plasma HIV-1 RNA: < 50 copies/mL (or undetectable HIV-1 RNA level according to the 
local assay being used if the limit of detection is > 50 copies/mL) for ≥6 consecutive months 
prior to screening on a stable ARV regimen, without documented history of resistance to any 
component of E/C/F/TAF LD STR
Unconfirmed HIV-1 RNA ≥50 copies/mL after previously reaching virologic 
suppression (transient detectable viremia, or “blip”) and prior to screening is acceptable
Currently receiving an ARV regimen that has been stable for at least 
6 consecutive months or has been newly initiated within 6 months for reasons other than 
virologic failure.
1.2.6.
Study Periods/Phases and Duration
Intensive PK evaluation occurs at Week 2 for all subjects, a 48-week safety and efficacy 
evaluation phase occurs for all subjects, and a 30-day follow up visit occurs for subjects who 
discontinued from the study drug prior to Week 48 and for subjects who complete 48 weeks on 
study drug CCI
:S 15 dll)'S prior 
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1.2.7. 
Pharmacokinetic Evaluation 
Final 
Version 1.0 
Subjects will participate in an intensive PK evaluation at Week 2. Samples will be collected at 0 
(predose, :S 30 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose. 
A trough PK sample (20 to 24 hours postdose) will be collected at Weeks 4, and 24. 
A timed PK sample will be collected between 0.25 to 4 hours post-dose at Weeks 8, 12 and 16. 
The PK of EVG, COBI, FTC, TAF, and tenofovir (TFV) will be evaluated. 
1.2.9. 
Schedule of Assessments 
Study procedures at screening, baseline, and during the study are outlined in the protocol and 
presented in Appendix 2 of the Statistical Analysis Plan (SAP). 
1.3. 
Sample Size and Power of Cohort 3 
Twenty-five evaluable subjects compared to historical adult data will provide 90% power for 
each of EVG ADC.au and TAF ADC1au to conclude exposure equivalence between children and 
adults. In this power analysis, it is assumed that the expected geometric mean ratio is 1, the 
equivalency boundary is 70% to 143%, two one-sided tests are each perfonned at an alpha level 
of 0.05, and the intersubject standard deviations (natural log scale) of EVG ADC1au and TAF 
ADC.au are 0.34 ng•h/mL and 0.52 ng•h/mL. For historical adult data, we used intensive PK data 
from 19 HIV-1 infected adults in Study GS-DS-292-0102 for EVG ADC1au and population PK 
data from Studies GS-DS-292-0104 and GS-DS-292-0111 combined forTAF ADC.au-
Twenty-five evaluable subjects will also provide> 99% power to target a 95% confidence 
interval (CI) within 60% and 140% of the geometric mean estimate of apparent CL and V z of 
TAF respectively, assmning the standard deviation in natural log scale is 0.51 for CL and 0.54 
for Vz (based on population PK data from Studies GS-DS-292-0104 and GS-DS-292-0111 
combined). 
Sample size and power calculations were made using the software package nQuery Advisor 
(Version 6.0) and R. 
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2.
PLANNED ANALYSES FOR COHORT 3
2.1.
Cohort 3 Week 24 Independent Data Monitoring Committee Analysis
Analyses of safety, PK, and efficacy data will be performed after all subjects from Cohort 3 have 
completed their Week 24 visit or prematurely discontinued study drug. The purpose of this 
interim analysis is to provide the Independent Data Monitoring Committee (IDMC) with a 
statistical report for review. More details are documented in the IDMC charter. 
2.2.
Interim 5 Analysis
An Interim 5 Analysis was conducted after all subjects in Cohort 3 had completed their Week 24
visit or prematurely discontinued study drug.
2.3.
Interim 6 Analysis
An Interim 6 Analysis will be conducted after all subjects in Cohort 3 have completed their
Week 48 visit or prematurely discontinued study drug.
This SAP describes the analysis plan for the Study GS-US-292-0106 Interim 6 Analysis. Results 
of this analysis will be included in the Interim 6 CSR.
2.4.
Final Analysis
A final statistical analysis will be conducted after all subjects have completed the study.
2.5.
Changes from Protocol-Specified Analysis
The timing of the analysis of the IDMC review was changed from the intensive PK visit at 
Week 2 to Week 24, so that IDMC members would have enough safety data for review.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSIS
Only Cohort 3 data will be included in this Interim 6 Analysis.
3.1.
Analysis Sets
Analysis sets define which subjects are included in an analysis. A summary of the number and 
percentage of subjects in each analysis set will be provided. A listing will be provided for each
analysis set.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set will include all subjects who are enrolled in this study. This is the 
primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) will include all subjects who are enrolled in the study and have 
received at least 1 dose of study drug. For FAS analysis, all efficacy data, including data 
collected after the last dose date of study drug, will be included, unless specified otherwise. This 
is the primary analysis set for efficacy analyses. 
3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all subjects who have received at least 1 dose of study drug.
All data collected from the first dose date up to 30 days after subjects permanently discontinue 
their study drug will be included in the safety summaries. This is the primary analysis set for 
safety analyses.
3.1.4.
DXA Analysis Set
3.1.4.1.
Spine DXA Analysis Set
The Spine DXA Analysis Set will include all subjects who are enrolled in the study, have 
received at least 1 dose of study drug, and have a nonmissing baseline and at least 
1 postbaseline spine bone mineral density (BMD) value.
3.1.4.2.
Total Body Less Head DXA Analysis Set
The Total Body Less Head (TBLH) DXA Analysis Set will include all subjects who are enrolled 
in the study, have received at least 1 dose of study drug, and have a nonmissing baseline and at 
least one postbaseline TBLH BMD value.


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3.1.5. 
3.1.5.1. 
PK Analysis Sets 
Intensive PK Analysis Set 
Final 
Version 1.0 
An Intensive PK Analysis Set will be defined separately for each of the 5 analytes (EVG, COBI, 
FTC, TAF, and TFV). The 5 Intensive PK Analysis Sets will include all enrolled and treated 
subjects who have any nomnissing key PK parameters (AUCtau, AUC1as1, Cmax) from Week 2 
intensive PK data for the respective analyte. The intensive PK analysis sets will be used for PK 
smmnary tables, figures, and listings of intensive PK data. 
3.1.5.2. 
PK Analysis Set 
A PK Analysis Set will be defined separately for each of the 5 analytes (EVG, COBI, FTC, TAF, 
and TFV). The 5 PK Analysis Sets will include all enrolled and treated subjects who have at least 
one observed single or trough concentration data of the respective analyte. The PK Analysis Sets 
will be used for analysis of single and trough blood concentrations. 
3.2. 
Subject Grouping 
The subjects will be grouped into one treatment group (ie, E/C/F/T AF) for efficacy and safety 
analyses. 
3.3. 
Strata and Covariates 
Not applicable. 
3.4. 
Multiple Comparisons 
Not applicable. 
3.5. 
Missing Data and Outliers 
3.5.1. 
Missing Data 
A missing datum for a given study visit window may be due to any of the following reasons: 
• 
A visit occurred in the window but data were not collected or were mmsable. 
• 
A visit did not occur in the window. 
• 
A subject pennanently discontinued from the study before reaching the window. 
In general, values for 1nissing data will not be imputed, unless specified otherwise. 
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3.5.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be done to evaluate the impact of outliers on PK, efficacy, or safety 
outcomes, unless specified otherwise. All data will be included in the analysis.
3.6.
Data Handling Conventions and Transformed Data
Logarithm (base 10) will be used to transform HIV-1 RNA data. Natural logarithm 
transformation will be applied to the PK concentrations for the PK analysis.
Concentration values (including intensive, trough, predose, postdose, timed or anytime PK 
concentration) that are below the lower limit of quantitation (BLQ) will be presented as “BLQ” 
in the concentration listing. Intensive PK concentration values that are BLQ will be treated as 0 
at predose time points and one-half the value of the lower limit of quantitation (LLOQ) at 
postdose time points for summary purposes. Other PK concentration values (including trough, 
predose, postdose, timed or anytime PK concentration) that are BLQ will be treated as one-half 
of the LLOQ.
The following conventions will be used for the presentation of order statistics and summary 
statistics for intensive PK concentration and trough PK concentrations: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration value of BLQ for a given time point, 
the minimum and Q1 values will be displayed as “BLQ.” 

If more than 50% of the subjects have a concentration 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 subjects have a concentration value of BLQ for a given time point, 
the minimum, Q1, median, and Q3 values will be displayed as “BLQ.” 

If all subjects have concentration values of BLQ for a given time point, all order statistics 
(minimum, Q1, median, Q3, and maximum) and summary statistics will be displayed as 
“BLQ.”
Data (eg, HIV-1 RNA data) that are continuous in nature but are less than the lower limit of 
quantitation or above the upper limit of quantitation will be imputed as follows: 

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “< x”. For example, if the values 
are reported as < 50 and < 5.0, then values of 49 and 4.9 will be used for calculation of 
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• 
A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the fonn of"> x" (x is considered as the 
limit of quantitation). Values with decimal points will follow the same logic as above. 
• 
The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the fonn of ":S x" or"~ x" (x is considered as the limit of quantitation). 
• 
For direct bilirubin, a value of"< 0.1" is imputed as 0.09. For urine creatinine, a value of 
"< 1" is handled as a missing value in the calculation of related ratios. 
3.7. 
3.7.1. 
Visit Windows 
Key Definitions 
Study Day 1 is defined as the day when the first dose of study drug E/C/F/TAF was taken, as 
recorded on the study drug administration electronic case report fonn ( eCRF). 
Study Day is calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1, Study Day is calculated as (visit date minus date of the first dose plus 1 ). For 
events that occurred prior to Study Day 1, Study Day is calculated as (visit date minus date of the 
first dose). 
Last Dose Date is defined as the maximum and nomnissing end date of study drug E/C/F/TAF 
on the study drug ad1ninistration eCRF fonn with "Study Drug Pennanently Discontinued" box 
checked for sub ·ects a who prematurel 
· 
· 
· 
If the date of last dose is incomplete or missing ( eg, due to lost to follow-up), the last dose date 
will be imputed using the instruction described in Appendix 7. 
Last Study Date is the maximum of the nomnissing study drug start dates, study drug end dates, 
and the clinic visit and laboratory visit dates, includin!! the 30-da follow-u visit date for 
w~~ts 
· 
Baseline Value is defined as the last nomnissing value obtained on or prior to Study Day 1. 
The baseline BMD value and Tanner Stage is defined as the last nomnissing value obtained prior 
to or up to Study Day 21 (inclusive). 
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3.7.2.
Analysis Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
Analysis windows for vital signs, weight, height, laboratory tests, and urine chemistry are 
presented in Table 3-1.
Table 3-1.
Analysis Windows for Vital Signs, Weight, Height, and Laboratory 
Testsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 1
7
[2,9] (NPa)
Week 2
14
[10, 20] ([2,20]a)
Week 4
28
[21, 41]
Week 8
56
[42, 69]
Week 12
84
[70, 97]
Week 16
112
[98, 139]
Week 24
168
[140, 195]
Week 32
224
[196, 251]
Week 40
280
[252, 307]
Week 48
336
[308, 377]
NP  Not planned by the protocol.
a
Laboratory tests include HIV 1 RNA, CD4 cell counts, CD4%, flow cytometry panel, hematology and chemistry. For flow 
cytometry panel, CD4 cell count and CD4 %, Week 1 is not applicable and the study day range for Week 2 is [2, 20].
Analysis windows for metabolic assessments are presented in Table 3-2.
Table 3-2.
Analysis Windows for Metabolic Assessmentsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 24
168
[2, 251]
Week 48
336
[252, 503]
a
Metabolic assessments include lipid panel (total cholesterol, high density lipoprotein [HDL], direct low density lipoprotein 
[LDL], and triglycerides).
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Analysis windows for fasting glucose and urine renal chemistry are presented in Table 3-3.
Table 3-3.
Analysis Windows for Fasting Glucose, Urine Chemistry, and Urine 
Renal Chemistry
Nominal Day
Visit Window
Baseline
≤ 1
Week 8
56
[2, 69]
Week 12
84
[70, 125]
Week 24
168
[126, 251]
Week 48
336
[252, 503]
a
Urine renal chemistry includes retinol binding protein, and beta 2 microglobulin.
Analysis windows for Tanner stage and BMD assessments are presented in Table 3-4.
Table 3-4.
Analysis Windows for Tanner Stage and BMD Assessments
Nominal Day
Visit Window
Baseline
≤ 21
Week 24
168
[22, 251]
Week 48
336
[252, 503]
Analysis windows for serum bone safety assessments are presented in Table 3-5.
Table 3-5.
Analysis Windows for Bone Safety Assessmentsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 12
84
[2, 125]
Week 24
168
[126, 251]
Week 48
336
[252, 419]
Week 24*k
 
168*k
[168*k 84, 168*k+83]
a
Bone safety assessments include bone specific alkaline phosphatase, PTH, 25 hydroxy vitamin D, 1,25 dihydroxyvitamin D.
3.7.3.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time to event analysis would not require one value per analysis window. When multiple valid 
and nonmissing observations fall within the bounds of a visit window and a single value is 
needed, the following rule(s) will be used. 
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3.7.3.1.
Numeric Observations

For efficacy data (ie, HIV-1 RNA level, CD4 cell count, and CD4%) and BMD data, the 
latest record within the window will be selected. 

For other numeric observations, the record closest to the nominal day for that visit within the 
window will be selected. If there are 2 records equidistant from the nominal day, the latest 
will be selected.

If there is more than one record on the selected day, the average will be taken 
(geometric mean for HIV-1 RNA and arithmetic mean for others).

For baseline and postbaseline HIV-1 RNA, the latest (considering both date and time) 
record(s) in the window will be selected. If both 'HIV RNA Taqman 2.0' and 'HIV RNA 
Repeat' (ie, the HIV-1 RNA result obtained from an additional aliquot of the original sample) 
are available with the same collection date/time, the results from the 'HIV RNA Repeat' will 
be selected for analysis purposes; otherwise, if there are multiple 'HIV RNA Taqman 2.0' 
records with the same collection date/time, the geometric mean will be taken for analysis 
purposes.
3.7.3.2.
Categorical Observations

For baseline, the last available record prior to the date of the first dose of the study drug will 
be selected. If there are multiple values recorded on the same day with the same time or 
missing time, select the value with the lowest severity.

For postdose visits, the most conservative value (eg, abnormal will be selected over normal, 
or the value with the highest severity) within the window will be selected.


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SUBJECT DISPOSITION 
4.1. 
Subject Enrollment 
Final 
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The number and percentage of subjects enrolled will be smmnarized by each country and by 
each investigator within a country. The denominator for this calculation will be the number of all 
enrolled subjects. 
A listin of enrollment, includin infonned consent date, enrollment status for the main phase 
, will be provided. 
Screen failure subjects will be listed, including screening number, inclusion criteria not met, and 
exclusion criteria met. 
4.2. 
Disposition of Subjects 
A smmnary of subject disposition will be provided for all screened subjects. This summary will 
include the number of subjects screened, screened subjects who were not enrolled, screen failure 
subjects who were not enrolled, subjects enrolled, subjects in the Safety Analysis Set, and 
subjects in the FAS. 
In addition, the nmnber and percentage of subjects in the following categories will be 
smmnarized: 
a) Still on study drug in the main phase 
b) Prematurely discontinued study treatment in the main phase (with smmnary of reasons for 
discontinuing treatment) 
c) Completed study treatment in the main phase 
d) Still on study treatment in the main phase 
e) Prematurely discontinued study in the main phase (with smmnary ofreasons for 
discontinuing study). 
f) Completed study in the main phase 
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The denominator for the percentages of subjects in each cate o 
in the Safet Anal sis Set for items a through 
4.3. 
4.3.1. 
Extent of Exposure 
Duration of Exposure to Study Drug 
Final 
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Duration of exposure will be calculated in the Safety Analysis Set for exposure during the entire 
study for all subjects. 
Duration of exposure during the entire study will be expressed in weeks (recorded to 1 decimal 
place for week, eg, 4.5 weeks), and calculated as (Date of last dose 
Date of first dose + 1) / 7, 
regardless of temporary interruptions in study drug administration. If subjects are still on study 
drug, the last dose date will be imputed for the calculation of study drug exposure using 
instructions provided in Appendix 7. 
Duration of exposure to study drug will be smmnarized using descriptive statistics (sample size, 
mean, SD, median, first quartile [Ql], third quartile [Q3], minimmn, and maximmn) and as the 
number and percentage of subjects exposed for specified periods, eg, 
1 week (7 days), 
2 weeks (14 days),~ 4 weeks (28 days),~ 8 weeks (56 days),~ 12 weeks (84 days). 
Summaries will be provided using the Safety Analysis Set. 
Time to premature discontinuation of study drug will be analyzed using the Kaplan-Meier 
method using the Safety Analysis Set. Subjects who are still on study drug will be censored on 
the imputed last dose date. 
4.3.2. 
Adherence with Study Drug 
Study drug adherence will be computed based on pill counts. The numbers of pills of study drug 
dispensed and returned are captured on the study drug accountability eCRF. 
Adherence(%) to the study drug will be calculated as follows: 
Number of pills taken 
Adherence(%) = 100 x ----------
Number of pills prescribed 
= 100 
Sum of Number of pills taken at each dispensing period [1] 
x--------------------------
Sum of Number of pills prescribed at each dispensing period [2] 
( l] Number of pills taken at each distinct dispensing period is calculated as the minimum of a) the daily number of pills 
prescribed multiplied by the duration of treatment at each dispensing period, and b) number of pills taken (number of 
pills dispensed minus the number of pills returned). Total number of pills taken is detem1ined by summing the number of 
pills taken from all evaluable dispensing periods. 
(2] Number of pills prescribed at each distinct dispensing period is calculated as the daily number of pills prescribed 
multiplied by the duration of treatment at each dispensing period. Total number of pills prescribed is detem1ined by 
summing the number of pills prescribed from all evaluable dispensing periods. 
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The duration of treatment at each dispensing period is calculated as the minimum of (the last 
returned date of the same dispensing period, the date of permanent discontinuation of study drug, 
and next pill dispensing date) minus the dispensing date. The next pill dispensing date is the 
following dispensing date of the study drug regardless of the bottle return date.
For a record where the number of pills returned was missing (with “Yes” answered for 
“Was Bottle returned?” question), it is assumed the number of pills returned was 0. If the number 
of pills dispensed was missing or any study drug bottle was not returned or the bottle return 
status was unknown for the same dispensing date, all records for the same dispensing date will 
be excluded from both denominator and numerator calculations.
Overall adherence will be calculated for each subject either up to the date of permanent 
discontinuation of the study drug for subjects who permanently discontinued study drug or 
completed study drug or using all data available for subjects ongoing on study drug.
Descriptive statistics for overall adherence with the study drug (sample size, mean, SD, median, 
Q1, Q3, minimum, and maximum) together with the number and percentage of subjects in
adherence categories (eg, < 80%, ≥80% to < 90%, ≥90% to < 95%, ≥95%) will be provided for 
the Safety Analysis Set. No inferential statistics will be provided.
Drug accountability and adherence data will be listed.
4.4.
Protocol Deviations
A listing will be provided for subjects in the Safety Analysis Set who violate at least
1 inclusion or exclusion criteria. The listing will include the eligibility criteria not met.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations and the 
total number of important protocol deviations by deviation reason (eg, nonadherence to study 
drug, violation of select inclusion/exclusion criteria) will be summarized for the Full Analysis 
Set for all important protocol deviations and important protocol deviations related to COVID-19.
The number and percentage of subjects with 1, 2 and ≥ 3 important protocol deviations related to 
COVID-19 will be summarized. The subjects with 1, 2 and ≥ 3 non-important protocol 
deviations related to COVID-19 will be summarized similarly as well. By-subject listings will be 
provided for those subjects with important protocol deviations and for those with either 
important protocol deviations or non-important protocol deviations related to COVID-19.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex, race, and ethnicity, age groups [2-5 years old, 6-11 years 
old]) and baseline characteristics (eg, body weight, weight Z-score, height, height Z-score, body 
surface area [BSA], body mass index [BMI], and Tanner Stage) will be summarized using 
descriptive statistics for all subjects in the Safety Analysis Set. The BSA will be calculated using 
the formula, BSA (m2)
SQRT([Height(cm) × Weight(kg)] / 3600). The percentage of subjects 
who reach Tanner Stage 4 or 5 will also be summarized. The sample size, mean, SD, median, 
Q1, Q3, minimum, and maximum will be provided for continuous data, and the number and 
percentage of subjects will be provided for categorical data. Age is calculated as age in years at 
first dose of study drug. The definition of baseline value is provided in Section 3.7.1.
In addition, the following baseline disease characteristics will be summarized:

HIV-1 RNA categories (copies/mL): < 50 and ≥50 

CD4 cell count (cells/µL) 

CD4 cell count categories (cells/µL): a) < 199, b) 200 to < 349, c) 350 to < 499, and d) ≥500 

CD4 percentage (%)

HIV disease status

Mode of infection (HIV risk factor)

Years diagnosed with HIV (to be calculated as time prior to first dose date, capped by the
subject’s age)

HBV surface antigen 

HCV antibody 

eGFR calculated by the Schwartz Formula (Section 7.4.2)

Proteinuria by urinalysis (dipstick)
Demographic characteristics, baseline characteristics, and baseline disease characteristics data 
will be listed for all enrolled subjects. The baseline ARV regimen, defined as the ARV regimen 
the subjects received on the day before the first dose date, will be summarized.
5.2.
Medical History
The HIV/AIDS-specific medical history and general medical history (ie, conditions not specific 
to the disease being studied) data will be listed only. Medical history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Definition of the Efficacy Endpoints
6.1.1.
Efficacy Endpoints
The efficacy endpoints include:

The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as 
defined by the United States (US) FDA-defined snapshot algorithm {Smith et al 2011}

The change from baseline in CD4 cell count (cells/µL) and percentage at Weeks 24 and 48

The percentage of subjects with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 
(Missing
Failure and Missing  Excluded analyses) 
6.1.2.
US FDA-Defined Snapshot Algorithm
The analysis window at Week 24 is defined as from Study Day 140 to Study Day 195, inclusive. 
All HIV-1 RNA data collected on-treatment (eg, data collected from Study Day 1 up to 1 day 
after the last dose date of study drug) will be used in the US FDA-defined snapshot algorithm. 
Virologic outcome will be defined as the following categories:

HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the Week 24 analysis window

HIV-1 RNA ≥ 50 copies/mL: this include subjects
1) Who have the last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the Week 24 
analysis window, or
2) Who do not have on-treatment HIV-1 RNA data in the Week 24 analysis window and
a) Who discontinue study drug prior to or in the Week 24 analysis window due to lack 
of efficacy, or
b) Who discontinue study drug prior to or in the Week 24 analysis window due to AE or 
death and have the last available on-treatment HIV-1 RNA ≥50 copies/mL, or
c) Who discontinue study drug prior to or in the Week 24 analysis window due to 
reasons other than AE, death, or lack of efficacy and have the last available on-
treatment HIV-1 RNA ≥50 copies/mL


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
No Virologic Data in Week 24 Window: this includes subjects who do not have 
on-treatment HIV-1 RNA data in the Week 24 analysis window because of the following:
1) Discontinuation of study drug prior to or in the Week 24 analysis window due to AE or 
death and the last available on-treatment HIV-1 RNA < 50 copies/mL, or
2) Discontinuation of study drug prior to or in the Week 24 analysis window due to reasons 
other than AE, death, or lack of efficacy and the last available on-treatment HIV-1 RNA 
is < 50 copies/mL, or
3) Missing data during the window but on study drug.
The flowchart of the snapshot algorithm is provided in Appendix 3.
The snapshot outcomes at Week 48 will also be summarized at this analysis. The analysis 
window for Week 48 is from Day 308 to Day 377, inclusive.
6.1.3.
Missing  Failure and Missing  Excluded Analyses
Virologic response, defined as HIV-1 RNA < 50 copies/mL, will also be analyzed using the 
following 2 methods for imputing missing HIV-1 RNA values:

Missing  Failure (M
 F)
In this approach, all missing data will be treated as virologic failure (ie, HIV-1 RNA 
≥50 copies/mL). This analysis will be done using the FAS.

Missing
 Excluded (M
 E) 
In this approach, all missing data will be excluded in the computation of virologic response 
(ie, missing data points excluded from both the numerator and denominator in 
response rate computation).
6.2.
Analysis Methods for Efficacy Endpoints
The analyses for all the efficacy endpoints will be conducted using the FAS. 
The numbers and percentages of subjects with HIV-1 RNA < 50 copies/mL based on
US FDA-defined snapshot algorithm, M  F analysis, and M  E analysis, will be summarized. 
The 95% CI for the percentage estimate in the M  F analysis and M  E analysis will be 
constructed using the Exact method. For the snapshot algorithm, the numbers and percentages of 
subjects with HIV-1 RNA < 50 copies/mL, HIV-1 RNA ≥ 50 copies/mL (including 
subcategories), and no virological data (including reasons) will be summarized. For the M
F 
analysis, results will be summarized for all visits up to Week 48. For the M  E analysis, results 
will be summarized at all visits through the data cut date for the FAS.


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The CD4 cell count and CD4% data will be summarized using observed, on-treatment data 
(ie, up to 1 day after the last dose date of study drug). The baseline values and changes from 
baseline in CD4 cell count (cells/μL), and CD4% at each visit will be summarized descriptively 
(sample size, mean, SD, 95% CI, median, Q1, Q3, minimum, and maximum). The mean and 
95% CI of change from baseline over time will be plotted.
A listing for plasma HIV-1 RNA, CD4 cell count, CD4%, and a listing for snapshot outcome 
will be provided.
6.3.
Changes From Protocol-Specified Efficacy Analyses
The secondary efficacy endpoint for the percentage of subjects with plasma HIV-1 RNA 
< 400 copies/mL at Weeks 24 and 48, as defined by the FDA snapshot analysis, was removed, 
because Cohort 3 is comprised of virologically suppressed subjects and these endpoints do not 
apply.


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7.
SAFETY ANALYSES
Safety data will be summarized for the subjects in the Safety Analysis Set. All safety data 
collected on or after the date of the first dose of study drug up to the last dose date of study drug 
plus 30 days will be summarized, unless specified otherwise. All safety data will be included in 
data listings.
7.1.
Adverse Events
7.1.1.
Adverse Event Dictionary
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). System organ class (SOC), high-level group term (HLGT), high-level 
term, preferred term (PT), and lower-level term will be attached to the clinical database.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe) or Grade 4 (life threatening) according to toxicity criteria specified in
Appendix 4 of the study protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for data listings and will be considered the least 
severe for the purposes of sorting for data presentation.
7.1.3.
Relationship of AEs to Study Drug
Related AEs are those for which the investigator answers ‘Related’ to the question 
‘Related to Study Treatment?’ in the eCRF. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. Data 
listings will show relationship as missing.
7.1.4.
Relationship of AEs to Study Procedure
Adverse events for which “Yes” is marked for the question “Related to Study Procedures?” in 
the eCRF will be identified and included in the AE listing.
7.1.5.
Serious AEs
Serious AEs are those identified in the eCRF, where “Yes” was marked for “AE serious”. The 
clinical database will be reconciled with the SAE database (from the Global Patient Safety
Department) before database finalization.
7.1.6.
Treatment Emergent AEs
7.1.6.1.
Definition of Treatment Emergent
Treatment-emergent AEs (TEAEs) are events that meet one of the following criteria up to 
30 days after the permanent discontinuation of the study drug:

Events with onset dates on or after the first dose date of study drug 

Events that result in permanent study drug discontinuation


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7.1.6.2.
Incomplete Dates
If the date of onset is incomplete or completely missing, the detailed definition of TEAE is 
specified in Appendix 7.
7.1.7.
Summaries of AEs and Deaths
A brief summary of AEs will show the number and percentage of subjects who a) had any 
treatment-emergent AE, b) had any Grade 3 or 4 treatment-emergent AE, c) had any 
Grade 2, 3, or 4 treatment-emergent AE, d) had any treatment-emergent study-drug-related AE, 
e) had any Grade 3 or 4 treatment-emergent study-drug-related AE, f) had any Grade 2, 3, or 4 
treatment-emergent study-drug-related AE, g) had any treatment-emergent SAE, h) had any 
treatment-emergent study-drug-related SAE, i) had any treatment-emergent AE leading to 
premature study-drug discontinuation, and j) had treatment-emergent death.
Treatment-emergent death refers to a death that occurred between the first dose date and the last 
dose date plus 30 days (inclusive).
Summaries (number and percentage of subjects) of AEs (by SOC and PT) will be provided using 
the Safety Analysis Set as follows:

All treatment-emergent AEs 

All treatment-emergent AEs by PT

Grade 3 or 4 treatment-emergent AEs

Grade 2, 3, or 4 treatment-emergent AEs

All treatment-emergent study-drug-related AEs 

Any Grade 3 or 4 treatment-emergent study-drug-related AEs 

Any Grade 2, 3, or 4 treatment-emergent study-drug-related AEs

All treatment-emergent SAEs

All treatment-emergent study-drug-related SAEs

All treatment-emergent AEs that caused premature discontinuation from study drug

AEs for COVID-19 and Suspected COVID-19 infection, defined as in Appendix 5.
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC will be ordered alphabetically, with PT sorted by decreasing total frequency. For 
summaries by severity grade, the most severe event will be selected.


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In addition to the summaries, data listings will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Study-drug related SAEs

Death report

Pregnancy report

AEs leading to premature discontinuation of study drug
7.1.8.
Category C Events
On an ongoing basis, AEs will be reviewed for events that might meet the definition of 
Category C events that are indicative of an AIDS-Defining Diagnosis (see Protocol Appendix 6). 
Gilead medical personnel will review the possible Category C events and approve the events that 
meet the definition. Events that meet the Category C definition of an AIDS-Defining Diagnosis 
will be listed.
7.2.
Laboratory Evaluations
Summaries of laboratory data will be provided for the Safety Analysis Set. Analysis will be 
based on values reported in conventional units. 
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided for each laboratory test specified in the study protocol as follows: 

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window

Percentage change from baseline to each postbaseline analysis window (if specified)
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.


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7.2.1.1.
Metabolic Assessments
For the lipid panel and glucose, only those measurements under fasting status will be 
summarized.
7.2.1.2.
Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized for the study. The following 
formula will be used when both serum calcium and albumin results for a given blood draw are 
available and serum albumin value is < 4.0 g/dL:
Calcium corrected for albumin (mg/dL)  serum calcium (mg/dL) + 0.8 × (4.0 albumin [g/dL])
Toxicity grading for calcium will be applied based on the corrected values.
7.2.2.
Graded Laboratory Values
The criteria specified in the protocol will be used to grade laboratory results as Grade 0, 
mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4). Grade 0 
includes all values that do not meet criteria for an abnormality of at least Grade 1. Some 
laboratory tests have criteria for both increased and decreased levels; analyses for each direction 
(ie, increased, decreased) will be presented separately.
Maximum postbaseline grade, instead of treatment-emergent grade, for nonfasting glucose will 
be summarized, as nonfasting glucose was not assessed at the baseline visit.
For triglycerides and cholesterol, the protocol-specified toxicity grading scale is for fasting test 
values, so nonfasting lipid results (or lipid results without known fasting status) will not be 
graded or summarized by toxicity grades.
If there is any laboratory toxicity grading scale overlapping with normal reference ranges 
(eg, Grade 1 scale overlaps with normal reference ranges), laboratory values within normal range 
will not be graded, except lipid tests.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
one toxicity grade from baseline at any time postbaseline up to and including the date of 
last dose of study drug plus 30 days. If the relevant baseline laboratory data are missing, 
any laboratory abnormality of at least Grade 1 is considered treatment-emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) of laboratory abnormalities will 
be provided (subjects categorized according to most severe abnormality grade):

Treatment-emergent laboratory abnormalities

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For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values in the given study period. Listings will be provided for 
treatment-emergent laboratory abnormalities and treatment-emergent Grade 3 or Grade 4 
laboratory abnormalities.
7.2.2.3.
Liver-Related Laboratory Tests
The number and percentage of subjects will be summarized for the following liver-related 
laboratory tests and categories:

Aspartate aminotransferase (AST): (a) > 3 × upper limit of normal (ULN), (b) > 5 × ULN, 
(c) > 10 × ULN, (d) > 20 × ULN

Alanine aminotransferase (ALT): (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, 
(d) > 20 × ULN

AST or ALT: (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, (d) > 20 × ULN

Total bilirubin: (a) > 1 × ULN, (b) > 2 × ULN

Alkaline phosphatase (ALP) > 1.5 × ULN

AST or ALT > 3 × ULN and total bilirubin: (a) > 1.5 × ULN, (b) > 2 × ULN

AST or ALT > 3 × ULN and total bilirubin > 2 × ULN and ALP < 2 × ULN
The summary will use data from all the postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For the composite endpoint of AST or ALT and total bilirubin, and 
the composite endpoint of AST or ALT, total bilirubin, and ALP, subjects will be counted once
when the criteria are met at the same postbaseline visit date. The denominator is the number of 
subjects in the Safety Analysis Set with nonmissing postbaseline values of the tests in evaluation 
at the same postbaseline visit date. 
Subjects with AST or ALT > 3 × ULN will be listed. 
7.3.
Bone Safety Analyses
7.3.1.
Bone Mineral Density
The BMD will be evaluated in 2 body sites: spine and TBLH. BMD standard Z-score will be
computed based on the chronological age-matched population of the same sex and ethnicity.
BMD height-age Z-score will be generated by substituting height-age for chronological age, 
where height-age will be determined as the age at which the child’s height is the median on the 
stature-for-age Centers for Disease Control (CDC) Year 2000 growth chart published on the 
following CDC website: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm


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If a subject’s height is greater than the median height for a 20-year-old according to the growth 
chart, both height-age and height-age Z-score will not be calculated. The BMD Z-scores 
(standard Z-score and height-age Z-score) will be calculated for the 2 body sites (ie, spine and
TBLH). For some subjects whose BMD Z-scores (standard Z-score and height-age Z-score)
cannot be computed because there is no reference population data, the extrapolated BMD 
Z-scores will be computed instead.
Percentage change from baseline in spine and TBLH BMD will be summarized by visit using 
descriptive statistics for subjects in the spine and TBLH DXA analysis sets, respectively.
Descriptive summaries for the BMD Z-scores (standard Z-score and height-age Z-score) and the 
change from baseline in Z-scores (standard Z-score and height-age Z-score) will be presented by 
visit for the spine and TBLH DXA Analysis Sets.
Shift tables of the clinical BMD status at baseline versus postbaseline visits will be presented for 
both spine and TBLH BMD. Clinical BMD status will be classified into 2 categories using the 
BMD Z-scores (standard Z-score and height-age Z-score): Z-scores > 2 versus Z-scores ≤
2 
{Gordon et al 2008}. The number and percentages of subjects with at least 4% decline in BMD 
from baseline to each postbaseline visit will be summarized by visit for the spine and TBLH
DXA Analysis Sets.
A listing of subjects with at least 4% decline from baseline in BMD from at least one of the body 
sites (ie, spine and TBLH) at any postbaseline visit will be provided. The BMD values, standard 
BMD Z-score, height-age BMD Z-score, and height-age will be listed. Listings of subjects with 
BMD Z-score ≤
2 at any postbaseline visit in spine and/or TBLH BMD based on standard 
Z-scores and height-age Z-scores, respectively, will also be provided. 
7.3.2.
Bone Safety Assessments
Bone safety assessments include the following in serum: bone-specific alkaline phosphatase, 
parathyroid hormone [PTH], 25-OH vitamin D, and 1, 25-OH vitamin D.
Baseline, postbaseline, changes from baseline, and percentage change from baseline in bone 
safety assessments will be summarized by visit using descriptive statistics.
7.3.3.
Fracture Events
The preferred terms included in analysis for fracture events are defined based on the
Standardized MedDRA Query (SMQ) of osteoporosis/osteopenia of fractures from MedDRA. 
The list of PTs selected by clinical review from all the PT terms under SMQ of 
osteoporosis/osteopenia fractures and HLGT of fractures is presented in Appendix 4. Fracture 
events will be listed only.


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7.4.
Renal Safety Analyses
7.4.1.
Serum Creatinine
The baseline and change from baseline in serum creatinine will be summarized by visit using 
descriptive statistics. 
7.4.2.
Estimated Glomerular Filtration Rate
The following formula will be used to calculate eGFR: 
Schwartz Formula: eGFR (ml/min/1.73m+) = k × L/SCr,
where k is the proportionality constant (0.55 for children [2-11 years old] or adolescent girls 
≥12 years old; 0.70 for adolescent boys ≥12 years old), L is height (cm), SCr is serum 
creatinine (mg/dL).
Change from baseline in eGFR at each postbaseline visit will be provided.
7.4.3.
Urine Retinol Binding Protein to Creatinine Ratio and Beta-2-Microglobulin 
to Creatinine Ratio
Baseline, postbaseline, change from baseline, and percentage change from baseline in urine 
retinol binding protein (RBP) to creatinine ratio and beta-2-microglobulin to creatinine ratio will 
be summarized by visit using descriptive statistics.
7.4.4.
Proteinuria by Quantitative Assessment
Subjects will be classified into three categories based on their urine protein (UP) and urine 
protein to creatinine ratio (UPCR) results: UPCR ≤ 200 mg/g (including subjects with UP 
< 4.0 mg/dL), UPCR > 200 mg/g, and Missing, where UPCR will only be calculated when UP 
≥4.0 mg/dL. The number and percentage of subjects in each UP and UPCR category will be 
summarized by baseline category at Weeks 8, 12, 24, 48.
7.5.
Tanner Stage Assessment
Tanner Stages will be used to evaluate the onset and progression of pubertal changes for children 
who are 6 years or older. Females will be rated for pubic hair growth and breast development, 
and males will be rated for pubic hair growth and genitalia development. The Tanner Stages 
(Pubic Hair and Breasts for female; Pubic Hair and Genitalia for male) at each postbaseline visit 
will be summarized by baseline Tanner Stages using frequency count and percentage.
Tanner Stage results at screening and during the study will be listed.


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7.6.
Palatability/Acceptability Assessment
Palatability and acceptability assessments will be summarized by visit (baseline, Week 4, 
Week 24, and Week 48) using frequency count and percentage and will be listed.
7.7.
Body Weight, Height, and Vital Signs
Body weight and height at each visit and change from baseline in body weight and height at each 
visit will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) by visit. 
An age- and sex-specific Z-score will be derived for each weight and height measurement 
according to the downloadable SAS program available on the Centers for Disease Control (CDC) 
website using the year 2000 growth charts. The methods and SAS program published on the 
following CDC websites will be applied to calculate the Z-score:
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm
Z-scores for body weight and height at each visit and change from baseline in Z-scores for 
postbaseline body weight and height will be summarized by visit. In the case of multiple values 
in an analysis window, data will be selected for analysis as described in Section 3.7.3. 
Body weight, weight Z-score, height, height Z-score, BMI, and BSA will be listed. Vital signs 
will be presented in data listings only.
7.8.
Nonstudy-Drug Antiretroviral Medications
Nonstudy-drug ARV medications used prior to the study, during study, and after study 
(if collected), will be coded using the GSI-modified World Health Organization (WHO) Drug 
Dictionary. The WHO preferred name and drug code will be attached to the clinical database. All 
nonstudy-drug ARV medications will be listed. 
Nonstudy-drug ARV medication with an end date on or one day before the first dose date of 
study drug will be considered as nonstudy-drug ARV medication received immediately prior to 
the first dose date of study drug (or pre-switch ARV used).
Nonstudy-drug ARV medication received immediately prior to the first dose date of study drug 
will be summarized by ARV drug class and generic name for subjects in the Safety Analysis Set. 
Multiple drug use (by drug class or generic name) will be counted only once per subject. Drug 
classes will be presented alphabetically and generic names within each drug class will be
presented by descending order of total frequency. No inferential statistics will be provided.


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7.9.
Concomitant Non-ARV Medications
Nonantiretroviral concomitant medications (ie, medications other than study drug that are taken 
while receiving study drug) will be coded using the WHO Drug Dictionary. The WHO preferred 
name and drug code will be attached to the clinical database. Use of concomitant medications 
from Study Day 1 up to the date of last dose of study drug will be summarized (number and 
percentage of subjects) by preferred name. Multiple drug use (by preferred name) will be 
counted once only per subject. The summary will be sorted alphabetically by drug class and then 
by decreasing total frequency within a class.
If the start or stop date of a nonantiretroviral medication is incomplete, the month and year 
(or year alone if month is not recorded) of the start or stop date will be used to determine 
whether the non-ARV is concomitant or not as follows. The medication is concomitant if the 
month and year of start or stop (or year of the start or stop) of the medication do not meet any of 
following criteria:

The month and year of start of the medication is after the date of the last dose of study drug

The month and year of stop of the medication is before the date of the first dose of study drug
If the start and stop date of a non-ARV medication is not missing, the start date is not after last 
dose date and the stop date is not before first dose date, or the non-ARV medication is marked as 
ongoing and start date is on or before last dose date, the non-ARV medication is concomitant.
Subjects with any non-ARV concomitant medications will be listed.
7.10.
Electrocardiogram Results
The ECG data collected at screening and early study drug discontinuation will be listed.
7.11.
Other Safety Measures
Hepatitis test results will be listed. A data listing will be provided for subjects experiencing 
pregnancy during the study.
7.12.
Missed and Virtual Visits due to COVID-19
A summary of subjects affected by the COVID-19 pandemic will be provided for each scheduled 
study visit. For each visit the summary will present the number and percentage of subjects who 
completed the visit as per protocol, missed the visit due to COVID-19, had a virtual visit due to 
COVID-19, or missed the visit for reasons other than COVID-19. For each column, the 
denominator for the percentage calculation will be the total number of subjects in the safety 
population for that column.
The determination of missing or virtual visits due to COVID-19 was done using Natural 
Language Processing (NLP) to search the CRF comment fields. A detailed explanation of the 
algorithm is given in Appendix 6. 
A by-subject listing will be provided by subject ID number in ascending order to support the 
above summary table.
7.13.
Changes from Protocol-Specified Safety Analysis
There is no change from protocol-specified safety analyses.


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8. 
PHARMACOKINETICS ANALYSIS 
Final 
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Only intensive PK parameters intensive PK concentrations and trou h PK concentrations will be 
summarized in this anal sis. 
Single PK will be included in a future 
Population PK analysis. 
8.1. 
Analysis Methods for Trough PK 
Plasma concentration data will be listed for all subjects. EVG, COBI, FTC, TFV trough samples, 
defined as the sampling time within a range of [20.0, 28.0] hours after observed dosing time, will 
be marked and included for smmnary statistics. Spare samples may be used for population PK 
assessment. Plasma concentrations for TAF will be listed only and will not be smmnarized. 
The following TFLs will be provided for the trough PK sampling: 
• 
Table with individual subject concentration data for EVG, COBI, FTC, TFV 
• 
Listing of PK sampling details 
• 
Listing of study drug administration record for PK dosing. 
8.2. 
Statistical Analysis Methods for Intensive PK 
The PK parameters for the 5 analytes (ie, TAF, EVG, COBI, FTC, and TFV) will be estimated 
for all subjects in the Intensive PK Analysis Set. 
The PK parameters to be estimated in this study are listed and defined in Appendix 1. 
In Cohort 3, the primary endpoints are the PK parameters of AUCtau for EVG and TAF. The 
secondary endpoints include PK parameters of C1au, Cmax, apparent CL/F and apparent V JF for 
EVG; Cmax, apparent CL/F and apparent V.JF for TAF; AUC1au, Cmax, and C1au for FTC, TFV, 
and COBI. 
8.3. 
Estimation of PK Parameters 
The PK parameters will be estimated by application of a nonlinear model using standard 
noncompartmental methods (WinNonlin® software v6.3). The linear up/log down trapezoidal 
rule will be used in conjm1ction with the appropriate noncompartmental model (usually input 
Model 200 for oral dosing), with input values for dose, time of dose, plasma concentration, and 
corresponding real time values, based on drug dosing times whenever possible. 
All baseline (predose) sample times will be assigned a concentration value of 0. Samples below 
the limit of quantitation of bioanalytical assays that occur prior to the achievement of the first 
quantifiable concentration will be assigned a concentration of O to prevent overestimation of the 
initial AUC. Samples that are BLQ at all other time points will be treated as missing data. The 
nominal time point for a key event ( eg, urine collection) or dosing interval (t) may be used to 
pennit direct calculation of A UC over specific time intervals. The appropriateness of this 
approach will be assessed by the phannacokineticist on a profile-by-profile basis. 
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Accurate estimation of several PK parameters, such as z, and t½, are dependent on the measured 
terminal elimination phase of the drug. The appropriateness of calculating these parameters will 
be evaluated upon inspection of PK data on a profile-by-profile basis by the pharmacokineticist.
A list of individual data on determination of plasma half-life and corresponding correlation 
coefficient will be provided, including intensive PK sampling day, number of data points in 
regression, start time, end time, and correlation coefficient.
8.4.
Statistical Analysis Methods
8.4.1.
General Considerations for Statistical Analyses
Plasma concentration data will be listed for all dosed subjects and summarized by nominal time 
point for the Intensive PK analysis set.
The PK parameters estimated for each analyte will be listed for all dosed subjects and 
summarized for the Intensive PK Analysis Set. For PK parameters, values that are incalculable 
will be excluded from the summary statistics.
The descriptive statistics (sample size, mean, SD, coefficient of variation [%CV], minimum, 
median, maximum, Q1, and Q3) will be presented for PK concentration data. The number of 
subjects with value of BLQ will be presented at each nominal time point.
For some PK parameter data (ie, Cmax, Ctau, AUClast, AUCtau, CL/F, and Vz/F), the geometric 
mean, its 95% CI, and the mean and SD of the natural-log transformed values will be presented 
in addition to the summaries mentioned above.
Missing plasma concentrations due to missed sample collection will be excluded from the 
figures, summary statistics, and log-normalized data.
The following tables, figures, and listings (TFLs) will be provided for each analyte for Week 2
intensive PK analysis using the Intensive PK Analysis Set:

Table of individual subject PK parameters and summary statistics for each analyte

Listing of the time points used in the calculation of the terminal elimination rate constant z
for each analyte

Listing of PK sampling details by subject including deviations in scheduled and actual draw 
times and procedures, individual blood sampling time deviations in minutes.

Listing of study drug administration record for intensive PK dosing
Listing of PK sample details and listing of study drug administration record for the intensive PK 
samples will be combined for presentation. 


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8.4.2.
Statistical Comparative Analysis 
To determine whether the low-dose tablet in children achieves similar systemic exposure to that 
in adults, statistical comparisons will be performed to compare the PK data from the current 
study with combined adult data included in the Genvoya label. More specifically, the 
comparisons will be carried out as follows.

For PK parameters for analytes TAF and TFV, the statistical comparison will be with the 
841 E/C/F/TAF-treated adults in Studies GS-US-292-0104 and GS-US-292-0111 who were 
included in the population PK modeling.

For PK parameters for analytes EVG, COBI and FTC, the statistical comparison will be with 
the 19 E/C/F/TAF-treated adults who participated in the GS-US-292-0102 PK substudy.
For TAF, a one-way analysis of variance (ANOVA) model will be fitted to the natural 
logarithmic transformed values of AUCtau (as the primary endpoint), AUClast, Cmax (as the 
secondary endpoint) respectively with treatment group as a fixed effect. The treatment groups are 
defined as the test treatment (children in this study) and reference treatment (adults from 
historical studies).
For EVG, COBI, FTC, and TFV, the PK parameters of AUCtau, Cmax, and Ctau will be analyzed 
similarly.
The ANOVA model will be carried out using the PROC MIXED procedure in SAS. An example 
SAS code is provided below: 
Proc Mixed;
by analyte paramcd; 
class group subjid;
model lnest = group;
repeated / group = group;
lsmeans group / e  diff cl alpha = 0.1;
estimate ‘Test versus Reference’ group  1 1 / cl alpha = 0.10; 
Run;
The geometric least-squares means (LS-means) of each treatment group, mean ratio 
(test/reference) and corresponding 90% CI for each PK parameter (ie, AUCtau, Cmax, and Ctau) of 
the analytes will be reported. 
The LSMEANS statement computes LS-means for each treatment group on the natural log scale. 
These values will then be exponentiated to produce the geometric LS-means on the original 
linear scale.
The ESTIMATE statement will produce the point estimate and 90% CI on the natural-log scale 
for the difference between treatments. The test/reference exposure ratio and associated 90% CIs
will be calculated by exponentiation of the natural-log scale point estimate and the associated 
90% CI lower and upper limits.


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For each analyte, 90% CIs for the ratio of the geometric LS (GLS) means of the test (children in 
this study) and reference (adults from historical studies) treatments will be calculated for AUCtau, 
Ctau, andCmax, consistent with the two 1-sided tests each performed at an alpha level of 0.05 {U.S. 
Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) 2003}, {U.S. Department of Health and Human Services Food 
and Drug Administration Center for Drug Evaluation and Research (CDER) 2001}. The 
equivalency in PK will be concluded if the 90% CIs are within the equivalence boundaries of 
70% to 143%.
In addition, the 95% CIs for the geometric means of apparent CL/F and Vz/F will be calculated 
for TAF, EVG, COBI, FTC, and TFV, and the ratios of the lower and upper bounds of the 
95% CIs versus the point estimate of the geometric means will be compared to the interval of 
60% to 140% of their respective parameters. 
8.5.
Changes from Protocol-Specified PK Analysis
There is no change from protocol-specified PK analyses.


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9.
REFERENCES
Gordon CM, Bachrach LK, Carpenter TO, Crabtree N, El-Hajj Fuleihan G, Kutilek S, et al. Dual 
energy X-ray absorptiometry interpretation and reporting in children and 
adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 2008;11 
(1):43-58.
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol 2009;20 (3):629-37.
Smith F, Hammerstrom T, Soon G, Zhou S, Chen B, Mai Y, et al. A meta-analysis to assess the 
FDA DAVP's TLOVR algorithm in HIV submissions. Drug Information Journal 
2011;45:291-300.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Revision 1. November 2015.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence.  January, 2001.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1).  March, 2003.


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10.
SOFTWARE
nQuery Advisor® (Statistical Solutions Ltd., Version 6.0, Cork, Ireland) will be used for the 
sample size and power calculation.
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) will be used for generating all TFLs. 
WinNonlin® (Pharsight Corporation Version 6.3, Mountain View, CA) will be used for all 
PK analyses.


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
PK Parameters
Appendix 2.
Study Procedures Table
Appendix 3.
Flowchart of US FDA-Defined Snapshot Algorithm
Appendix 4.
Fracture Events
Appendix 5.
COVID-19 and Suspected COVID-19 Infections
Appendix 6.
Determining Missing and Virtual Visits Due to COVID-19
Appendix 7.
Programming Specifications


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Appendix 1.
PK Parameters
PK parameters evaluated in this study are listed below.
Parameter
Description
AUCtau
area under the plasma drug concentration versus time curve over the dosing interval
AUClast
area under the plasma drug concentration versus time curve from time zero to the last quantifiable 
concentration
Cmax
maximum observed plasma drug concentration 
Ctau
observed plasma drug concentration at the end of the dosing interval
CL/F
apparent oral clearance after administration of the drug: 
at steady state: CL/F = Dose/AUCtau, where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
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 plasma concentration of drug versus time curve


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Appendix 2.
Study Procedures Table
Study Procedures
Screeninga
Baseline 
(Day 1)
Week 1 
(Day 7)
Week 2b
Intensive 
PKc
End of Weekb
30-Day 
Follow-upd ESDDe
4
8
12
16
24
32
40
48
Assent/Informed 
Consent
X
Medical History
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Exam
X
X
X
X
X
Symptom Directed 
Physical Examg
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tanner Stage 
Evaluationsh
X
X
X
12 lead ECG 
performed supine
X
HIV 1 Genotypei
X
Hematology Profilej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Profilek
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic 
Assessmentsl
Xff
Xee
X
X
Plasma HIV 1 RNAm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI


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Serologies 
X 
Urinalysis 
X 
X 
X 
Estimated Glomernlar 
X 
X 
X 
X 
Urine Pregnancy 
X 
X 
Testq 
Dispense Dosing 
Diary (for Part A 
x ff 
subjects, inclusive of 
Cohort 3) 
Review Dosing Diary 
(For Part A subjects, 
inclusive of Cohort 3) 
Single PK Samplingr 
Trough PK Samples 
Xee 
CONFIDENTIAL 
X 
X 
X 
X 
Xee 
Intensive 
X 
X 
X 
X 
X 
X 
X 
xz 
X 
x ff 
Page 44 
End ofWeekb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xdd 
X 
X 
X 
X 
X 
X 
X 
xdd 
X 
X 
X 
X 
Final 
Version 1.0 
X 
X 
X 
X 
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Study Procedures 
Bone Safetyw 
Urine Renal Safety' 
Study Dmg 
Dispensation 
In clinic DosingY 
Dmg Accountability 
Palatability and 
Acceptability 
Assessment 
X 
x ff 
xee 
x ff 
xee 
X 
X 
xbb 
Week l 
(Day 7) 
X 
X 
Intensive 
PKc 
4 
X 
X 
X 
X 
X 
X 
X 
End ofWeekb 
8 
12 
16 
24 
32 
40 
48 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xaa, bb xaa 
xaa 
a 
Evaluations to be completed within 35 days prior to Baseline (or 42 days for subjects who re.quire repeat testing of the HIV I genotype). 
Final 
Version 1.0 
30-Day 
Follow-upd ESDDe 
X 
xcc 
xcc 
b 
All study visits are to be scheduled relative to the Baseline/Day I visit date. Visit windows are ± 2 da s of the rotocol s ecified visit date from Week 2 through Week 8, 
± 4 days of the protocol specified visit date from Week 12 through Week 48, 
, unless otherwise specified. 
c 
Part A subjects only, inclusive of Cohort 3. The Intensive PK evaluation will occur at the Week 4 (Cohorts I and 2) or Week 2 (Cohort 3) visit. For the purpose of scheduling 
the Intensive PK visit, a + 7 days window may be used. If the subject has already dosed prior to the Intensive PK evaluation visit or is not in a fasted state, the Intensive PK 
assessments must not be completed. The subject should be instmcted to return in a fasted state within 7 days of their Week 4 (Cohorts I and 2) or Week 2 (Cohort 3)visit for 
the Intensive PK visit. 
d 
Only re.quired for those subjects not enrolling in the-
phase of the study or those subjects who pem1anently discontinue study dmg and do not continue in the study 
through at least one subsequent visit after the Early Study Dmg Discontinuation Visit. For the purpose of scheduling a 30 Day Follow Up Visit, a± 6 days window may be used. 
e 
ESDD visit should occur within 72 hours of last dose of study dmg. 
f 
Vital signs include blood pressure, pulse, respiration rate, and temperature. 
g 
Symptom directed physical examinations perfomied as needed. 
h 
Tanner assessments will be perfomied on sub·ects 2:: 6 ears of age and no longer be erfomied once a subject has been documented as Tanner Stage 5. Tanner stage 
assessments will be perfomied 
until subjects reach Tanner Stage 5, after which point Tanner assessments will no longer 
be perfomied. 
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Final 
Version 1.0 
Analysis for reverse transcriptase, protease and integrase resistance will be done at Screening. The investigator must have received the results from the Screening genotype 
before proceeding with the Baseline visit. (Cohort I only) 
j 
CBC with differential and platelet count. 
k 
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect bilirnbin, cystatin C (Cohorts I and 2; Baseline, Weeks 2 [Cohort I only], 4, 24, and 
48), total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, hos horns, ma nesium, otassium, sodium, CPK, and uric acid 
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 
If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return wit m 
ours ma aste state to raw oo 
or t e meta o 1c assessments. 
m 
For Part A subjects (inclusive of Cohort 3), back up samples will not be collected at Weeks I, 2, and 4 visits for Cohort I and at Weeks I through 16 for Cohorts 2 and 3. For 
Part B sub· ects back u sam les will be collected at all visits. 
I' 
0 r 
q 
Females of chtldbeanng potential only. Positive unne pregnancy tests will be con 1rn1ed with a semm test at any v1s1t. 
r 
Cohort I: a timed random PK sample collected at Week 4 (Cohort I Part B subjects only) and Week 12 (all Cohort I) between 0.24 4 hours post dose. A random PK sample 
collected at all other visits through Week 48. Cohort 2: a timed random PK at Week 12 between 0.24 4 hours post dose and Week 8 and Week 16 random single PK sample . 
Cohort 3: a random timed PK sample collected between 0.25 and 4 hours post dose at Week 8, 12, and 16. 
s 
Subjects must come into the clinic without taking their dose of E/C/Ffr AF STR and subjects should fast overnight (a minimum of 8 hours) .. A trough (20 to 24 hours 
post dose) plasma PK sample will be collected at Weeks I, 2, and 24 for subjects in Cohort I and 2 and Week 48 for Cohort I only. For subjects in Cohort 3, a trough sample 
will be collected at Weeks 4 and 24. 
Part A subjects only, inclusive of Cohort 3. Intensive PK sampling will be perforn1ed on Week 4 (Cohorts I and 2) or Week 2 (Cohort 3). For the purpose of scheduling the 
Intensive PK visit a + 7 days window may be used. If the subject has already dosed prior to the Intensive PK visit or is not in a fasted state, the Intensive PK assessments must 
not be completed. The subject should be instmcted to return within four days for the Intensive PK visit. If dosing non compliance is identified on or prior to the Intensive PK 
visit, the Intensive PK assessments must not be completed. The subject should be counseled regarding proper dosing and asked to return for the Intensive PK visit no sooner 
than three da s following com liant dosing and no later than Week 4 + 7 da s. Please refer to the PK/PBMC manual for sam le collection and rocessing details. 
I' 
V 
w 
o arts 
an 
, one sa ety me u mg: 
Semm: bicarbonate, N telopeptide, C telopeptide (CTX), osteocalcin, procollagen type I N tern1inal propeptide (P I NP) 
Urine: bicarbonate, N telopeptide 
For all cohorts, bone safety including: 
Semm: bone specific alkaline phosphatase, parathyroid horn10ne (PTH), 2501-1 Vitamin D and I, 2501-1 Vitamin D 
x 
Urine Renal Safety including: urine chemistry, retinal binding protein, and beta 2 microglobulin. 
4 and48 (± 10 days). -
y 
All subjects will be given their dose of E/C/Ffr AF STR with food. For those subjects that take their medication in the evening, the in clinic dosing will not be perforn1ed. 
z 
Cohort I Part B subjects only 
aa 
To be perforn1ed for all Cohort I subjects currently on study at their next scheduled visit. 
bb To be perforn1ed at Baseline and Week 4 for all Cohort 2 subjects and at Baseline, Weeks 4, 24, and 48 for all Cohort 3 subjects enrolled. 
cc To be perforn1ed at ESDD or 30 Day Follow Up visit for either Cohort I or 2, as applicable. 
dd 
Cohort I subjects only 
ee 
Cohort I and 2 subjects only 
ff 
Cohort 3 subjects 
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Final 
Version 1.0 
Appendix 3. 
Flowchart of US FDA-Defined Snapshot Algorithm 
The following flowchart for US FDA-defined snapshot algorithm in switch trial is based on the 
US FDA Guidance on Human bmnunodeficiency Virus-1 Infection: Developing Antiretroviral 
Drugs for Treatment {U. S. Department of Health and Human Services et al 2015}. 
Yes 
ls there at least I on-
treatment* HIV-I RNA 
collected in the Snapshot 
window? 
0 
Is the last available on-treatment* 
HlV-1 RNA in the Snapshot 
window < 50 copies/mL? 
Is study drug prematurely 
discontinued on or prior to the 
upper limit of the Snapshot 
window? 
Yes 
RIV-1 RNA < 
50 copies/m L 
HIV-I RNA2:: 
50 copies/m L 
Yes 
ls discontinuation of the study 
drug due to Lack of Efficacy? 
No 
Is discontinuation of the study 
drug due to AE/Death? 
Is the last available on-
treatment* H[V-1 RNA < 
50 copies/mL 
Yes 
No Virologic Data: 
Discontinued Study Drug 
Due to Other Reasons and 
Last HIV-1 RNA < 50 
copies/mL 
Yes 
No Virologic Data: 
Discontinued Study 
Drug Due to AE/Death 
No 
No Virologic Data: 
Missing Data during 
Window but on Study 
Drug 
* On-treatment data include all data collected up to 1 day after permanent discontinuation of study 
drug or all available data for subjects who were still on study drug. 
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Appendix 4.
Fracture Events
The selected PTs from the SMQ of osteoporosis/osteopenia and HLGT of fractures based on 
clinical review are listed as follows.
Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Acetabulum fracture
Ankle fracture
Atypical femur fracture
Atypical fracture
Avulsion fracture
Bone fissure
Bone fragmentation
Cervical vertebral fracture
Chance fracture
Clavicle fracture
Closed fracture manipulation
Comminuted fracture
Complicated fracture
Compression fracture
Craniofacial fracture
Epiphyseal fracture
External fixation of fracture
Facial bones fracture
Femoral neck fracture
Femur fracture
Fibula fracture
Flail chest
Foot fracture
Forearm fracture
Fracture
Fracture displacement
Fracture of clavicle due to birth trauma
Fracture treatment
Fractured coccyx


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Fractured ischium
Fractured sacrum
Fractured skull depressed
Greenstick fracture
Hand fracture
Hip fracture
Humerus fracture
Ilium fracture
Impacted fracture
Internal fixation of fracture
Jaw fracture
Limb fracture
Lisfranc fracture
Lower limb fracture
Lumbar vertebral fracture
Multiple fractures
Open fracture
Open reduction of fracture
Open reduction of spinal fracture
Osteochondral fracture
Osteoporotic fracture
Patella fracture
Pathological fracture
Pelvic fracture
Periprosthetic fracture
Pubis fracture
Radius fracture
Rib fracture
Sacroiliac fracture
Scapula fracture
Scapulothoracic dissociation
Skull fracture
Skull fractured base


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Spinal compression fracture
Spinal fracture
Sternal fracture
Stress fracture
Tartrate-resistant acid phosphatase decreased
Thoracic vertebral fracture
Tibia fracture
Torus fracture
Traumatic fracture
Ulna fracture
Upper limb fracture
Vertebroplasty
Wrist fracture
Vertebral body replacement
Note: AEs are coded by MedDRA 23.0.


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Appendix 5.
COVID-19 and Suspected COVID-19 Infections
Selected PTs
SARS-CoV-2 test positive
COVID-19 immunisation
COVID-19 prophylaxis
Exposure to SARS-CoV-2
Occupational exposure to SARS-CoV-2
COVID-19 treatment
SARS-CoV-2 test false negative
SARS-CoV-2 carrier
Coronavirus test positive
SARS-CoV-1 test positive
Asymptomatic COVID-19
Coronavirus infection
COVID-19
COVID-19 pneumonia
Severe acute respiratory syndrome
Suspected COVID-19
Note: AEs are coded by MedDRA 23.1.


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Appendix 6.
Determining Missing and Virtual Visits Due to COVID-19
This appendix describes the site collection of COVID-19 data as pertains to missed/virtual visits 
and the data processing algorithm used to determine which visits were missing and which visits 
were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites should enter “Visit 
missed due to COVID-19.” If a visit which was to be conducted in-person was conducted 
virtually, sites should enter “Virtual visit due to COVID-19.”
Determination of Missed and Virtual visits
Natural Language Processing (NLP) was used to search the CRF comment fields to identify 
instances of “COVID-19” (or synonyms, see Table X 1) and “Virtual” (or synonyms, see 
Table X 1). The search terms are maintained in a global lookup and can be modified and/or 
corrected to tune the NLP model. For each comment field the following algorithm was applied:
STEP 1: Eliminate extraneous text from each comment field, e.g. “and”, “or”, “for”, etc. This is 
done using the list of extraneous terms given in Table X 2.
STEP 2: Check each of the remaining comment text strings against the “COVID-19” terms and 
“Virtual” terms with the Levenshtein distance, using SAS function COMPGED (Computes a 
generalized edit distance using the Levenshtein operations to compute/summarize the degree of
difference between two text strings): 
i.
If Levenshtein distance < 149 for any of the “COVID-19” terms then COVIDFL
1, 
else COVIDFL
 0
ii. If Levenshtein distance < 149 for any of the “Virtual” terms then VIRTFL
1, 
else VIRTFL
0
STEP 3: For any comments with COVIDFL
 1, assign “Missed visit” or “Virtual visit as 
follows
i.
IF COVIDFL 1 and the visit date is missing then result is ‘Missed Visit’
ii. IF COVIDFL 1 and VIRTFL  1 then result is  ‘Virtual Visit’
iii. Otherwise result is missing


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Table X 1.
Examples of search terms for “COVID-19” and “Virtual” used to 
identify missed and virtual visits.
Search terms for “COVID-19”
Search terms for “Virtual”
COVID19
VIRTUAL
CORONA
TELEMED
CORONAVIRUS
TELEHEALTH
PANDEMIC
TELEPHONE
OUTBREAK
REMOTE
CRISIS
TELEMEDICINE
LOCKDOWN
TELECONSULTATION
QUARANTINE
TELEPHONICALLY
SHELTER
PHONE
HOME VISIT
ZOOM
SKYPE


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Table X 2.
Examples of extraneous text terms to eliminate from the comment 
fields.
a
down
in
she'd
until
about
during
into
she'll
up
above
each
is
she's
very
after
few
it
should
was
again
for
its
so
we
against
from
it's
some
we'd
all
further
itself
such
we'll
am
had
i've
than
were
an
has
let's
that
we're
and
have
me
that's
we've
any
having
more
the
what
are
he
most
their
what's
as
he'd
my
theirs
when
at
he'll
myself
them
when's
be
her
nor
themselves
where
because
here
of
then
where's
been
here's
on
there
which
before
hers
once
there's
while
being
herself
only
these
who
below
he's
or
they
whom
between
him
other
they'd
who's
both
himself
ought
they'll
why
but
his
our
they're
why's
by
how
ours
they've
with
could
how's
ourselves
this
would
did
i
out
those
you
do
i'd
over
through
you'd
does
if
own
to
you'll
doing
i'll
same
too
your
down
i'm
she
under
you're
you've
yourself
yourselves
yours


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Appendix 7.
Programming Specifications
General Conventions
1) The standard mock tables 
(http://gnet/biometrics/stat/doc/Standard%20TFL_Final%20GNET%202009%2005%2015.doc
) are default outputs developed based on standard CRF and standard SAP template. Changes 
to the CRFs or SAP may warrant changes to these outputs.
2) Italicized text in the mocks indicates that the entry is either optional or can be replaced by a 
more suitable term depending on the content.
3) Whenever possible, do not reference footnote by symbol within the body of the table and 
table title unless it greatly improves the clarity.
4) Titles should not exceed 128 characters (including the word “table,” the table number, 
punctuation, and spaces). If a title must exceed 128 characters, key descriptive information 
should be presented in the first 128 characters.
5) For completeness, please always include all the possible categories on standard CRF, 
including those with zero counts.
6) Treatment groups will be ordered as Gilead product in the first and then the rest of active 
control groups in alphabetical order, and placebo in the last column. Within each treatment, 
dose level will be in ascending order. Separate column for total or subtotal are allowed if 
space permits depending on study design, eg, a subtotal column could combine dose levels 
within the same treatment.
7) The ordering of these mock tables is the default ordering in the TFLs, ie, enrollment, 
disposition, demographic, baseline data, efficacy, drug exposure, and safety. 
8) Number TFLs consecutively and do not use decimal numbering for unique items.
9) A maximum of three titles and seven footnotes is allowed. Additional lines document the date 
of date extraction, source of SAS program, output files, and date-time of outputs generated.
10) The precision in reporting numerical values should be as follows: 
a) Raw measurements will be reported the same as the data captured electronically or on the 
CRFs.
b) Standard deviation and standard error will be reported to one more significant decimal 
place than the raw measurement.
c) Mean, median, minimum, Q1, Q3, maximum, 95% CIs will be reported to the same 
number of decimal places as the raw measurements. 
d) Exceptions may be considered; for example if more than 4 significant digits are provided 
for the measurement.


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11) The number of decimal places in reporting p-values should be as follows:
a) Values Less than 0.0001 < 0.0001
b) Values 0.0001 and greater round to 4 decimal places
12) For lab summaries, tests will be grouped as Chemistry, Hematology, and Urinalysis. 
Disease related biomarkers, eg, bone biomarkers, will be grouped separately. Summaries will 
be sorted alphabetically by test within group.
13) Study day calculation: if visit date ≥first dose date, study day
visit date first dose date 
+1. If visit date < first dose date, study day  visit date first dose date.
Other Definitions
1) AGE is calculated as follows:
a) AGE (years) is calculated from the number of days between the date of birth (DOB) and 
Day 1 (first dose date),
b) Use the SAS INTCK function to determine the number of “1st-of-month days” 
(eg, January 1st, February 1st, March 1st) between DOB and Day 1 (inclusive),
c) Divide the result in (b) by 12,
d) AGE  the integer of the result in (c),
e) If the DOB and Day 1 have the month in common and the birthday is later in the month 
than the date of Study Day 1, then subtract one from the AGE result above.
f)
For subjects who are enrolled and never dosed with study drug, AGE is calculated based 
on the date of enrollment.
2) All screened subjects refers to all subjects who are screened and have a screening number. 
For summarization, same subject is counted only once. DOB and other demographic 
information such as gender, race, and ethnicity will be used for identifying unique screened
subjects.
3) Screen failure subjects are the subjects who answered “Yes” to “Was subject a 
Screen Failure?” in informed consent and eligibility criteria eCRF.
4) BMI is calculated from height in meters (eg, height in cm/100) and weight in kilograms as:
BMI  (weight [kg]) / (height [meters]2)
BSA is calculated as:
BSA = 0height [meters] × weight [kg]/3600


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5) For HIV test using HIV Taqman kit, if a value is reported as “< 20 cp/mL HIV-1 RNA 
Detected” or “No HIV-1 RNA detected”, a numeric value of 19 will be used for summary 
purpose.
6) For direct bilirubin, a value of “< 0.1” will be treated as 0.09 for calculation of 
summary statistics {Nehls et al 1973}.
7) Generally for AE summary tables, SOC and PT will be included in all treatment-emergent 
AE tables.
8) Last Dose Date has been defined in Section 3.7.1.
Last Dose Date Imputation for Subjects Who Prematurely Discontinued Study or 
Completed Study

For subjects with a partial last dosing date (ie, month and year of last dose are known), 
use the maximum of the dispensing dates of study drug bottles, study drug start dates and 
end dates, the imputed last dose date (day imputed as 15) to impute the final last dose 
date. However if dispensing date’s month is after last dose date’s month, data query is 
needed.

If the date of last dose is missing (ie, only year of last dose is known or completely 
missing due to lost to follow-up), use the maximum of study drug start dates and end 
dates, clinical visit dates, and laboratory visit dates excluding the 30-day follow-up visit 
to impute the last dose date.
Last Dose Date Imputation for Ongoing Subjects (for the Purpose of Duration of 
Exposure)

If subjects are still on study drug (ie, defined as subjects who do not have study drug 
completion eCRF filled out), the last dose date will be estimated as follows:

If the last record in the study drug administration eCRF has a nonmissing study drug end
date, the estimated last dose date will be the last study drug end date.

If the last record in the study drug administration eCRF has a missing end date, the 
estimated last dose date will be the maximum of nonmissing study drug start dates and 
end dates, the clinical visit dates, and the laboratory visit dates excluding the date of 
30-day follow-up visit.
9) Last Study Date
Last Study Date is the maximum of nonmissing study drug start dates and end dates, clinic 
visit and laboratory visit dates, including the 30-day follow-up visit date for subjects who 
prematurely discontinued study or who completed study according to study completion 
eCRF. Please note, if study drug start date or end date is partially missing, the imputed date 
(day imputed as 15) will be used.


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10) Toxicity Grades: 
Final 
Version 1.0 
a) With regards to metabolic assessment of lipids tests (triglycerides, total cholesterol, and 
LDL cholesterol), if the fasting status is 'N' or blank, the lab test values will not be 
graded as non-fasting values are not interpretable. 
b) For the smmnary of the toxicity graded tests, all post-baseline graded results (not just 
those at summarized visits) up to 30 days after the last dose of study drug will be 
included. 
c) For hematuria grading, the laboratory reports both dipstick results (urine blood test with 
values of 1 +, 2+, etc) and quantitative results (urine RBC test with a m1it of /HPF), only 
summarize toxicity grades of the quantitative (urine RBC) results, but list the grades from 
both tests. 
11) In the listing for virologic outcomes using snapshot algorithm, flag all HIV-RNA records that 
are used in detennining snapshot outcomes including the following: 
• 
HIV-1 RNA < 50 copies/mL - the last available HIV -1 RNA value in the snapshot 
analysis window of< 50 copies/mL 
• 
HIV-1 RNA 
50 copies/mL - the last available HIV-1 RNA value in the snapshot 
analysis window of~ 50 copies/mL 
• 
HIV-1 RNA > 50 copies/mL- the last available HIV-1 RNA value of> 50 copies/mL 
if subjects discontinued study drug due to AE or Death 
• 
No Virologic Data - the last available HIV-1 RNA value of< 50 copies/mL if subjects 
discontinued study drug due to AE or Death 
12) "On-treatment" data in the SAP refer to the data on or prior to the date of pennanent 
discontinuation of study drug ( eg, last dose date). For subjects who are ongoing on study 
drug, "on-treatment" data refer to all data up to the data cut for the analysis. 
I 
I 
I 
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14) For HIV-1 RNA Missing
Failure or Missing
Excluded analysis:
Missing
Failure when

The subject has a visit after the missing.

The subject is missing HIV-1 RNA because he has already discontinued the study drug.

The subject came for a lab visit for that visit but the HIV-1 RNA value is missing 
(e.g. sample issue).
Missing is excluded from the denominator when

For ongoing subjects, HIV-1 RNA is missing and upcoming visit has not happened yet 
(excluding ongoing subjects who haven't reached the upper limit of the analysis window 
for corresponding visit).

This subject has neither baseline nor postbaseline lab data.

‘Have not reached the upper limit of that analysis window for the corresponding visit’
refers to: the latest lab collection date first dose date + 1 < the upper limit of the 
analysis window for a visit.
15) TEAE
Events with Missing Onset Day and/or Month
The event is treatment emergent if the following 3 criteria are met:

The month and year (or year) of onset date is the same as or after the month and year 
(or year) of the first dose of study drug, and

The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of 30th day after the date of the last dose of study drug, and

End date is as follows: 
o
The (complete) end date is on or after the first dose date, or
o
The month and year (or year) of end date is the same or after the month and year 
(or year) of the first dose of study drug, or
o
End date is completely missing


E/C/F/TAF
GS-US-292-0106
Final
Statistical Analysis Plan (Interim 6 Analysis)
Version 1.0
CONFIDETNIAL
Page 60
25 November 2020
Events with Completely Missing Onset Date
An AE with a completely missing onset date is defined as TEAE if end date is as follows:

The (complete) end date is on or after the first dose date, or

The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of study drug, or

End date is completely missing
16) LDL: Conversions between 2nd and 3rd generations
LDL was analyzed by 2 different assays in the study: 2nd generation (including RCT2394, 
RCT2312, and RCT2811) and 3rd generation (RCT3870). Samples collected at earlier visits 
were analyzed using LDL 2nd generation assay. Samples collected at later visits were 
analyzed using LDL 3rd generation assay. The conversion formulas are as follow:
2nd Gen (mmol/L)  (3rd Gen - 0.0626)/0.882
3rd Gen (mmol/L)  (0.882 x 2nd Gen) + 0.0626
For this analysis, since LDL samples were analyzed by 2nd generation assay at Baseline, we 
only requested conversion from 3rd generation to 2nd generation.
For the analysis of change from baseline in fasting direct LDL: the sample analyzed by LDL 
3rd generation assay will be converted to 2nd generation as a new record with test codes of 
LIP.LDL.00.02 in raw data. During ADaM stage, a derived parameter code (FLDL2) for 
“Fasting LDL Cholesterol 2ND GEN Combined” will be generated to pool the records from 
both original (including test codes RCT2394, RCT2312, and RCT2811) and converted 
(LIP.LDL.00.02) 2nd generation results to calculate the change from baseline in fasting 
direct LDL.
For the analysis of toxicity grade for fasting direct LDL: toxicity grade will be based on the 
Gilead grading results (ie, toxgrg) from original values before conversion. In other words, 
during ADaM stage, a derived parameter code (FLDLTOX) for “Fasting LDL Cholesterol 
for Toxicity” will be generated to pool the records from 2nd generation (including RCT2394, 
RCT2312, and RCT2811) and 3rd generation (ie, RCT3870) to derive treatment-emergent 
toxicity grades, maximum postbaseline toxicity grades, etc.


SAP for GS-US-292-0106 Interim 6 Analysis
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 25-Nov-2020
18:18:04
Biostatistics eSigned
25-Nov-2020
22:55:25
PPD
PPD

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral 
Activity of the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) Single Tablet Regimen (STR) in HIV-1 Infected Antiretroviral 
Treatment-Naive Adolescents and Virologically Suppressed Children
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive 
Foster City, CA 94404
IND No.:
EudraCT Number:
Clinicaltrials.gov 
Identifier:
111007
2013-002780-26
NCT01854775
Indication:
HIV-1
Protocol ID:
GS-US-292-0106
Contact 
Information: 
The medical monitor name and contact information will be provided on the 
Key Study Team Contact List.
Protocol 
Version/Date:
Original:
04 February 2013
Amendment 1:
22 March 2013
Amendment 2:
09 January 2015
Amendment 3:
11 August 2016
Amendment 4:
11 June 2018
Amendment 5:
17 August 2018
Amendment 6:
21 February 2020
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.
(rJ GILEAU 


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Final 
Amendment6 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 4 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 4 
PROTOCOL SYNOPSIS .............................................................................................................................................. 5 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 17 
1. 
INTRODUCTION .............................................................................................................................................. 21 
1.1. 
Backgrowid ............................................................................................................................................ 21 
1.1.1. 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) ......................................................................................................................... 23 
1.2. 
Rationale for the Cwl'ent Study ............................................................................................................. 28 
1.3. 
Rationale for Dose Selection .................................................................................................................. 29 
2. 
OBJECTIVES ..................................................................................................................................................... 34 
3. 
STUDYDESIGN ................................................................................................................................................ 36 
3 .1. 
Treatment Plan and Regimen ................................................................................................................. 36 
4. 
SUBJECT POPULATION .................................................................................................................................. 39 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 39 
4.2. 
Inclusion Criteria .................................................................................................................................... 39 
4.3. 
Exclusion Criteria ................................................................................................................................... 42 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................................. 45 
5.1. 
Rando1nization and Blinding .................................................................................................................. 45 
5.2. 
Description and Handling ofE/C/F/TAF STR ...................................................................................... .45 
5.2.1. 
Foimulation .......................................................................................................................... 45 
5.2.2. 
Packaging and Labeling ....................................................................................................... 46 
5.2.3. 
Storage and Handling ........................................................................................................... 46 
5.3. 
Dosage and Ad1ninistrntion ofE/C/F/TAF STR .................................................................................... 46 
5 .4. 
Prior and Concomitant Medications ....................................................................................................... 4 7 
5.5. 
Study Thug Retwn or Disposal .............................................................................................................. 53 
6. 
STUDYPROCEDURES ..................................................................................................................................... 55 
6.1. 
6.2. 
6.3. 
6.4. 
6.5. 
6.7. 
6.8. 
Subject Enrollment and Treatment Assignment ..................................................................................... 55 
Screening Visit ....................................................................................................................................... 55 
Treatment Assess1nents .......................................................................................................................... 57 
6.3.1. 
Baseline/Day 1 Assessments ................................................................................................ 57 
6.3.2. 
Treatment Assessments through 48 Weeks (Weeks 1 (Day 7) - 48) ................................... 59 
6.3.3. 
Intensive PK Evaluation 
a11 A sub·ects onl , inclusive of Coho113 ................................ 62 
6.3.6. 
Eary Stu y Drng D1scontmuahon ESDD ......................................................................... 65 
6.3.7. 
30-Day Follow-Up Visit ....................................................................................................... 66 
Bone Evaluations ................................................................................................................................... 67 
Bone and Renal Safe ........................................................................................................................... 68 
Cntena or D1scontmuahon o Stu y Treatment. ................................................................................... 68 
Virologic Failw·e .................................................................................................................................... 69 
6.8.1. 
Management of Suboptimal Virologic Response (Coho11 1 only) ....................................... 69 
CONFIDENTIAL 
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EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Final 
Amendment6 
6.8.2. 
Manage1nent ofVirologic Rebound ..................................................................................... 70 
6.8.3. 
Subjects with e:: 400 copies/mL of HIV-I in Absence of SVR orVR .................................. 72 
7. 
ADVERSE EVENTS AND TOXICITYMANAGEMENT ................................................................................ 73 
7. I. 
Adverse Events ....................................................................................................................................... 73 
7.2. 
Assess1nent of Adverse Events .............................................................................................................. 74 
7.3. 
Serious Adverse Events .......................................................................................................................... 74 
7 .4. 
Special Situations ................................................................................................................................... 7 6 
7.4.1. 
Definitions of Special Situations .......................................................................................... 76 
7.4.2. 
Instmctions for Reporting Special Situations ....................................................................... 77 
7.5. 
Serious Adverse Event Reporting Requirements ................................................................................... 78 
7 .5. I. 
All Serious Adverse Events .................................................................................................. 78 
7.5.2. 
Investigator and Sponsor Repo1ting Requirements for SAEs .............................................. 79 
7.5.3. 
Post-Study Repo1ting Requirements .................................................................................... 79 
7.6. 
Clinical Laborato1y Abnonnalities and Other Abno1mal Assessments as Adverse Events or 
Serious Adverse Events .......................................................................................................................... 80 
7.7. 
Toxicity Management ............................................................................................................................ 80 
7.7.1. 
Management of Changes in Estimated Glomemlar FiltrntionRate ...................................... 81 
7.7.2. 
Management of Posterior Uveitis Cases ............................................................................... 81 
7.7.3. 
Grades I and 2 Laborat01y Abnonnality or Clinical Event.. ................................................ 81 
7.7.4. 
Grade 3 Laborato1y Abno1mality or Clinical Event.. ........................................................... 81 
7.7.5. 
Grade 4 Laborato1y Abno1mality or Clinical Event.. ........................................................... 82 
8. 
STATISTICALCONSIDERATIONS ................................................................................................................. 83 
8.1. 
Analysis Objectives and Endpoints ........................................................................................................ 83 
8.1.1. 
Analysis Objectives .............................................................................................................. 83 
8.1.2. 
Pri1na1y Endpoints ................................................................................................................ 84 
8.1.3. 
Secondaiy Endpoints ............................................................................................................ 85 
8.2. 
Analysis Conventions ............................................................................................................................. 86 
8.2.1. 
Analysis Sets ........................................................................................................................ 86 
8.2.2. 
Data Handling Conventions ................................................................................................. 87 
8.3. 
Demographic Data and Baseline Characteristics ................................................................................... 87 
8.4. 
Efficacy Analysis ................................................................................................................................... 87 
8.5. 
Safety Analysis ....................................................................................................................................... 88 
8.5.1. 
Extent ofExposure ............................................................................................................... 88 
8.5 .2. 
Adverse Events ..................................................................................................................... 88 
8.5.3. 
Laborato1yEvaluations ........................................................................................................ 89 
8.5.4. 
Bone Safety .......................................................................................................................... 89 
8.5.5. 
Renal Safety ......................................................................................................................... 89 
8.5.6. 
Spine and Total Body Less Head Bone Mineral Density ..................................................... 89 
8.5.7. 
Tanner Stage Assessment ..................................................................................................... 89 
8.5 .8. 
Palatability ............................................................................................................................ 89 
8.5.9. 
Acceptability ........................................................................................................................ 89 
8.6. 
Pha1macokinetic Analysis ...................................................................................................................... 90 
8. 7. 
Independent Data Monitoring Committee .............................................................................................. 90 
8.8. 
Analysis Schedule .................................................................................................................................. 90 
8.9. 
Sa1nple Size and Power .......................................................................................................................... 91 
9. 
RESPONSIBILITIES .......................................................................................................................................... 93 
9 .1. 
Investigator Responsibilities .................................................................................................................. 93 
9 .1.1. 
Good Clinical Practice .......................................................................................................... 93 
9.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval .................................................................... 93 
CONFIDENTIAL 
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EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 4
21 February 2020
9.1.3.
Informed Consent.................................................................................................................94
9.1.4.
Confidentiality......................................................................................................................94
9.1.5.
Study Files and Retention of Records ..................................................................................94
9.1.6.
Electronic Case Report Forms (eCRFs) ...............................................................................96
9.1.7.
Drug Accountability.............................................................................................................96
9.1.8.
Inspections............................................................................................................................96
9.1.9.
Protocol Compliance ............................................................................................................96
9.2.
Sponsor Responsibilities ........................................................................................................................96
9.2.1.
Protocol Modifications.........................................................................................................96
9.2.2.
Study Report and Publications .............................................................................................97
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................97
9.3.1.
Payment Reporting...............................................................................................................97
9.3.2.
Access to Information for Monitoring..................................................................................97
9.3.3.
Access to Information for Auditing or Inspections ..............................................................98
9.3.4.
Study Discontinuation ..........................................................................................................98
10.
REFERENCES ...................................................................................................................................................99
11.
APPENDICES ..................................................................................................................................................101
Appendix 1.
Investigator Signature Page..................................................................................................102
Appendix 2.
Study Procedures Table........................................................................................................103
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................107
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............108
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................129
Appendix 6.
Stage-3-Defining Opportunistic Illnesses in HIV Infection .................................................131
Appendix 7.
Tanner Stages .......................................................................................................................132
LIST OF IN-TEXT TABLES
Table 1-1.
Pooled Virologic Outcomes of Studies 104 and 111 at Weeks 48a and 144b ........................24
Table 1-2.
Measures of Bone Mineral Density in Studies 104 and 111 (Week 144 Analysis) ................26
Table 1-3.
Change from Baseline in Renal Laboratory Tests in Studies 104 and 111 (Week 144
analysis)..................................................................................................................................26
LIST OF IN-TEXT FIGURES
Figure 1-1.
Predicted EVG AUC in Children Following Administration of E/C/F/TAF 
90/90/120/6 mg.......................................................................................................................31
Figure 1-2.
Predicted COBI AUC in Children Following Administration of E/C/F/TAF 
90/90/120/6 mg.......................................................................................................................32
Figure 1-3.
Predicted FTC AUC in Children Following Administration of E/C/F/TAF 
90/90/120/6 mg.......................................................................................................................32
Figure 1-4.
Predicted TAF AUC in Children Following Administration of E/C/F/TAF 
90/90/120/6 mg.......................................................................................................................33
Figure 1-5.
Predicted TFV AUC in Children Following Administration of E/C/F/TAF 
90/90/120/6 mg.......................................................................................................................33
Figure 3-1.
Study Schema .........................................................................................................................38
Figure 6-1.
Suboptimal Virologic Response Schema (Cohort 1 only)......................................................70
Figure 6-2.
Virologic Rebound Schema....................................................................................................71


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 5
21 February 2020
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, 
and Antiviral Activity of the Elvitegravir/Cobicistat/Emtricitabine/ 
Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen (STR) 
in HIV-1 Infected Antiretroviral Treatment-Naive Adolescents and 
Virologically Suppressed Children
IND Number: 
EudraCT Number: 
ClinicalTrials.gov 
Number:
111,007
2013-002780-26
NCT01854775
Study Centers
Planned:
Approximately 15 centers in North America, Africa, andThailand
Objectives:
Cohort 1
The primary objectives of this study are:
Part A:

To evaluate the steady state pharmacokinetics (PK) for 
elvitegravir (EVG) and tenofovir alafenamide (TAF) and 
confirm the dose of the elvitegravir/cobicistat/emtricitabine/ 
tenofovir alafenamide (E/C/F/TAF) single tablet regimen (STR) 
in HIV-1 infected, antiretroviral (ARV) treatment-naive 
adolescents
Part B:

To evaluate the safety and tolerability of the E/C/F/TAF STR 
through Week 24 in HIV-1 infected, ARV treatment-naive 
adolescents
The secondary objectives of this study are:

To evaluate the safety and tolerability of the E/C/F/TAF STR 
through Week 48 in HIV-1 infected, ARV treatment-naive 
adolescents

To evaluate the antiviral activity of the E/C/F/TAF STR through 
Week 48 in HIV-1 infected, ARV treatment-naive adolescents


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 6
21 February 2020
Cohort 2
The primary objectives of this study are:
Part A:

To evaluate the PK of EVG and TAF in virologically suppressed 
HIV-1 infected children 6 to < 12 years of age weighing ≥25 kg 
administered E/C/F/TAF STR
Part B:

To evaluate the safety and tolerability of E/C/F/TAF STR 
through Week 24 in virologically suppressed HIV-1infected 
children 6 to < 12 years of age weighing ≥25 kg
The secondary objectives of this study are:

To evaluate the antiviral activity of switching to E/C/F/TAF 
STR through Week 48 in virologically suppressed HIV-1 
infected children 6 to < 12 years of age weighing ≥25 kg

To evaluate the safety and tolerability of E/C/F/TAF STR 
through Week 48 in virologically suppressed HIV-1infected 
children 6 to < 12 years of age, weighing ≥25 kg
Cohort 3
The primary objectives of this study are:

To evaluate the PK of EVG and TAF and confirm the dose of 
the STR in virologically suppressed HIV-1 infected children
≥2 years of age weighing ≥ 14 to < 25 kg administered 
E/C/F/TAF low dose (LD) (90/90/120/6 mg) STR

To evaluate the safety and tolerability of E/C/F/TAF LD STR 
through Week 24 in virologically suppressed HIV-1 infected 
children ≥ 2 years of age and weighing ≥ 14 to < 25 kg
The secondary objectives of this study are:

To evaluate the antiviral activity of switching to E/C/F/TAF LD 
STR through Week 48 in virologically suppressed HIV1 infected 
children ≥ 2 years of age and weighing ≥ 14 to < 25 kg

To evaluate the safety and tolerability of E/C/F/TAF LD STR 
through Week 48 in virologically suppressed HIV-1 infected 
children ≥ 2 years of age and weighing ≥ 14 to < 25 kg


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
All Cohorts 
I 
I 
Final 
Amendment6 
Open-label, multicenter, multi-coho1i, single-ann study of the 
phaimacokinetics, safety, tolerability, and antiviral activity of the 
E/C/F/TAF STR in HIV-1 infected ARV treatment-naive 
adolescents and virologically suppressed children. 
A total of 50 adolescents (12 to < 18 years of age), and upto 
75 children (2 to < 12 years of age) of either sex will be enrolled to 
receive the E/C/F/TAF STR once daily with food as follows: 
Part A 
Intensive PK samples will be analyzed once they are available from 
18 subjects regai·dless of age distribution (Coho1is 1 and 2 only). 
Coho1i 1, Paii A: EVG, TAF and COBI exposures will be compai·ed 
to historical data from adult HIV-1 infected subjects. T AF data will 
also be compared to HIV-negative subjects from 292-0103 study. 
FTC and TFV exposures will be compared to historical data in 
HIV-infected adults and available data in adolescent subjects. 
Coho1i 2 Paii A and Coho1i 3: EVG, TAF, COBI, FTC and TFV 
exposures will be compared to historical adult data. 
EVG and TAF dose confnmation will be established if the 90% CI 
of geometric mean ratios for AUC in adolescents and children 
(respectively) versus those in adults are within the equivalency 
bounds of 70-143%. 
Following completion of the Intensive PK visit, subjects will 
continue to receive the E/C/F/TAF STR and return for scheduled 
study visits through Week 48. 
Cohort 1 (Adolescents 12 to < 18 years of age) 
• 
Eighteen to 24 eligible subjects will be initially enrolled to 
evaluate the steady state phaimacokinetics, and confnm the dose 
of the E/C/F/TAF STR. 
• 
Pa1i A will aim to enroll at least 6 subjects 12 to < 15 years of 
age and at least 6 subjects 15 to < 18 yeai·s of age. 
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21 Febrna1y 2020 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 8
21 February 2020

If at least 6 subjects ages 12 to < 15 years and 6 subjects ages 
15 to < 18 have not been enrolled at the time of the Intensive PK 
analysis, Part A enrollment will remain open in order to enroll 
sufficient subjects to meet the minimum enrollment of the 2 age 
subgroups.

Subjects enrolled in Part A will participate in an Intensive PK 
evaluation at Week 4. Samples will be collected at 0(pre-dose, 
≤30 minutes prior to dosing), 5 minutes, 0.25, 0.5, 1, 1.5, 2, 4, 
5, 8 and 24 hours post-dose.
Cohort 2 (Children 6 to < 12 years of age and weigh ≥25 kg)

Eighteen to 24 eligible subjects will be initially enrolled to 
evaluate the EVG and TAF plasma PK and confirm the dose of 
EVG and TAF.

Subjects enrolled in Part A will participate in an Intensive PK 
evaluation at Week 4. Samples will be collected at 0 (pre-dose, 
≤30 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 
24 hours post-dose.
Cohort 3 (Children ≥ 2 years of age and weighing ≥ 14 to 
< 25 kg)

Approximately 25 eligible subjects will be initially enrolled to 
evaluate the EVG and TAF plasma PK and confirm the dose of 
EVG and TAF.

Subjects enrolled in Part A will participate in an Intensive PK 
evaluation at Week 2. Samples will be collected at 0 (pre-dose, 
≤30 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 
8 hours post-dose.
Part B
Cohort 1 (Adolescents 12 to < 18 years of age)
Screening will be initiated into Cohort 1, Part B following 
confirmation of EVG and TAF exposure in at least 18 subjects from 
Cohort 1, Part A. The additional 26 – 32 subjects will be enrolled in 
Cohort 1, Part B to evaluate the safety, tolerability and antiviral 
activity of the E/C/F/TAF STR in at least 50 patients, including all 
subjects enrolled in Cohort 1 (Parts A and B combined).


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 9
21 February 2020
Cohort 2 (Children 6 to < 12 years of age and weigh ≥25 kg)
Screening will be initiated into Cohort 2, Part B based on exposure 
data from at least 18 subjects from Cohort 2, Part A. The additional 
26 – 32 subjects will be enrolled in Cohort 2, Part B to evaluate the 
safety, tolerability and antiviral activity of the E/C/F/TAF STR in at 
least 50 patients, including all subjects enrolled in Cohort 2 (Parts A 
and B combined).
Cohort 3 (Children ≥ 2 years of age and weighing ≥ 14 to 
< 25 kg)

No Part B for this cohort. All subjects will be enrolled in Part A 
and will complete an Intensive PK evaluation.
Number of Subjects 
Planned:
Cohort 1
50 subjects
Part A: Eighteen to 24 subjects representing 2 age subgroups 
(at least 6 subjects must be 12 to <15 years of age and at least 
6 subjects must be 15 to < 18 years of age)
Part B: Twenty-six to 32 subjects between 12 to < 18 years of age 
(dependent upon enrollment in Part A)
Cohort 2
50 subjects
Part A: Eighteen to 24 subjects between 6 to < 12 years of age 
weighing ≥ 25 kg
Part B: Twenty-six to 32 subjects must be 6 to < 12 years of age 
and weigh ≥ 25 kg (dependent upon enrollment in Part A)
Cohort 3
Approximately 25 subjects ≥ 2 years of age and weighing ≥14 to 
< 25 kg
Target Population:
Cohort 1
Antiretroviral treatment-naive, HIV-1 infected adolescents (12 to 
< 18 years of age) of either sex with plasma HIV-1 RNA levels 
≥1,000 copies/mL
Cohort 2
Virologically suppressed, HIV-1 infected children (6 to < 12 years 
of age and screening weight ≥ 25 kg) of either sex with plasma 
HIV-1 RNA levels < 50 copies/mL for ≥ 6 consecutive months prior 
to screening on a stable antiretroviral regimen, with no documented 
history of resistance to any component of E/C/F/TAF STR.


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Dmation of 
Treatment: 
Cohort 3 
Final 
Amendment6 
Virologically suppressed, HIV-1 infected children (:::: 2 years of age 
and screening weight of :::: 14 to < 25 kg) of either sex with plasma 
HIV-1 RNA levels < 50 copies/mL for :::: 6 consecutive months prior 
to screening on a stable antiretroviral regimen, with no documented 
histo1y of resistance to any component of E/C/F IT AF STR. 
48 weeks 
Diagnosis and Main HIV-1 infected subjects who meet the following criteria: 
Eligibility Criteria: 
Cohort 1 
CONFIDENTIAL 
• 
Age at Baseline: 12 to < 18 years old 
• 
Weight at Screening::::: 35 kg (77 lbs) 
• 
Plasma HIV-1 RNA :::: 1,000 copies/mL at Screening 
(Roche COBAS TaqMan v2.0) 
• 
Screening genotype repo1i shows sensitivity to EVG, FTC and 
TFV (Monogram Biosciences, Inc.) 
• 
Subjects with HIV subtype AE who meet all inclusion/exclusion 
criteria and who have a non-repo1iable integrase genotype result 
may proceed with study emollment. (For Thailand only) 
• 
No prior use of any approved or experimental anti-HIV-I dmg 
for any length of time ( other than that given for prevention of 
mother-to-child transmission) 
Cohort2 
• 
Age at Baseline: 6 to < 12 years old 
• 
Weight at Screening: :::: 25 kg (55 lbs) 
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EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 11
21 February 2020

Plasma HIV-1 RNA: < 50 copies/mL (or undetectable HIV-1 
RNA level according to the local assay being used if the limit of 
detection is > 50 copies/mL) for ≥ 6 months prior to screening 
on a stable antiretroviral regimen, without prior history of 
resistance to any component of E/C/F/TAF STR

Unconfirmed HIV-1 RNA ≥ 50 copies/mL after previously 
reaching virologic suppression (transient detectable viremia, or 
“blip”) and prior to screening is acceptable

Currently receiving an antiretroviral regimen that has been stable 
for at least 6 months or has been newly initiated within 6 months 
for reasons other than virologic failure.
Cohort 3

Age at Baseline: ≥ 2 years old

Weight at Screening: ≥ 14 kg (31 lbs) to < 25 kg (55 lbs)

Plasma HIV-1 RNA: < 50 copies/mL (or undetectable HIV-1 
RNA level according to the local assay being used if the limit of 
detection is > 50 copies/mL) for ≥ 6 months prior to screening 
on a stable antiretroviral regimen, without documented history 
of resistance to any component of E/C/F/TAF STR
Unconfirmed HIV-1 RNA ≥ 50 copies/mL after previously 
reaching virologic suppression (transient detectable viremia, 
or “blip”) and prior to screening is acceptable

Currently receiving an antiretroviral regimen that has been stable 
for at least 6 months or has been newly initiated within 6 months 
for reasons other than virologic failure.
Study Procedures/ 
Frequency:
All Subjects (All Cohorts unless specified):
At the Screening, Baseline/Day 1, and all subsequent study visits 
laboratory analyses (hematology, chemistry and urinalysis), HIV-1 
RNA, vital signs, and complete or symptom-directed physical 
examinations and estimated GFR using the Schwartz formula will 
be performed.
At Screening, HIV-1 protease, reverse transcriptase and integrase 
genotype will be analyzed (for Cohort 1 only).
HBV and HCV serologies will be analyzed and supine ECG will be 
performed.
Blood samples will be collected for full flow cytometry panel testing 
at Screening, Baseline and Weeks 2 - 48.


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Adverse events and concomitant medications will be assessed at 
each visit.
Subjects will return for study visits at Weeks 1 (Day 7), 2, 4, 8, 12,
16, and then every 8 weeks through Week 48.
Subjects enrolled in Part A will participate in an Intensive PK 
Evaluation at Week 2 (Cohort 3, all subjects) or Week 4 (Cohorts 1 
and 2). Subject diary cards will be provided to all Part A subjects to 
record administration of study drugs prior to the Intensive PK visit.
For subjects in Cohort 1 and 2, a trough PK sample (20 to 24 hours 
post-dose) will be collected at Weeks 1, 2, and 24. For Cohort 1, a 
trough PK sample will also be collected at Week 48. For subjects in 
Cohort 3, a trough sample will be collected at Weeks 4 and 24.
For subjects in Cohort 1, a timed random PK sample will be 
collected between 0.25 to 4 hours post-dose at Week 4 (Cohort 1 
Part B subjects only) and at Week 12 (all Cohort 1). For subjects in 
Cohort 2, a timed random PK sample will be collected between 0.25 
to 4 hours post-dose at Week 12 and a random single PK sample 
will be collected at Week 8 and Week 16. For subjects in Cohort 3, a 
timed single PK sample will be collected between 0.25 to 4 hours 
post-dose at Weeks 8, 12, and 16.
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, 
and triglycerides) will be collected at Baseline, Week 24, and
Week 48.
The following serum bone safety parameters will be collected at 
Screening (Cohort 3), Baseline (Cohorts 1 and 2), Week 8 (Cohort 1 
only), and Weeks 12, 24, and 48:

Cohorts 1 and 2: bicarbonate, N-telopeptide, C-telopeptide 
(CTX), osteocalcin, and procollagen type 1 N-terminal 
propeptide (P1NP).

For all cohorts: bone specific alkaline phosphatase, parathyroid 
hormone (PTH), 25OH Vitamin D, and 1,25OH Vitamin D.
The following urine bone safety parameters will be collected at 
Baseline, Weeks 8, 12, 24, and 48:

Cohorts 1 and 2: bicarbonate and N-telopeptide.
Urine will be collected for renal safety parameters at Screening 
(Cohort 3), Baseline (Cohorts 1 and 2), Weeks 8, 12, 24, and 48.

For all cohorts: urine chemistry, retinol binding protein, and 
beta-2-microglobulin.


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
CONFIDENTIAL 
Final 
Amendment6 
Tanner stage will be assessed for subjects::::: 6 years of age at 
Baseline, Weeks 24 and 48 or until subjects reach Tanner Stage 5, 
after which point Tanner assessments will no longer be perfo1med. 
For all coho1ts, dual energy x-ray absorptiometiy (DXA) scans of 
the lumbar spine and total body will be perfo1m ed at Baseline, 
Weeks 24 and 48 to measure spine bone mineral density (BMD) and 
total body BMD. 
Resistance testing will be perfo1med using the RT/PR PhenoSense 
GT assay, the IN GeneSeq assay, and the IN PhenoSense assay 
(Monogram Biosciences, Inc.) in subjects who experience 
suboptimal virologic response or virologic rebound, if HIV-I RNA 
is ::::: 400 copies/mL. 
Palatability and Acceptability assessment will be perfo1med at 
Baseline and Week 4 for Coho1t 2 subjects, and Baseline, Week 4, 
Week 24, and Week 48 for Coho1t 3 subjects. For Cohort 1 subjects 
cmTently on study, it will be perfonned at their next scheduled visit. 
Subjects who are pe1manently discontinued from the study before 
Week 48 and subjects who do not wish to continue on the study 
after completing Week 48 will be required to return to the clinic 
30 days after the completion of study dmg for a 30-Day Follow-Up 
Visit. 
Cohorts 1 and 2: 
Elvitegravir 150 mg/cobicistat 150 mg/emti·icitabine 200 mg/ 
tenofovir alafenamide 10 mg STR administered orally once daily 
with food 
Cohort 3: 
Elvitegravir 90 mg/cobicistat 90 mg/emti·icitabine 120 mg/ tenofovir 
alafenamide 6 mg STR low dose tablet administered orally 
once daily with food 
None 
Page 13 
21 Febrna1y 2020 


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
PK: 
Statistical Methods: 
CONFIDENTIAL 
Final 
Amendment6 
Adverse events, clinical laborato1y tests, Tanner stage assessment 
(subjects ~ 6 years of age), selected bone biomarkers, renal safety, 
and BMD to evaluate the safety and tolerability of the treatment 
regimen. 
Cohort 1 
The efficacy endpoints are: 
• 
• 
• 
The percentage of subjects with plasma HIV-1 RNA 
< 50 copies/mL at Weeks 24 and 48 as defined by the FDA 
snapshot analysis 
The percentage of subjects with plasma HIV-1 RNA 
< 400 copies/mL at Weeks 24 and 48 as defined by the FDA 
snapshot analysis 
The change from baseline in plasma log10 HIV-1 RNA 
( copies/mL) and in CD4 + cell count ( cells/ µL) and percentage at 
Weeks 24 and 48 
Cohorts 2 and 3 
• 
The percentage of subjects with plasma HIV-1 RNA 
< 50 copies/mL and < 400 copies/mL at Weeks 24 and 48 by the 
FDA snapshot analysis 
• 
The change from baseline in CD4+ cell count (cells/µL) and 
percentage at Weeks 24 and 48 
The following plasma phannacokinetic parameters will be 
calculated for EVG, COBI, FTC, TAF and TFV, as applicable: 
AUCtau, AUC1ast, Ctau, Cmax, C1ast, Tmax, T1ast, 1,.,z, CL/F, VJF, and T½ 
(where possible) 
PK Analyses 
PK parameters (AUCtau, Ctau, and Cmax) ofEVG and PK parameters 
(AUC and Cma.x) ofTAF will be summarized and compared to 
historical adult data. Plasma concentration and parameter data of 
EVG, COBI, FTC, TAF, and TFV will be summarized using 
descriptive statistics. 
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Amendment 6
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An analysis of variance (ANOVA) using a mixed-effects model for 
appropriate parallel group design will be fitted to natural-logarithm 
transformed AUC for TAF and AUCtau for EVG to evaluate whether 
the exposures of these two analytes achieved in adolescent 
(Cohort 1) or children (Cohorts 2 and 3) are similar to the exposure 
achieved in adult subjects. An appropriate adult comparator 
database will be identified and integrated as historical control data. 
For each cohort, two one-sided tests with each performed at an alpha
level of 0.05 and a boundary of 70% to 143% will be used for 
exposure equivalence assessment.
Efficacy Analyses
The percentage of subjects who achieve HIV-1 RNA < 50 copies/mL 
and < 400 copies/mL at Weeks 24 and 48 as defined by the FDA 
snapshot analysis algorithm will be summarized by cohort. The 95% 
confidence intervals will also be presented.
The change from baseline in log10 HIV-1 RNA (Cohort 1 only) and 
CD4+ cell count and percentage at Weeks 24 and 48 will be 
summarized by cohort using descriptive statistics.
Sample Size and Power
Cohorts 1 and 2
A minimum of 18 Part A subjects from each cohort compared to 51 
HIV-infected adult subjects in GS-US-292-0102 and HIV-negative 
adult subjects in GS-US-292-0103 combined, will provide 92% 
power to conclude exposure equivalence of TAF AUClast in 
adolescent subjects and children, respectively vs in adult subjects, 
assuming the expected geometric mean ratio is 1, equivalency 
boundary is 70% to 143%, two one-sided tests are each performed at 
an alpha level of 0.05, and the standard deviation of AUClast is 
0.37 ng•hr/mL (natural log scale).
A minimum of 18 Part A subjects from each cohort will also provide 
> 99% power to target a 95% confidence interval within 60% and 
140% of the geometric mean estimate of clearance and volume of 
distribution of TAF respectively, assuming a coefficient of variation 
(CV) of 38% for clearance and 42% for volume of distribution 
(GS-US-292-0102 and GS-US-292-0103 combined).
For each cohort, with a total of 50 subjects from Parts A and B 
combined, the chance to observe at least 1 SAE is 92%, assuming 
the SAE incidence rate is 5% (observed in GS-US-292-0102). After 
amendment 2 of the study protocol was finalized, the adult data 
included in Genvoya label have become available and will be used 
as historical control for comparison for Cohort 2 (ie, intensive PK 
data from 19 HIV-1 infected adults in Study GS-US-292-0102 for 


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EVG AUCtau and population PK data from 539 HIV-1 infected 
adults in Studies GS-US-292-0104 and GS-US-292-0111 combined 
for TAF AUClast). Given the actual number of enrollments in Cohort 
2 Part A was 23, a total of 23 subjects would provide 90% power for 
EVG AUCtau and 88% power for TAF AUClast to conclude exposure 
equivalence between children and adults, assuming the expected 
geometric mean ratios was 1, equivalency boundary was 70% to 
143%, two one-sided tests were each performed at an alpha level of 
0.05, and the intersubject standard deviation (natural log scale) of 
EVG AUCtau and TAF AUClast was 0.34 ng•hr/mL and 0.52 
ng•hr/mL, respectively.
A total of 23 subjects from Cohort 2 Part A would also provide 86% 
power to target a 95% confidence interval within 60% and 140% of 
the geometric mean estimate of clearance and volume of distribution 
of TAF respectively, assuming a CV of 53% for clearance and 76% 
for volume of distribution (based on population PK data from 
GS US-292-0104 and GS-US-292-0111 combined).
Cohort 3
Twenty-five evaluable subjects compared to historical adult data 
will provide 90% power for each of EVG AUCtau and TAF AUCtau 
to conclude exposure equivalence between children and adults. In 
this power analysis, it is assumed that the expected geometric mean 
ratios is 1, equivalency boundary is 70% to 143%, two one-sided 
tests are each performed at an alpha level of 0.05, and the 
intersubject standard deviations (natural log scale) of EVG AUCtau 
and TAF AUCtau are 0.34 ng•hr/mL and 0.52 ng•hr/mL. For 
historical adult data, we used intensive PK data from 19 HIV-1 
infected adults in Study GS-US-292-0102 for EVG AUCtau and 
population PK data from Studies GS-US-292-0104 and
GS-US-292-0111 combined for TAF AUCtau.
Twenty-five evaluable subjects will also provide > 99% power to 
target a 95% confidence interval within 60% and 140% of the 
geometric mean estimate of apparent clearance and volume of 
distribution of TAF respectively, assuming the standard deviation 
natural log scale is 0.51 for CL and 0.54 for Vz (based on population 
PK data from Studies GS-US-292-0104 and GS-US-292-0111 
combined).
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
degrees Celsius
°F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
Antiretroviral
AST
Aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration 
versus time curve
AUClast
the area under the concentration versus time curve from time zero to the last 
quantifiable concentration
AUCtau
the area under the concentration verses time curve over the dosing interval AV
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CDC
centers for disease control
CI
confidence interval
AUClast
the area under the concentration versus time curve from time zero to the last 
quantifiable concentration
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
Clast
the last observed quantifiable concentration of the drug in plasma
COBI
cobicistat (GS-9350)
CNS
central nervous system
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRO
contract (or clinical) research organization
CYP
cytochrome P450
DAVG
average area under the dosing interval
DXA
dual energy x-ray absorptiometry
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DRV
darunavir
DSPH
Drug Safety and Public Health


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E/C/F/TDF
Single tablet regimen of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 
mg/ tenofovir disoproxil fumarate 300 mg
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic case report form(s)
EFV
Efavirenz, Sustiva®
EFV/FTC/TDF
Single tablet regimen of efavirenz 600 mg/emtricitabine 200 mg/tenofovir
disoproxil fumarate 300 mg, Atripla®
EU
European Union
EVG
elvitegravir (GS-9137)
EVG/COBI/FTC/TAF, 
E/C/F/TAF
Single tablet regimen of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 
mg/ tenofovir alafenamide 10 mg
FDA
(United States) Food and Drug Administration
FTC
emtricitabine, Emtriva®
FTC/RPV/TDF
emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg,
Complera® FTC/TDF
GCP
Good Clinical Practice (Guidelines)
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLP
Good Laboratory Practices
GSI
Gilead Sciences, Inc.
GS-9137
elvitegravir, EVG,6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-
2-yl]- 7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
GS-9350
cobicistat, COBI, 1,3-Thiazol-5-ylmethyl (2R,5R)-(5-(((2S)-2-((methyl((2-(propan-
2-yl)- 1,3-thiazol-4-yl(methyl(carbamoyl)amino((-4-(morpholin-4-yl)butanamido
FDA
(United States) Food and Drug Administration
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high-density polyethylene
hERG
human Ether-à-go-go Related Gene
HIV
Human Immunodeficiency Virus
HMG-CoA
5-hydroxy-3-methylglutaryl-coenzyme A
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
Identification
IDMC
Independent Data Monitoring Committee


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IgG
Immunoglobulin
IND
investigational New Drug (Application)
INH
isonicotinylhydrazine, Isoniazid (Laniazid, Nydrazid)
INSTI
integrase strand transfer inhibitor
IRB
Institutional Review Board
ITT
intent-to-treat (analysis or subset)
IV
Intravenous
KS
Kaposi’s sarcoma
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
Min
Minute
mmHg
millimeters mercury
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NOEL
no observable effect levels
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
OTC
over the counter
PAH
Pulmonary arterial hypertension
PBMC
Peripheral blood mononuclear cell
PI
protease inhibitor
PI/r
ritonavir boosted-protease inhibitor
PK
Pharmacokinetic
PR
pulse rate
PT
preferred term (in Section 8)
PT
prothrombin time (in Appendix 4)
PVE
Pharmacovigilance and Epidemiology
PXR
human pregnane X receptor
QD
once daily
QTc
corrected QT
RAL
Raltegravir
REB
Research Ethics Board
RNA
ribonucleic acid
RTV
ritonavir, Norvir®
SAE
serious adverse event


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Scr
serum creatinine
SOP
standard operating procedure
Spo4
serum phosphate concentration
STR
Single Tablet Regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVR
suboptimal virologic response
T½
half life
TAF
tenofovir alafenamide (GS-7340)
TDF
tenofovir disoproxil fumarate, Viread®
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TLOVR
time to loss of virologic response
tmax
the time (observed time point) of Cmax
TPV/r
ritonavir-boosted tipranavir
TSH
thyroid stimulating hormone
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
Upo4
urine phosphate concentration
VR
virologic rebound
RPV
Rilpivirine
λz
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the plasma concentration of drug verses time curve


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 (HIV-1) infection is a life-threatening and serious disease that 
is of major public health interest around the world. There are approximately 2.1 million people in 
North America and Western and Central Europe living with HIV-1 and 36.7 million people 
worldwide {Joint United Nations Programme on HIV/AIDS (UNAIDS) 2016}, including
2.1 million children under 15 years of age {Joint United Nations Programme on HIV/AIDS 
(UNAIDS) 2016}. This figure is likely to underestimate the HIV disease burden in the pediatric 
population using the European Medicines Agency (EMA) categorization of adolescence as from 
12 to 16 or 18 years, depending on the region (EMA, Note for Guidance CPMP/ICH/2711/99). 
The infection, if left untreated or suboptimally treated, is characterized by deterioration in 
immune function, ultimately resulting in death. Therapeutic strategies for the treatment of HIV-1 
disease have been significantly advanced by the availability of highly active antiretroviral 
therapy (HAART); the introduction of HAART was associated with a dramatic decrease in 
acquired immune deficiency syndrome (AIDS)-related morbidity and mortality {Mocroft 1998, 
Palella 1998, Sterne 2005}.
Disease Pathophysiology
The pathogenesis of HIV-1 infection and the general virologic and immunologic principles 
underlying the use of ARV therapy are similar between HIV-1 infected adult and pediatric 
patients. However, there are some important and unique issues for HIV-1 infected infants, 
children, and adolescents, including the following {Panel on Antiretroviral Therapy and Medical 
Management of HIV-infected Children 2011}:

Acquisition of infection through perinatal exposure for many infected children

In utero, intrapartum, and/or postpartum neonatal exposure to zidovudine and other ARV 
medications in most perinatally infected children

Age-specific differences in CD4+ cell counts and percentages

Changes in pharmacokinetic parameters with age caused by the continuing development and 
maturation of organ systems involved in drug metabolism and clearance

Differences in the clinical and virologic manifestations of perinatal HIV-1 infection 
secondary to the occurrence of primary infection in growing, immunologically immature 
persons

Special considerations associated with adherence to ARV treatment for infants, children, and 
adolescents


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
Need for longer duration of therapy, with potentially greater implications than in adults for 
long-term toxicity and development of resistance

Differences in physiological development of certain body systems, including the skeletal 
system, where peak bone mass is not achieved until early adulthood
Treatment
The goal of ARV therapy for HIV-1 infection is to delay disease progression, improve immune 
function, and increase the duration of survival by achieving maximal and prolonged suppression 
of HIV-1 replication. The availability of highly active antiretroviral therapy (HAART) 
combinations for the treatment of HIV-1 infection has resulted in a dramatic reduction in 
Acquired Immunodeficiency Syndrome (AIDS) related morbidity and mortality in the US and 
Europe {Mocroft 1998, Palella 1998, Sterne 2005}. However, eradication of the virus is not 
possible with therapies that are currently available. These therapies have several distinct adverse 
events such as mitochondrial dysfunction, metabolic abnormalities, hematologic toxicities, and 
allergic reactions.
The 2018 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection generally 
recommend the use of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in 
combination with a 3rd agent (a non-nucleoside reverse transcriptase inhibitor [NNRTI], a 
boosted protease inhibitor [PI] or an integrase strand transfer inhibitor [INSTI]) for treatment of 
children and adolescents with HIV infection depending on age and sexual maturity rating for 
adolescents (DHHS guidelines May 2018). The choice of a regimen, including the 3rd agent, is 
individualized based on a number of factors including characteristics of the proposed regimen, 
patient characteristics and results of resistance testing {Department of Health and Human 
Services (DHHS) 2018}.
Studies have shown that a once-daily STR significantly improved adherence, treatment 
satisfaction, and virologic outcomes for patients infected with HIV-1 {Airoldi 2010, Bangsberg 
2010, Dejesus 2009, Hodder 2010, Sax 2015}. Due to a longer duration of high adherence, 
patients taking STRs also have better clinical outcomes, such as fewer hospitalizations, 
compared with multiple-tablet regimens {Sax 2010}. The following STRs are currently approved 
for once-daily administration in the treatment of HIV-1 infection in adolescents and/or children: 
EFV/FTC/TDF (Atripla®), FTC/RPV/TDF (Complera®/Eviplera®), EVG/COBI/FTC/TDF 
(Stribild®), EVG/COBI/FTC/TAF (Genvoya®), BIC/FTC/TAF (Biktarvy®), R/F/TAF (Odefsey®)
and Triumeq®.
Tenofovir disoproxil fumarate (TDF) is a preferred NRTI among recommended regimens for 
treatment-naive HIV-infected adults and adolescents, but is associated with nephrotoxicity and 
reduced bone mineral density {Panel on Antiretroviral Guidelines for Adults and Adolescents 
2012}. Lifelong antiretroviral treatment and the increasing comorbidities being recognized and 
treated in HIV-infected patients creates an urgent need to improve the safety profile of regimens 
that most effectively suppress HIV replication.


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Tenofovir alafenamide (TAF, also known as GS-7340) is an oral prodrug of tenofovir (TFV), a 
nucleotide analog that inhibits HIV-1 reverse transcription. Gilead has coformulated TAF with 
the integrase strand transfer inhibitor EVG, COBI, and FTC into a STR. Compared to TDF, the 
use of TAF in the E/C/F/TAF STR provides enhanced lymphatic delivery of TFV, resulting in 
higher intracellular levels of the active phosphorylated moiety tenofovir-diphosphate (TFV-DP), 
and lower systemic circulating levels of TFV. These features are hypothesized to translate into 
more effective suppression of viral replication, and an improved tolerability and safety profile. 
FTC/TAF (Descovy), Genvoya, R/F/TAF (Odefsey), and GS-9883/Emtricitabine/Tenofovir 
Alafenamide (Biktarvy) are all FDC’s containing TAF that have been approved in adolescents 
(US and EU) and children 6 to <12 years of age weighing ≥25 kg (GEN in the US and EU and 
DVY in the US only).
EVG can be dosed once daily when used with a pharmacoenhancing (boosting) agent like 
ritonavir 100 mg or cobicistat (COBI, GS-9350). COBI is devoid of anti-HIV activity, may have 
less adverse biochemical effects (e.g., effect on adipocyte functions such as lipid accumulation) 
relative to ritonavir, and can be coformulated as a tablet with other ARV agents that require 
boosting. Gilead Sciences has coformulated a single tablet regimen of COBI with EVG, FTC and 
TAF. This STR may be an attractive option for adolescents and children with HIV-1 infection.
This study represents the first use of the E/C/F/TAF STR in adolescents and children 6 to 
< 12 years of age. E/C/F/TAF was approved in adults and pediatric patients 12 years of age and 
older in the US and EU in 2016 and most recently for 6 to < 12 year olds > or equal to 25 kg. 
Please refer to the E/C/F/TAF local labeling and the investigator brochure for contraindications, 
warnings and precautions, and interactions.
1.1.1.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)
A brief summary of the clinical trials of E/C/F/TAF STR for the treatment of HIV-1 infection are 
below. Please refer to the E/C/F/TAF IB for additional details:
The efficacy and safety of E/C/F/TAF (GENVOYA) in HIV-1 infected, treatment-naïve adults 
are based on 144-week data from two randomized, double-blind, active-controlled studies,
GS-US-292-0104 (“Study 104”) and GS-US-292-0111 (“Study 111”) (N=1733).
The efficacy and safety of GENVOYA in virologically-suppressed HIV-1 infected adults are 
based on 96-week data from a randomized, open-label, active-controlled study, GS-US-292-0109 
(“Study 109”) (N=1436).
The efficacy and safety of GENVOYA in HIV-1 infected, virologically-suppressed patients with 
mild to moderate renal impairment is based on 144-week data from an open-label study,
GS-US-292-0112 (“Study 112”) (N=242).
The efficacy and safety of GENVOYA in HIV-1 infected pediatric patients are based on
48-week data in treatment-naïve patients between the ages of 12 to < 18 years (≥35 kg) (N=50) 
and 24-week data in virologically suppressed patients between the ages of 6 to < 12 years
(≥25 kg) (N=23) from cohort 1 and 2, respectively, of this study (GS-US-292-0106).


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Treatment-Naïve Patients
In both Study 104 and Study 111, patients were randomized in a 1:1 ratio to receive either 
GENVOYA (N = 866) once daily or STRIBILD (elvitegravir 150 mg/cobicistat 150 mg/ 
emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; N = 867) once daily.
In Studies 104 and 111, the mean age was 36 years (range 18-76), 85% were male, 57% were 
White, 25% were Black, and 10% were Asian. Nineteen percent of patients identified as 
Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL
(range 1.3-7.0). The mean baseline CD4+ cell count was 427 cells/mm3 (range 0-1360) and 13% 
had CD4+ cell counts less than 200 cells/mm3. Twenty-three percent of patients had baseline 
viral loads greater than 100,000 copies/mL.
In both studies, patients were stratified by baseline HIV-1 RNA (less than or equal to
100,000 copies/mL, greater than 100,000 copies/mL to less than or equal to 400,000 copies/mL, 
or greater than 400,000 copies/mL), by CD4 count (less than 50 cells/μL, 50-199 cells/μL, or 
greater than or equal to 200 cells/μL), and by region (US or ex-US).
Treatment outcomes of Studies 104 and 111 through 48 and 144 weeks are presented in
Table 1-1.
Table 1-1.
Pooled Virologic Outcomes of Studies 104 and 111 at Weeks 48a and
144b
Week 48
Week 144
GENVOYA
(N = 866)
STRIBILD
(N = 867)
GENVOYA
(N = 866)
STRIBILD
(N = 867)
HIV-1 RNA < 50 copies/mL
92%
90%
84%
80%
Treatment Difference
2.0% (95% CI = −0.7% to 4.7%)
4.2% (95% CI = 0.6% to 7.8%)
HIV-1 RNA ≥50 copies/mLc
4%
4%
5%
4%
No Virologic Data at Week 48 or 144 
Window
4%
6%
11%
16%
Discontinued Study Drug Due to 
AE or Deathd
1%
2%
1%
3%
Discontinued Study Drug Due to 
Other Reasons and Last Available 
HIV-1 RNA < 50 copies/mLe
2%
4%
9%
11%
Missing Data During Window but 
on Study Drug
1%
<1%
1%
1%


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Week 48
Week 144
GENVOYA
(N = 866)
STRIBILD
(N = 867)
GENVOYA
(N = 866)
STRIBILD
(N = 867)
Proportion (%) of Patients with HIV-1 RNA <50 copies/mL by Subgroup
Age
< 50 years
≥ 50 years
716/777 (92%)
84/89 (94%)
680/753 (90%)
104/114 (91%)
647/777 (83%)
82/89 (92%)
602/753 (80%)
92/114 (81%)
Sex
Male
Female
674/733 (92%)
126/133 (95%)
673/740 (91%)
111/127 (87%)
616/733 (84%)
113/133 (85%)
603/740 (81%)
91/127 (72%)
Race
Black
Nonblack
197/223 (88%)
603/643 (94%)
177/213 (83%)
607/654 (93%)
168/223 (75%)
561/643 (87%)
152/213 (71%)
542/654 (83%)
Baseline Viral Load
≤ 100,000 copies/mL
100,000 copies/mL
629/670 (94%)
171/196 (87%)
610/672 (91%)
174/195 (89%)
567/670 (85%)
162/196 (83%)
537/672 (80%)
157/195 (81%)
Baseline CD4+ cell count
< 200 cells/mm3
≥ 200 cells/mm3
96/112 (86%)
703/753 (93%)
104/117 (89%)
680/750 (91%)
93/112 (83%)
635/753 (84%)
94/117 (80%)
600/750 (80%)
a
Week 48 window was between Day 294 and 377 (inclusive).
b
Week 144 window was between Day 966 and 1049 (inclusive).
c
Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or 
loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and 
at the time of discontinuation had a viral value of ≥ 50 copies/mL.
d
Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted 
in no virologic data on treatment during the specified window.
e
Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, 
loss to follow-up, etc.
At Week 144, GENVOYA demonstrated statistical superiority (p = 0.021) in achieving HIV-1 
RNA < 50 copies/mL when compared to STRIBILD.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 144 was 
326 cells/mm3 in GENVOYA-treated patients and 305 cells/mm3 in STRIBILD-treated patients 
(p=0.06).
Bone Mineral Density: In a pooled analysis of Studies 104 and 111, the effects of GENVOYA 
compared to that of STRIBILD on bone mineral density (BMD) change from baseline to
Week 144 were assessed by dual-energy X-ray absorptiometry (DXA). As shown in Table 1-2, 
in patients who had both baseline and Week 144 measurements (N = 690 and 702 in the 
GENVOYA group and N = 683 and 686 in the STRIBLD group, for hip and spine, respectively) 
there were smaller decreases in BMD in the GENVOYA group as compared to STRIBILD.


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Table 1-2.
Measures of Bone Mineral Density in Studies 104 and 111 (Week 144
Analysis)
GENVOYA
STRIBILD
Treatment Difference
Hip DXA Analysis
N=690
N=683
Mean Percent Change in BMD
−0.8%
−3.4%
2.6%
p < 0.001
Patients with Categorical Change:
3% Decrease in BMD
3% Increase in BMD
28%
13%
55%
6%
--
Patients with No Decrease (≥ zero % change) in BMD
40%
19%
--
Lumbar Spine DXA Analysis
N=702
N=686
Mean Percent Change in BMD
−0.9%
−3.0%
2.0%
p < 0.001
Patients with Categorical Change:
3% Decrease in BMD
3% Increase in BMD
30%
13%
49%
7%
--
Patients with No Decrease (≥ zero % change) in BMD
39%
22%
--
Changes in Renal Laboratory Tests: Laboratory tests were performed in Studies 104 and 111 to 
compare the effect of TAF, administered as a component of GENVOYA, to that of TDF, 
administered as a component of STRIBILD, on renal laboratory parameters. As shown in
Table 1-3, statistically significant differences were observed between treatment groups that 
favored GENVOYA. In these studies, there were statistically significant differences between 
treatment groups for increases in serum creatinine and changes in proteinuria, including Urine 
Protein to Creatinine Ratio (UPCR), Urine Albumin to Creatinine Ratio (UACR), urine retinol 
binding protein (RBP) to creatinine ratio, and urine beta-2-microglobulin to creatinine ratio that 
favored GENVOYA.
Table 1-3.
Change from Baseline in Renal Laboratory Tests in Studies 104 and 
111 (Week 144 analysis)
GENVOYA N=866
STRIBILD N=867
Treatment Difference
Serum Creatinine (mg/dL)a
0.04 ± 0.12
0.07 ± 0.13
−0.04
p < 0.001
Proteinuria by Urine Dipstickb
40%
45%
p = 0.027
Urine Protein to Creatinine Ratio [UPCR]c
−10.5%
25.2%
p < 0.001
Urine Albumin to Creatinine Ratio [UACR]c,d
−5.2%
5.2%
p < 0.001
Urine RBP to Creatinine Ratioc
34.8%
111%
p < 0.001
Urine Beta-2-Microglobulin to Creatinine Ratioc
−25.7%
53.8%
p < 0.001
a
Mean change ± SD
b
Includes all severity grades (1-3).
c
Median percent change.
d
Week 96 analysis.


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Virologically Suppressed Patients
In Study 109, the efficacy and safety of switching from either ATRIPLA, TRUVADA plus 
atazanavir (boosted by either cobicistat or ritonavir), or STRIBILD to GENVOYA were 
evaluated in a randomized, open-label study of virologically-suppressed (HIV-1 RNA
< 50 copies/mL) HIV-1 infected adults (N = 1436). Patients must have been stably suppressed 
(HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months and had no 
resistance mutations to any of the components of GENVOYA prior to study entry. Patients were 
randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N = 959), or stay on their 
baseline antiretroviral regimen (N = 477). Patients had a mean age of 41 years (range 1-77), 89% 
were male, 67% were White, and 19% were Black. The mean baseline CD4+ cell count was
697 cells/mm3 (range 79-1951)
Patients were stratified by prior treatment regimen. At screening, 42% of patients were receiving 
TRUVADA plus atazanavir (boosted by either cobicistat or ritonavir), 32% of patients were 
receiving STRIBILD, and 26% of patients were receiving ATRIPLA.
Pediatric Patients
In this study (GS-US-292-0106), the efficacy, safety, and pharmacokinetics of GENVOYA in 
HIV-1-infected patients were evaluated in open-label studies in treatment-naïve patients between 
the ages of 12 to < 18 years (≥ 35 kg) (N=50) and in virologically suppressed patients between 
the ages of 6 to < 12 years (≥ 25 kg) (N=23).
Cohort 1: Treatment-naïve adolescents (12 to < 18 years; ≥ 35 kg), Week 48 Analysis
Patients in Cohort 1 had a mean age of 15 years (range: 12 to 17), 44% were male, 12% were 
Asian, and 88% were black. At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies/mL, 
median CD4+ cell count was 456 cells/mm3 (range: 95 to 1110), and median CD4% was 23% 
(range: 7% to 45%). 22% had baseline plasma HIV-1 RNA > 100,000 copies/mL.
Among the patients in Cohort 1 treated with GENVOYA, 92% (46/50) achieved HIV-1 RNA
< 50 copies/mL at Week 48. The mean increase from baseline in CD4+ cell count at Week 48 
was 224 cells/mm3. Three of 50 patients had virologic failure at Week 48; no emergent resistance 
to GENVOYA was detected through Week 48.
Among the patients in Cohort 1 who had both baseline and Week 48 measurements (N=47 and 
44 for the lumbar spine and total body less head [TBLH], respectively), mean BMD increased 
from baseline to Week 48, +4.2% at the lumbar spine and +1.3% for TBLH.


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Cohort 2: Virologically suppressed children (6 to < 12 years; ≥ 25 kg), Week 24 Analysis
Patients in Cohort 2, Part A had a mean age of 10 years (range: 8 to 11), a mean baseline weight 
of 31.6 kg (range: 26 to 58), 39% were male, 13% were Asian, and 78% were black. At baseline, 
median CD4+ cell count was 969 cells/mm3 (range: 603 to 1421), and median CD4% was 39% 
(range: 30% to 51%).
After switching to GENVOYA, 100% (23/23) of patients in Cohort 2 remained suppressed 
(HIV-1 RNA < 50 copies/mL) at Week 24. The mean change from baseline in CD4+ cell count 
at Week 24 was -150 cells/mm3. No patient qualified for resistance analysis through Week 24.
Among the patients in Cohort 2 who had both baseline and Week 24 measurements (N=21 and 
23, for lumbar spine and TBLH, respectively), mean BMD increased from baseline to Week 24,
+2.9% at the lumbar spine and +1.7% for TBLH.
For further information, including the results of studies of GENVOYA in adults and adolescents, 
please refer to the current GENVOYA Investigator’s Brochure.
1.2.
Rationale for the Current Study
The success of HAART and the apparent benefits of maximally suppressed viremia has shifted 
clinical attention towards antiretroviral agents that optimize long-term safety and tolerability. 
Young, newly infected patients are diagnosed earlier, initiate therapy earlier, and look ahead 
towards lifelong therapy, often greater than fifty years {Prejean 2011}. Renal and bone health, in 
both of these contexts, are increasingly important {Capeau 2011}.
Based on the data from this study and extrapolation to adult efficacy and safety data, 
GENVOYA was approved in adults and pediatric patients 12 years of age and older in the US 
and EU in 2016 and approved in 2017 for use in pediatric patients 6 to < 12 year of age weighing 
≥25 kg.
HIV-infected children ages ≥ 2 years of age will benefit from the availability of an age-
appropriate formulation containing TAF, which has the potential for an improved renal and bone 
safety profile relative to TDF, an important consideration for a population in which peak bone 
mass has not yet been achieved and for whom HIV treatment is anticipated to be life-long.
The objective of this study is to characterize the pharmacokinetics (PK), and confirm the dose of 
E/C/F/TAF and to evaluate the safety, tolerability and antiviral activity of E/C/F/TAF as an STR 
in treatment-naive HIV-1 infected adolescents 12 to less than 18 years of age and in virologically 
suppressed HIV-1 infected children 2 to < 12 years of age.


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1.3.
Rationale for Dose Selection
The proposed E/C/F/TAF doses for this study are expected to provide plasma exposures in the 
pediatric population that are comparable to those associated with safety and efficacy in adults.
E/C/F/TAF Dose in Adolescents 12 to < 18 years old, weighing ≥ 35 kg
The FDA-approved dose of E/C/F/TAF in adolescents 12 to < 18 years, ≥ 35 kg is the adult 
strength STR (150/150/200/10 mg).
E/C/F/TAF Dose in Children ≥ 2 years old weighing ≥ 25 kg, and weighing ≥ 14 to < 25 kg
The FDA-approved dose of E/C/F/TAF in children weighing ≥ 25 kg is the adult strength STR 
(150/150/200/10 mg). For children weighing ≥ 14 to ˂ 25 kg, a low dose E/C/F/TAF tablet of 
90/90/120/6 mg is proposed for evaluation. The observed exposures following administrationof 
E/C/F/TAF 150/150/200/10 mg in children weighing ≥ 25 kg or predicted exposures of 
E/C/F/TAF 90/90/120/6 mg in children weighing ≥ 14 to ˂ 25 kg are comparable to those
observed in adults for all analytes (EVG, COBI, FTC, TAF and TAF-metabolite TFV). The 
dosing nomogram is structured to avoid subtherapeutic dosing in a population requiring lifelong 
therapy from a young age, in which the implications of virologic failure may be greater than in 
adults.
Rationale for E/C/F/TAF Dose in Children weighing ≥ 25 kg 
EVG:
EVG is differentially dosed in adults in order to achieve comparable EVG exposures depending 
on the co-administered regimen: 85 mg with LPV/r or ATV/r; EVG 150 mg with COBI and 
other boosted PIs.
Preliminary data are available in treatment-experienced children 6 to < 12 years old on a regimen 
containing LPV/r or ATV/r from Study GS-US-183-0160. Of 14 participants who completed the 
PK substudy, 6 were taking the adult strength EVG 85 mg (bodyweight ≥ 30 kg) and 8 were 
taking a reduced strength EVG 50 mg (body weight 17 to < 30 kg). Plasma exposures of EVG 
were similar to those previously observed in adolescents, and higher than in adults (GMR AUC 
1.36; GMR Ctrough 1.29) with all participants having an EVG Ctrough above the protein-binding 
adjusted IC95 of 44.5 ng/mL. Plasma exposures support using the adult EVG dose in 6 to 
< 12 years olds ≥ 30 kg. Simulation for children with a bodyweight between 25 and < 30 kg 
demonstrated that when combined with LPV/r, administration of the higher dose (85 mg) would 
result in slightly higher, but acceptable EVG exposures. EVG was well-tolerated in this study, 
with no related SAEs or AEs leading to EVG discontinuation (with one related AE of mild 
dizziness). Therefore, the adult 150 mg dose of EVG is proposed for use in children 6 to 
< 12 years old weighing ≥ 25 kg.


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COBI:
The 150 mg dose of COBI is the adult dose, selected for its efficacy in boosting EVG exposures. 
COBI dose selection was guided by dose/data available for ritonavir boosting in various pediatric 
weight bands and similarities in observed dose-dependent PD effects (CYP3A inhibition) for 
COBI versus RTV in adults. Comparison of ritonavir (RTV) and COBI dose-ranging PK and PD 
(Studies GS-US-183-0113, GS-US-216-0101, GS-US-216-0110, and GS-US-236-0101) indicate
comparable CYP inhibition/boosting of probe/other substrates, including ARVs. The proposed 
COBI doses generally represent a higher dose on a mg/kg basis relative to the adult dose, and are 
expected to provide sufficient boosting activity within the context of E/C/F/TAF STR. The adult 
150 mg dose of COBI is proposed for administration to pediatric subjects ≥25 kg.
FTC:
Emtricitabine is approved to be dosed at ≤ 6.1 mg/kg in children with either a capsule or oral 
solution formulation {EMTRIVA® 2012}. Per the current Emtriva label, the approved dose of 
200 mg FTC can be administered in adults with normal renal function and those with mild renal 
impairment (50-80 mL/min), in whom FTC exposures were shown to be approximately 70%
higher than adults with normal renal function {EMTRIVA® 2012}. In addition, a proposal for
FTC/TDF low-dose tablets from the WHO Paediatric Antiretroviral Working Group {World 
Health Organization (WHO) 2011} allows FTC doses up to 8.57 mg/kg (corresponding to a 40% 
increase in dose over 6.1 mg/kg) for use in children. Given the approved doses for FTC and its 
dose-proportional pharmacokinetics, a modest increase of FTC dose in children is expected to
result in exposures in the range of those providing a favorable risk:benefit profile. The E/C/F/TAF
(150/150/200/10 mg) adult-strength STR for use in patients 6 to < 12 years of age ≥25 kg 
provides a range of FTC doses comparable to the approved doses, and does not exceed
8.57 mg/kg.
TAF:
The TAF dose selection in children 6 to < 12 years of age is based on the established TDF dose 
to exposure relationship in children and adults, where it has been shown that administration of 
TDF doses at approximately twice the average adult dose (on a mg/kg basis) result in TFV 
exposures in children within the range observed in adults {Gilead Sciences Inc 2012}.
The TAF dose proposed for a 75 kg adult is 0.13 mg/kg when used with boosted regimens such 
as E/C/F/TAF STR. For a subject ≥ 25 kg to < 35 kg, administration of TAF 10 mg (in the 
context of E/C/F/TAF STR) corresponds to a range of TAF dose per body weight of 0.29 to 
0.40 mg/kg (approximately 2 to 3 times the adult dose). This is predicted to result in TAF 
exposures in children within the range observed in adults and to yield maximum exposures in the 
lowest weight ranges of each band less than 2-fold above mean TAF exposure in adults.


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Rationale for E/C/F/TAF Dose in Children weighing ≥ 14 to < 25 kg
For dose selection in children weighing ≥ 14 to < 25 kg, EVG, COBI, FTC, TAF and TFV 
exposures were predicted by allometric scaling of adult exposures considering correlations 
between body weight and clearance (CL) capacity. Model-predicted systemic exposures of EVG, 
COBI, FTC, TAF and TFV in children weighing ≥ 14 to < 25 kg administered the low dose 
E/C/F/TAF STR (90/90/120/6 mg) are presented in Figure 1-1, Figure 1-2, Figure 1-3, 
Figure 1-4 and Figure 1-5, respectively. These simulations indicate that the predicted exposure 
ranges of EVG, COBI, FTC, TAF and TFV in children 2 to < 12 years weighing ≥ 14 to < 25 kg 
following administration of E/C/F/TAF 90/90/120/6 mg are comparable to those observed in the 
adult Phase 2/3 population, and in children 6 to < 12 years weighing ≥ 25 kg who received the 
adult strength STR.
Figure 1-1.
Predicted EVG AUC in Children Following Administration of 
E/C/F/TAF 90/90/120/6 mg
The adult exposures for EVG were the population PK predicted exposures from the STB Phase 2/3 program 
(Stribild NDA 203100 SN 0000, m5.3.3.5, COBI-boosted EVG Population PK report)
::r 
E -
C, 
C • 
.c 
u 
::::, 
<C 
80000 
~10000· 
w 
E/C/F/TAF 90/90/120/6 mg 
:':" ... - · - .... _ ·.;. ·;.; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph2/3 Adult Max 
------ .. ,. ~-------------------
[.-:-: .. .. : .. :-'.'. -~-~-.:': .. ~. -~--~-:":'. -~-_......, __ ,,_ . ..,. ·;.;.· ~-· .:.;,--~· ·.:.;· -~--:.:,· :_:,· ·.:,:--.:_:· ·.:_· -~-~--~--~--~--~--~· ~--~--~--~--~-~-· ~--~--~--~--J· Ph2/3 Adult 95th % 
,---------------
. .......................................... _ ,_,_. ........................................... . 
----------------
Ph2/3 Adult Median 
Ph2/3 Adult 5th % 
-
· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph 2/3 Adult Min 
. 
. 
. 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
Weight (kg) 
Predicted AUC: 
-
Median 
- -
5th/95th percentile 


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Figure 1-2.
Predicted COBI AUC in Children Following Administration of 
E/C/F/TAF 90/90/120/6 mg
The adult exposures for COBI were the population PK predicted exposures from Phase 2/3 studies with Stribild (STB) or 
ATV/co + Truvada (ATV/co + TVD) (Studies GS-US-236-0102, GS-US-236-0103, GS-US-236-0104, GS-US-216-0105, and 
GS-US-216-0114)
Figure 1-3.
Predicted FTC AUC in Children Following Administration of 
E/C/F/TAF 90/90/120/6 mg
The adult exposures for FTC were the exposures from Phase 2/3 studies with STB (Studies GS-US-236-0101, GS-US-236-0102, 
GS-US-236-0103, GS-US-236-0104, and GS-US-236-0110)
40000 
E/C/FITAF 90/90/120/6 mg 
Ph2/3 Adult Max 
::f 
[·~··~··~·~··~··~··:"!"'· ·~·""· ----.......... · ·.,.··;.;.·:.:.··~··.:.;··.:;··:.:.·;.;,· ·.:.;··.:.:··:.;_··:.:,·:.:,··.:_:··_;,;··:.:_·:,:_··:_:··.:_:··.:_:· ·~·~··::··.:_:··.:.··~·~··~··~··j· Ph2/3 Adult 95th % 
E 10000 
- - - - - - - - - - __ _ 
c3, 
................................. -~ .• . 11111 - ·- _ . .., ... -w ·• ·:.; ·..;,· :..: ·..:.· ;.: -~ -
·_:· :_: :.:,·:: :.:,·: 
C: • 
.c: 
Ph2/3 Adult Median 
-u 
:::> 
<( 
iii 
0 u 
:J" 
E -
C) 
C: • 
:S 
u 
:::> 
Ph 2/3 Adult 5th % 
1000 
· · · · · · · · · · · · · · · · · · · · .... · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph2/3 Adult Min 
14 
15 
16 
17 
18 
19 
20 
21 
Weight (kg) 
22 
23 
24 
25 
Predicted AUC: -
Median 
- -
5th/95th percentile 
E/C/FITAF 90/90/120/6 mg 
50000 
· · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · · · · · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · .. · · • · · · · · Ph2/3 Adult Max 
-------------------------------------
[ ~· ·~· -~-·~· ·~ .. ~· .. .. ':°: .. ".': .. "'.°'. •• :"." •• :":'. :":' 
•• •• ":": 
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.. .:_:· ·.:.· -~· ·~· ~· ·~· ·~· -~-·~· ·~· ~-• J· · Ph2/3 Adult 95th % 
----------------
......................................... ::.~.:":.":"'. :-:-.~. -·-- ···--······················ 
Ph2/3 Adult Median 
<( 
10000 
u 
---------
I-
LL 
Ph2/3 Adult 5th % 
· · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · • · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · .. • · · · • · · · · • · · · · · · · · · · · · · · Ph2/3 Adult Min 
14 
15 
16 
17 
18 
19 
20 
21 
Weight (kg) 
22 
23 
Predicted AUC: -
Median (60%) 
- -
5th/95th percentile 
24 
25 


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Figure 1-4.
Predicted TAF AUC in Children Following Administration of 
E/C/F/TAF 90/90/120/6 mg
The adult exposures for TAF were the population PK predicted exposures from the GEN Phase 2/3 program
(Genvoya NDA 207561, m5.3.3.5, Population PK Analysis of TAF and TFV following Administration of E/C/F/TAF STR)
Figure 1-5.
Predicted TFV AUC in Children Following Administration of 
E/C/F/TAF 90/90/120/6 mg
The adult exposures for TFV were the population PK predicted exposures from the GEN Phase 2/3 program
(Genvoya NDA 207561, m5.3.3.5, Population PK Analysis of TAF and TFV following Administration of E/C/F/TAF STR)
E/C/F/TAF 90/90/120/6 mg 
4000 
~1000 . ________________ _ 
E 
-------------------
-
C) 
C: • 
.c -u 
·-----------------
<( 
100 
- - - - - - - - - - - - - - - - - - • 
LL 
Ph2/3 Adult Max 
Ph2/3 Adult 95th % 
Ph2/3 Adult Median 
Ph2/3 Adult 5th % 
· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph2/3 Adult Min 
10+--------,--...-.-....... -----,--...---,..--........ ---.---..---+ 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
Weight (kg) 
Predicted AUC: -
Median 
- -
5th/95th percentile 
E/C/F/TAF 90/90/120/6 mg 
2000 
Ph2/3 Adult Max 
-1000 • - - - - - - - ------------
E 
-----------------
0, 
C: • :S 
(.J 
<( 
> 
LL 
.... 
Ph2/3 Adult 95th % 
"::-.:-:.~---•-•,..•a.:·~·:.:·.::;,;·~·:,:··············································
········ Ph2/3 Adult Median 
----------------------
· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph 2/3 Adult 5th % 
· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ph2/3 Adult Min 
100+---.-------....... -
....... ---,,.....-..---.--....... --,......-+ 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
Weight (kg) 
Predicted AUC: -
Median 
- -
5th/95th percentile 


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2.
OBJECTIVES
Cohort 1
The primary objectives of this study are:
Part A:

To evaluate the steady state pharmacokinetics (PK) for elvitegravir (EVG) and tenofovir 
alafenamide (TAF) and confirm the dose of the elvitegravir/cobicistat/emtricitabine/tenofovir 
alafenamide (E/C/F/TAF) single tablet regimen (STR) in HIV-1 infected, antiretroviral 
(ARV) treatment-naive adolescents
Part B:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 24 in HIV-1 
infected, ARV treatment-naive adolescents
The secondary objectives for Cohort 1 for this study are:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 48 in HIV-1 
infected, ARV treatment-naive adolescents

To evaluate the antiviral activity of the E/C/F/TAF STR through Week 48 in HIV-1infected, 
ARV treatment-naive adolescents
Cohort 2
The primary objectives of this study are:
Part A:

To evaluate the PK of EVG and TAF in virologically suppressed HIV-1 infected children 
6 to < 12 years of age, weighing ≥ 25 kg, administered E/C/F/TAF STR
Part B:

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 24 in HIV-1 
infected children 6 to < 12 years of age
The secondary objectives for this study are:

To evaluate the antiviral activity of switching to E/C/F/TAF STR through Week 48 in 
virologically suppressed HIV-1 infected children 6 to < 12 years of age weighing ≥25 kg.

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 48 in virologically 
suppressed HIV-1 infected children 6 to < 12 years of age, weighing ≥25 kg


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Cohort 3 
The prima1y objectives of this study are: 
Final 
Amendment6 
• 
To evaluate the PK of EVG and TAF and confnm the dose of the STR in virologically 
suppressed HIV-I infected children 
2 years of age weighing 
14 to < 25 kg administered 
E/C/F IT AF LD STR 
• 
To evaluate the safety and tolerability ofE/C/F/TAF LD STR through Week 24 in 
virologically suppressed HIV-I infected children ~ 2 years of age and weighing~ 14 to 
< 25 kg 
The secondaiy objectives of this study are: 
• 
To evaluate the antiviral activity of switching to E/C/FffAF LD STR through Week 48 in 
virologically suppressed HIV-I infected children ~ 2 years of age and weighing~ 14 to 
< 25 kg 
• 
To evaluate the safety and tolerability ofE/C/F/TAF LD STR through Week 48 in 
virologically suppressed HIV-I infected children ~ 2 yeai·s of age and weighing ~ 14 to 
< 25 kg 
All Cohorts 
I 
CONFIDENTIAL 
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21 Febrna1y 2020 


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Protocol GS-US-292-0106
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Amendment 6
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21 February 2020
3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This protocol describes an open-label, multicenter, multi-cohort, single-arm study of the 
pharmacokinetics (PK), safety, tolerability, and antiviral activity of the E/C/F/TAF STR in 
HIV-1 infected ARV treatment-naive adolescents and virologically suppressed children.
A total of 50 adolescents (12 to < 18 years of age) and up to 75 children (6 to < 12 years of age) 
of either sex will be enrolled to receive the STR of E/C/F/TAF once daily with food as follows:
Part A
Intensive PK samples will be analyzed for Cohort 1 and 2 once they are available from 
18 subjects regardless of age distribution and for all Cohort 3 subjects.
Cohort 1, Part A: EVG, TAF and COBI exposures will be compared to historical data from adult 
HIV-1 infected subjects. TAF data will also be compared to HIV-negative subjects from
292-0103 study. FTC and TFV exposures will be compared to historical data in HIV-infected 
adults and available data in adolescent subjects. Cohort 2, Part A: EVG, TAF, COBI, FTC and 
TFV exposures will be compared to historical adult data.
EVG and TAF dose confirmation will be established if the 90% confidence intervals of 
geometric mean ratios for AUC in adolescents and children (respectively) versus those in adults 
are within the equivalency bounds of 70-143%.
Following completion of the Intensive PK visit, subjects will continue to receive E/C/F/TAF 
STR and return for scheduled study visits through Week 48.
Cohort 1 (Adolescents 12 to < 18 years of age)

Eighteen to 24 eligible subjects will be initially enrolled to evaluate the steady state PK, and 
confirm the dose of the E/C/F/TAF STR.

Part A will aim to enroll at least 6 subjects 12 to < 15 years of age and at least 6 subjects 
15 to < 18 years of age.

If at least 6 subjects ages 12 to < 15 years and 6 subjects ages 15 to < 18 have not been 
enrolled at the time of the Intensive PK analysis, Part A enrollment will remain open in order 
to enroll sufficient subjects to meet the minimum enrollment of the 2 agesubgroups.

Subjects enrolled in Part A will participate in an Intensive PK evaluation on Week 4. 
Samples will be collected at 0 (pre-dose, ≤ 30 minutes prior to dosing), 5 minutes, 0.25, 0.5, 
1, 1.5, 2, 4, 5, 8 and 24 hours post-dose.


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Cohort 2 (Children 6 to < 12 years of age and weight ≥ 25 kg)

Eighteen to 24 eligible subjects will be enrolled to evaluate the EVG and TAF plasma PK 
and confirm the dose of EVG and TAF.

Subjects will participate in an Intensive PK evaluation on Week 4.
Cohort 3 (Children ≥ 2 years of age and weighing ≥ 14 to < 25 kg)

Up to 25 eligible subjects will be enrolled to evaluate the EVG and TAF plasma PK and 
confirm the dose of EVG and TAF.

Subjects will participate in an Intensive PK evaluation on Week 2.
Part B 
Cohort 1
Screening will be initiated into Cohort 1, Part B following confirmation of EVG and TAF 
exposure in at least 18 subjects from Cohort 1, Part A. The additional 26 – 32 subjects will be 
enrolled in Cohort 1, Part B to evaluate the safety, tolerability and antiviral activity of the 
E/C/F/TAF STR in at least 50 patients, including all subjects enrolled in Cohort 1 (Parts A and 
Part B combined).
Cohort 2
Screening will be initiated in subjects 6 to < 12 years of age into Cohort 2, Part B based on 
exposure data from at least 18 subjects from Cohort 2, Part A. The additional 26 – 32 subjects 
will be enrolled in Cohort 2, Part B to evaluate the safety, tolerability and antiviral activity of the 
E/C/F/TAF STR in at least 50 patients, including all subjects enrolled in Cohort 2 (Parts A and B 
combined).
Cohort 3
No Part B for this cohort. All subjects will be enrolled in Part A and will complete an Intensive 
PK evaluation.


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Figure 3-1.
Study Schema
Cohort 1:
a
Screening for Part B will commence after the PK data from Part A confirms the adolescent dose of the E/C/F/TAF STR
Cohort 2:
Cohort 3:
Screening 
:, 35 days prior 
B~" 
to Baseline 
(Day l} 
Pan A: E/C/F/TAF QD 
N=IS-2~ 
PK 
\Veek 24 
\Veek 48 
Screening" 
'.':: 35 daF pria,-
B~" 
Week24 
to Baseline 
(Day l) 
Screening 
-:, 35 days prior 
B~ 
to Baseline 
(Day ]) 
Part A E/C/Fc AF QD 
N=18-H 
PK 
Week24 
Week 48 
30 Day f -
We<!k 48 
30 Day F1U 
30 Dayf -
( 
creeningH.___P_art_. B_: ---....... ~--# .... m 
....... 
1-----------------1 
-:, 35 days prior 
&:,eliru, 
Week48 
30 Day F/U 
to Baseline 
(Day I) 
( ScreeningH.__ __ 
~-/~;.;....;!_j!_:m Q;._
,H _ 
__.~ .....
. ....... ...... " ....... 
'.':: 3.> day~ prior 
Baseiin,, 
PK 
to Baseline 
(Day I) 
\Veek 24 
W'"'148 
30 Day f -


EVG/COBI/FTC/TAF
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Amendment 6
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of 50 adolescents (12 to < 18 years of age) and up to 75 children (2 to < 12 years of age) 
who meet the eligibility criteria will be enrolled into this study.
Replacement subjects may be enrolled if subjects do not complete all Intensive PK procedures or 
if PK data are incomplete. Replacement subjects will not be enrolled in Part A for subjects who 
discontinue the study due to treatment-related toxicity.
Cohort 1:
Part A
Eighteen to 24 subjects representing two age strata (at least 6 subjects must be 12 to < 15 years 
of age and at least 6 subjects must be 15 to < 18 years of age).
Part B
Twenty-six to 32 subjects between 12 to < 18 years of age (dependent upon enrollment in 
Part A).
Cohort 2:
Part A
Eighteen to 24 subjects 6 to < 12 years of age and weigh ≥ 25 kg.
Part B
Twenty-six to 32 subjects 6 to < 12 years of age and weigh ≥ 25 kg.
Cohort 3:
Approximately 25 subjects ≥ 2 years of age and weighing ≥ 14 to < 25 kg.
4.2.
Inclusion Criteria
All Cohorts
Subjects must meet all of the following inclusion criteria, as well as the Cohort specific criteria 
listed below, to be eligible for participation in this study. Subjects with screening results that do 
not meet eligibility criteria will not be allowed to rescreen:

CD4+ cell count ≥ 400 cells/μL and CD4+ percentage of 20%

Adequate renal function: estimated glomerular filtration rate ≥ 90 mL/min/1.73m2
Estimated Glomerular Filtration Rate (eGFR) using Schwartz Formula (mL/min/1.73m2)
= k L/Scr [(k is a proportionality constant, for females ≥ 2 years old is 0.55; and for 
males ≥ 12 years old is 0.70) and males and females 2 to ≤ 11 years old is 0.55; L is 
height in centimeters (cm); and Scr is serum creatinine (mg/dL)]


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
Clinically normal ECG (or if abnormal, determined by the investigator to be not clinically 
significant)

Documented screening for active pulmonary tuberculosis per local standard of care within 
6 months of a Screening visit.

Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)

Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin

Adequate hematologic function:
Absolute neutrophil count ≥500/mm3
Platelets ≥50,000/mm3
Hemoglobin ≥ 8.5 g/dL

Note that subjects with chronic neutropenia, defined as having an ANC of < 500/mm3
documented at least twice within 6 months of screening, and in whom, according to the 
investigator, there is no evidence of active opportunistic or serious infection can enroll in the 
study contingent upon approval from the Gilead study Medical Monitor.

Negative serum pregnancy test for all female subjects

Females of childbearing potential (as defined in Appendix 5) must have a negative serum 
pregnancy test at screening and Baseline/Day 1

Male subjects and female subjects of childbearing potential who engage in heterosexual
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 5

Subjects able to give written assent prior to any screening evaluations

Parent or guardian able to give written informed consent prior to any screening evaluations 
and willing to comply with study requirements

Able to swallow oral tablets

Must be willing and able to comply with all study requirements

Life expectancy > 1 year
Cohort 1

12 to < 18 years of age at Baseline

Weight ≥ 35 kg (77 lbs) at Screening


EVG/COBI/FTC/TAF
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
Plasma HIV-1 RNA levels of > 1,000 copies/mL at Screening (Roche COBAS TaqMan v2.0)

Screening genotype report shows sensitivity to EVG, FTC andTFV (Monogram Biosciences,
Inc.)
Subjects with HIV subtype AE who meet all inclusion/exclusion criteria and who have a 
non-reportable integrase genotype result may proceed with study enrollment
(Thailand only)

No prior use of any approved or experimental anti-HIV-1 drug for any length of time 
(other than that given for prevention of mother-to-child transmission)
Cohort 2

6 to < 12 years of age at Baseline

Weight ≥ 25 kg (55 lbs) at Screening

Plasma HIV-1 RNA: < 50 copies/mL (or undetectable HIV-1 RNA level according to the 
local assay being used if the limit of detection is > 50 copies/mL) for ≥ 180 consecutive days 
(6 months) prior to Screening on a stable antiretroviral regimen, without documented history 
of resistance to any component of E/C/F/TAF STR
Unconfirmed HIV-1 RNA ≥ 50 copies/mL after previously reaching virologic 
suppression (transient detectable viremia, or “blip”) prior to Screening is acceptable
Currently receiving an antiretroviral regimen that has been stable for at least
180 consecutive days (6 months) or has been newly initiated within 6 months for reasons 
other than virologic failure.
Cohort 3

≥ 2 years of age at Baseline

Weight ≥ 14 to < 25 kg (≥ 31 to < 55 lbs) at Screening

Plasma HIV-1 RNA: < 50 copies/mL (or undetectable HIV-1 RNA level according to the 
local assay being used if the limit of detection is > 50 copies/mL) for ≥ 180 consecutive days 
(6 months) prior to Screening on a stable antiretroviral regimen, without documented history 
of resistance to any component of E/C/F/TAF STR
Unconfirmed HIV-1 RNA ≥ 50 copies/mL after previously reaching virologic 
suppression (transient detectable viremia, or “blip”) prior to Screening is acceptable
Currently receiving an antiretroviral regimen that has been stable for at least 180 
consecutive days (6 months) or has been newly initiated within 6 months for reasons 
other than virologic failure.


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

A new AIDS-defining condition diagnosed within the 30 days prior to Screening (Referto
Appendix 6).

Positive Hepatitis C antibody. Note: Subjects with false positive hepatitis antibody confirmed 
by negative Hepatitis C PCR are permitted to enroll.

Positive Hepatitis B surface antigen or other evidence of active HBV infection.
Note: Subjects with positive HBV surface antibody and no evidence of active HBV infection 
are permitted to enroll.

Prior treatment with any approved or investigational or experimental anti HIV-1 drug for any 
length of time (other than that given for prevention of mother-to-child transmission)
(Cohort 1 only)

Evidence of active pulmonary or extra-pulmonary tuberculosis disease within 3 months of 
the Screening visit.

Anticipated to require rifamycin treatment for mycobacterial infection while participating in 
the study. Note: prophylactic INH therapy for latent TB treatment isallowed.

Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)

Pregnant or lactating subjects

Have an implanted defibrillator or pacemaker

Have any serious or active medical or psychiatric illness which, in the opinion of the 
Investigator, would interfere with subject treatment, assessment, or compliance with the 
protocol. This would include uncontrolled renal, cardiac, hematological, hepatic, pulmonary 
(including chronic asthma), endocrine (e.g., diabetes), central nervous, gastrointestinal 
(including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), 
immunodeficiency disorders, active infection, or malignancy that are clinically significant or 
requiring treatment within 30 days prior to the study dosing.

Current alcohol or substance abuse judged by the Investigator to potentially interfere with 
subject compliance.

Have history of significant drug sensitivity or drug allergy.

Known hypersensitivity to the study drugs, the metabolites or formulation excipients 
(see Section 5.2)


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
Have been treated with immunosuppressant therapies or chemotherapeutic agents within 
3 months of study Screening or expected to receive these agents during the study
(e.g., immunoglobulins, and other immune- or cytokine-based therapies).

A history of malignancy within the past 5 years (prior to Screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 30 days of Baseline and must not be anticipated 
to require systemic therapy during the study.

Active, serious infections (other than HIV-1 infection) requiring parenteral antibioticor 
antifungal therapy within 30 days prior to Baseline.

Have previously participated in an investigational trial involving administration of any 
investigational agent within 30 days prior to the study dosing.

Participation in any other clinical trial (including observational trials) without priorapproval 
from sponsor is prohibited while participating in this trial.

Subjects receiving ongoing therapy with any of the medications in the table below, including 
drugs not to be used with EVG, COBI, FTC, TDF and TAF (For EVG, COBI, and FTC refer 
to the individual agents Prescribing Information; for EVG, and TAF refer to the E/C/F/TAF 
STR Investigator’s Brochure); or subjects with any known allergies to the excipients of 
E/C/F/TAF STR tablets.


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Drug Class
Agents Disallowed*
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Antibacterials
Telithromycin
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antiplatelets
Clopidogrel
Endothelin Receptor Antagonists
Bosentan
Calcium Channel Blockers
Bepridil
Ergot Derivatives
Ergotamine, Ergonovine Dihydroergotamine 
Methylergonovine Ergometrine
Direct Acting Anticoagulants
Apixaban, Rivaroxaban
GI Motility Agents
Cisapride
Herbal Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Sedatives/Hypnotics
Midazolam, Triazolam
Systemic** Corticosteroids with the exception of
short-term (≤ 1 week) use of prednisone as a steroid burst
All agents, including dexamethasone
*
Administration of any of the above medications must be discontinued at least 21 days prior to the Baseline/Day 1 visit and 
for the duration of the study.
**
Systemic use defined as intravenously or orally administered corticosteroid.


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5.
INVESTIGATIONAL MEDICINALPRODUCTS
5.1.
Randomization and Blinding
This is an open-label, non-blinded study. All eligible subjects will receive open-label E/C/F/TAF 
STR.
Once eligibility is confirmed, the Sponsor will assign a unique subject number for each eligible 
subject and provide the subject number information to the study site.
The subject number assignment may be performed up to 7 days prior to the in-clinic Baseline 
visit provided that all screening procedures have been completed and subject eligibility has been 
confirmed. Once a subject number has been assigned, it will not be reassigned to any other 
subject.
All Baseline tests and procedures must be completed and eligibility confirmed prior to the 
administration of the first dose of study drug.
It is the responsibility of the Investigator to ensure that the subject is eligible for the study prior 
to enrollment.
5.2.
Description and Handling of E/C/F/TAF STR
5.2.1.
Formulation
E/C/F/TAF 150/150/200/10 mg
E/C/F/TAF 150/150/200/10 mg STR tablets are capsule-shaped, film-coated green tablets and 
are debossed with “GSI” on one side of the tablet and “510” on the other side of the tablet.
E/C/F/TAF STR tablets contain 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg 
of TAF (as 11.2 mg of TAF fumarate). The E/C/F/TAF 150/150/200/10 mg STR tablet cores 
contain silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, 
magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate as inactive ingredients 
and are film-coated with indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, 
talc, titanium dioxide, and yellow iron oxide.
E/C/F/TAF 90/90/120/6 mg (Low Dose)
E/C/F/TAF LD STR tablets are capsule-shaped, film-coated green tablets and are debossed with 
“GSI” on one side of the tablet and “306” on the other side of the tablet. E/C/F/TAF LD STR 
tablets contain 90 mg of EVG, 90 mg of COBI, 120 mg of FTC, and 6 mg of TAF (as 6.7 mg of 
TAF fumarate). The E/C/F/TAF LD STR tablet cores contain silicon dioxide, croscarmellose 
sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline 
cellulose, and sodium lauryl sulfate as inactive ingredients and are film-coated with polyethylene 
glycol, polyvinyl alcohol, talc, titanium dioxide, black iron oxide, and yellow iron oxide.


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5.2.2.
Packaging and Labeling
E/C/F/TAF 150/150/200/10 mg tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 30 tablets, a silica gel desiccant canister and polyester coil fiber.
Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene screw cap 
fitted with an induction-sealed, aluminum-faced liner.
E/C/F/TAF LD tablets are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 30 tablets, a silica gel desiccant canister and polyester coil fiber. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drug bottles to be distributed to centers in all countries will meet all 
applicable requirements of the FDA and Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (July 2010) and/or other local regulations as 
applicable.
5.2.3.
Storage and Handling
The E/C/F/TAF STR tablets should be stored at a controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). To ensure the stability of the 
tablets, the drug product should not be dispensed into a container other than the container in 
which it is supplied. Measures that minimize drug contact with the body should always be 
considered during handling, preparation, and disposal procedures.
All study medications should not be stored in any containers other than the container in which it 
is supplied.
5.3.
Dosage and Administration of E/C/F/TAF STR
The E/C/F/TAF STR tablets will be provided by Gilead Sciences and will be administered orally, 
once daily with food at approximately the same time each day.
In-clinic dosing will be performed at Baseline/Day 1 and Weeks 1, 2, 4, 12, 24, and 48. For 
those subjects that take their medication in the evening, the in-clinic dosing will not be 
performed.
Subjects in Part A (inclusive of Cohort 3) will be administered their dose of study 
medication in the clinic with food during the Intensive PK visit, at Week 4 (Cohorts 1 and 2) 
or Week 2 (Cohort 3). In order to allow for ease of PK sampling over a 24-hour period, subjects 
should be instructed to take their dose of E/C/F/TAF STR together with food at the same time 
every day in the morning (breakfast), during the days leading up to Intensive PK assessments.
Prior to the scheduled trough and Intensive PK visits, subjects should fast overnight (a minimum 
of 8 hours).


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Subjects will be instructed to bring all study medication in the original container at each study 
visit for drng accountability (unless othe1wise specified in Section 6). The Investigator will be 
responsible for maintaining accurate records for all study drng bottles dispensed and tablets 
returned. The invento1y and dispensing logs must be available for inspection by the study 
monitor. Study medication supplies, including paiiially used or empty bottles, must be accounted 
for by the study monitor prior to desti11ction or return. 
For subjects in Cohort 3 unable to swallow the tablet whole, it is acceptable to split the tablet in 
two and administer both palis sequentially. 
5.4. 
Prior and Concomitant Medications 
• 
Concenti·ations of ethinyl estradiol may decrease and progestin level may increase on 
coadminisu-ation of honnonal conti·aceptives with study diug. Please see the table below and 
refer to Appendix 5 for guidance on the use of conti·aception methods. 
• 
Coadininisti·ation of GENVOY A with diugs that have active metabolite(s) fonned by 
CYP3A may result in reduced plasma concenti·ations of the active metabolite(s). 
• 
Drngs that induce CYP3A activity ai·e expected to increase the clearance ofEVG and COB!, 
resulting in decreased plasma concenti·ation of COB!, and thus that of EVG, which may lead 
to loss of therapeutic effect of GENVOY A, and development of resistance. 
• 
Medications listed in the following table and use of herbaVnatural supplements are excluded 
or should be used with caution while subjects ai·e participating in the study due to potential 
diug-diug interactions with the study diug. Inclusion of medications in this list does not 
imply approval for use in pediatric populations. 
• 
The list below should be utilized in jurisdictions in which E/C/FffAF has NOT been 
approved. 
CONFIDENTIAL 
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21 Febrna1y 2020 


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents 
Antacids
Elvitegravir plasma concentrations are lower with 
antacids due to local complexation in the GI tract and 
not to changes in gastric pH. It is recommended to 
separate E/C/F/TAF STR and antacid administration 
by at least 2 hours.
Alpha-1 Adrenoreceptor 
Antagonist
Alfuzosin
Antiarrhythmics
Amiodarone, Bepridil, Digoxin, Disopyramide, 
Flecainide, systemic Lidocaine, Mexiletine, 
Propafenone, Quinidine:
Concentrations of these antiarrhythmics may increase 
when coadministered with Cobicistat. Caution is 
warranted and clinical monitoring is recommended 
upon coadministration of these agents with 
E/C/F/TAF STR.
Antibacterials
Telithromycin
Clarithromycin and Telithromycin:
Concentrations of Clarithromycin and/or Cobicistat 
may be altered when Clarithromycin is 
coadministered with E/C/F/TAF STR.
Patients with CLcr greater than or equal to 60 mL/min: 
No dose adjustment of Clarithromycin is required.
Patients with CLcr between 30 mL/min and 
60 mL/min: The dose of Clarithromycin should be 
reduced by 50%. Concentrations of Telithromycin 
and/or Cobicistat may be increased when 
Telithromycin is coadministered with E/C/F/TAF 
STR. Clinical monitoring is recommended
upon coadministration with E/C/F/TAF STR.
Anticoagulants
Concentrations of Warfarin may be affected upon 
coadministration with E/C/F/TAF STR. It is 
recommended that the international normalized ratio 
(INR) be monitored upon coadministration with 
E/C/F/TAF STR.
Direct Oral 
Anticoagulants (DOACs)
Apixaban, Rivaroxaban
Dabigatran, Edoxaban: Concentrations may increase 
with study drug(s). Clinical monitoring and/or dose 
adjustment is recommended
Anticonvulsants
Carbamazepine, Phenobarbital, 
Phenytoin,
Ethosuximide, Oxcarbazepine,
Coadministration of Oxcarbazepine, a CYP3A 
inducer, may decrease Cobicistat and Elvitegravir 
plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative anticonvulsants should be considered.
Concentrations of Ethosuximide may be increased 
when coadministered with Cobicistat. Clinical 
monitoring is recommended upon coadministration 
with E/C/F/TAF
STR.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antidepressants
Bupropion:
Concentrations may increase or decrease with study 
drug. Subjects receiving bupropion should be 
monitored for adequate clinical response.
SSRI dosing should be titrated in conjunction with 
clinical monitoring.
SSRIs except Sertraline, and Trazodone, tricyclic 
antidepressants (TCAs):
Concentrations may increase when coadministered 
with Cobicistat.
Concentrations of Sertraline are not affected upon 
coadministration with study drug. No dose adjustment 
is required upon coadministration.
Concentrations of other antidepressant agents may be 
increased when coadministered with Cobicistat. Dose 
titration may be required for most drugs of the SSRI 
class. Concentrations of Trazodone may increase 
upon coadministration with Cobicistat. Dose 
reduction should be considered when Trazodone is 
coadministered with
E/C/F/TAF STR.
Antifungals
Concentrations of ketoconazole, itraconazole and/or 
cobicistat may increase with coadministration of 
E/C/F/TAF STR. When administering with 
E/C/F/TAF STR, the maximum daily dose of 
ketoconazole and itraconazole should not exceed 
200 mg per day.
Concentrations of voriconazole may be increased 
when coadministered with cobicistat. Clinical 
monitoring may be needed upon coadministration 
with E/C/F/TAF STR.
Antigout
Colchicine:
Concentrations may increase with study drug(s). Dose 
reductions of colchicine may be required. Should not 
be coadministered in patients with renal or hepatic 
impairment.
Dose reductions of colchicine may be required. 
E/C/F/TAF STR should not be coadministered with 
colchicine in patients with renal or hepatic 
impairment.
Treatment of familial Mediterranean fever:
Maximum daily dose of 0.6 mg (may be given as 
0.3 mg twice a day)
Antihistamines
Astemizole, Terfenadine:
Concentrations of Astemizole and Terfenadine may 
be increased when coadministered with Cobicistat. 
Clinical monitoring is recommended when these 
agents are coadministered with E/C/F/TAF STR.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antimycobacterials
Coadministration of rifampin, 
rifabutin, and rifapentine, potent 
CYP3A inducers, may significantly 
decrease cobicistat and elvitegravir 
plasma concentrations, which may 
result in loss of therapeutic effect 
and development of resistance.
Coadministration of E/C/F/TAF 
STR with rifampin is 
contraindicated.
Coadministration of E/C/F/TAF 
STR with rifabutin or rifapentine is 
not recommended.
Antiplatelets
Coadministration of clopidogrel 
with cobicistat is expected to 
decrease clopidogrel active 
metabolite plasma concentrations, 
which may reduce the antiplatelet 
activity of clopidogrel. 
Coadministration of clopidogrel 
with GENVOYA is not 
recommended.
GENVOYA is not expected to have 
a clinically relevant effect on 
plasma concentrations of the active 
metabolite of prasugrel.
Benzodiazepines
Orally administered Midazolam and 
Triazolam
Diazepam: Concentrations of other benzodiazepines, 
including Diazepam and parenterally administered 
Midazolam, may be increased when administered 
with E/C/F/TAF STR. Coadministration should be 
done in a setting that ensures close clinical 
monitoring and appropriate medical management in 
case of respiratory depression and/or prolonged 
sedation. Dose reduction may be necessary.
Based on non-CYP-mediated elimination pathways 
for Lorazepam, no effect on plasma concentrations is 
expected upon coadministration with E/C/F/TAF 
STR.
β-Blockers
Concentrations of beta-blockers may be increased 
when coadministered with Cobicistat. Clinical 
monitoring is recommended and a dose decrease may 
be necessary when these agents are coadministered 
with E/C/F/TAF STR.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Calcium Channel 
Blockers
Amlodipine, Diltiazem, Felodipine, Nicardipine, 
Nifedipine, Verapamil:
Concentrations of calcium channel blockers may be 
increased when coadministered with Cobicistat. 
Caution is warranted and clinical monitoring is 
recommended upon coadministration with E/C/F/TAF 
STR.
Endothelin Receptor 
Antagonists
Coadministration of Bosentan with study drug may 
lead to decreased Elvitegravir and/or Cobicistat 
exposures and loss of therapeutic effect and 
development of resistance. Alternative endothelin 
receptor antagonists may be considered.
Ergot Derivatives
Ergotamine, Ergonovine (known as 
ergometrine in some regions), 
Dihydroergotamine 
Methylergonovine
GI Motility Agents
Cisapride
Hepatitis C Virus 
Antiviral Agents
Concentrations of Cobicistat, Ledipasvir, Sofosbuvir, 
and GS-331007 (the predominant circulating 
metabolite of sofosbuvir) are increased when 
ledipasvir/sofosbuvir is coadministered with 
Elvitegravir and Cobicistat. The effect of 
coadministration of ledipasvir/sofosbuvir and 
E/C/F/TAF STR on concentrations of all components 
of these fixed-dose combinations is unknown. There 
are insufficient data to make a dosing 
recommendation for coadministration of E/C/F/TAF 
STR with ledipasvir/sofosbuvir.
Herbal/Natural 
Supplements
St. John’s Wort
HMG-CoA Reductase 
Inhibitors
Simvastatin, Lovastatin
Concentrations of Atorvastatin may be increased 
when coadministered with Elvitegravir and 
Cobicistat. Start with the lowest possible dose of 
Atorvastatin with careful monitoring upon 
coadministration with E/C/F/TAF STR.
Concentrations of Rosuvastatin are transiently 
increased when coadministered with Elvitegravir and 
Cobicistat. Dose modifications are not necessary 
when Rosuvastatin is administered in combination 
with E/C/F/TAF STR.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Hormonal Contraceptives
Drospirenone: Plasma concentrations may be 
increased when administered with E/C/F/TAF STR. 
Clinical monitoring is recommended due to the 
potential for hyperkalemia.
Coadministrationofstudydrug and a
norgestimate/ethinyl estradiol-containing hormonal 
oral contraceptive is expected to decrease plasma 
concentrations of ethinyl estradiol and increase
norgestimate.
Use caution when coadministering study drug and a 
hormonal contraceptive. The hormonal contraceptive 
should contain at least 30 mcg of ethinyl estradiol.
The long-term effects of substantial increases in 
progesterone exposure are unknown. The effect of 
coadministration of E/C/F/TAF STR with oral 
contraceptives or hormonal contraceptives containing 
progestogens other than drospirenone, norgestimate, 
or less than 25 mcg of ethinyl estradiol, is not known.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase when coadministered 
with Cobicistat. Therapeutic monitoring is 
recommended upon coadministration with E/C/F/TAF 
STR.
Inhaled Beta Agonist
Salmeterol:
Coadministration with study drug may result in 
increased plasma concentrations of Salmeterol, which 
is associated with the potential for serious and/or
life-threatening reactions. Coadministration of 
Salmeterol and E/C/F/TAF STR is not recommended.
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine, Quetiapine:
Consider reducing the dose of the neuroleptic upon 
coadministration with E/C/F/TAF STR.
Phosphodiesterase-5 
Inhibitors
Coadministration of E/C/F/TAF 
STR with Sildenafil for the 
treatment of pulmonary arterial 
hypertension (PAH) is 
contraindicated.
PDE5 inhibitors are primarily metabolized by 
CYP3A. Coadministration with E/C/F/TAF STR may 
result in increased plasma concentrations of Sildenafil 
and Tadalafil, which may result in PDE5 
inhibitor-associated adverse reactions.
Caution should be exercised, including consideration 
of dose reduction, when coadministering E/C/F/TAF 
STR with Tadalafil for the treatment of pulmonary 
arterial hypertension.
For the treatment of erectile dysfunction, it is 
recommended that a single dose of sildenafil no more 
than 25 mg in 48 hours, vardenafil no more than 
2.5 mg in 72 hours, or tadalafil no more than 10 mg in 
72 hours be coadministered with E/C/F/TAF STR.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Sedatives/Hypnotics
Midazolam, Triazolam
Buspirone, orally administered Zolpidem:
With sedative/hypnotics, dose reduction may be 
necessary upon coadministration with E/C/F/TAF 
STR and clinical monitoring is recommended.
Corticosteroids: Systemic
Systemic Dexamethasone, a CYP3A inducer, may 
decrease Elvitegravir and Cobicistat plasma 
concentrations, which may result in loss of 
therapeutic effect and development of resistance. 
Alternative systemic corticosteroids should be 
considered.
Corticosteroids: (all 
routes excluding 
cutaneous)
Betamethasone, Budesonide, Fluticasone, 
Mometasone, Triamcinolone:
Coadministration with corticosteroids that are 
sensitive to CYP3A inhibition can increase the risk 
for Cushing’s syndrome and adrenal suppression, 
which have been reported during postmarketing use 
of cobicistat-containing products. Consider the risk of 
systemic corticosteroid effects if E/C/F/TAF STR is 
coadministered with corticosteroids that are sensitive 
to CYP3A inhibition.
Alternative corticosteroids should be considered, 
particularly for long-term use.
In jurisdictions in which E/C/F/TAF has been approved, consult the local prescribing 
information for E/C/F/TAF dose recommendations with concomitant medications.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Gilead Science Medical Monitor must be consulted prior to initiation of the new medication. In 
instances where an excluded medication is initiated prior to discussion with the Sponsor, the 
Investigator must notify Gilead Sciences as soon as he/she is aware of the use of the excluded 
medication.
5.5.
Study Drug Return or Disposal
Gilead recommends that used and unused study drug supplies be destroyed at the site. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused study drug supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for the electronic trial master file. If study drug is destroyed on site, the investigator must 
maintain accurate records for all study drugs destroyed. Records must show the identification 
and quantity of each unit destroyed, the method of destruction, and the person who disposed of 
the study drug. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead. 


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If the site does not have an appropriate SOP for drug destruction, used and unused study drug 
supplies are to be sent to the designated disposal facility for destruction. The study monitor will 
provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
For both disposal options listed above, the study monitor must first perform drug accountability 
during an on-site monitoring visit.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2, and also described in the text that follows.
All subjects will participate in all study visits and assessments. Additionally, subjects in Part A 
(inclusive of Cohort 3) will complete the Intensive PK visit at Week 4 (Cohorts 1 and 2) or 
Week 2 (Cohort 3).
Any deviation from protocol procedures should be noted and the Sponsor or Contract Research 
Organization (CRO) should be notified.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that each subject is eligible for the study 
before enrollment.
Please refer to Section 5.1 for details about subject number assignment.
6.2.
Screening Visit
Each subject must sign an assent (and parent or legal guardian sign an informed consent form) 
prior to the conduct of any screening procedures. Subjects will be assigned a screening number at 
the time of assent/consent. Screening evaluations are used to determine the eligibility of each 
candidate for study enrollment.
The following evaluations are to be completed at the Screening visit:

Obtain medical and medication history, including history of HIV-1 disease-relatedevents, 
and any other ongoing medications within 30 days of the Screeningvisit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the investigator)

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Height and weight

12-lead ECG performed supine

Urine collection for the following laboratory procedures:
Urinalysis
For Cohort 3, urine renal safety including: urine chemistry, retinol binding protein and 
beta-2-microglobulin. 


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
Blood sample collection for the following laboratory analyses:
Serum pregnancy test (females of childbearing potential only). If the test is positive, the 
subject will not be enrolled.
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, CPK, and uric acid
For Cohort 3, metabolic assessments: Fasting (no food or drinks, except water, at least 
8 hours prior to blood collection) glucose and lipid panel (total cholesterol, HDL, direct 
LDL, and triglycerides). If the subject has not fasted prior to the visit, the visit may
proceed, but the subject must return within 72 hours in a fasted state to draw blood for the 
metabolic assessments.
Hematology profile: complete blood count (CBC) with differential and platelet count
Estimated Glomerular Filtration Rate (GFR) using Schwartz Formula (mL/min/1.73m2) = 
k L/Scr
Plasma HIV-1 RNA (Roche COBAS TaqMan® v2.0)
Whole blood sample (Cohort 3 only)
Full flow cytometry panel testing
HIV-1 genotype (protease, reverse transcriptase and integrase) testing (Cohort 1 only). 
The HIV-1 genotype may not be performed for subjects that fail to meet other screening 
laboratory criteria.
Hepatitis B virus (HBV) surface antigen serology (HBsAg)
Hepatitis C virus (HCV) serology (HCVAb)
For Cohort 3, serum bone safety including: Bone specific alkaline phosphatase, 
parathyroid hormone (PTH), 25OH Vitamin D, and 1,25OH Vitamin D

Review of Adverse Events (AEs) and Concomitant Medications

Historical genotype report(s) should be collected, if available (Cohorts 2 and 3 only)
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 35 days after the Screening visit for the Baseline/Day 1 assessments. For Cohort 1, 
the Screening window may be extended to 42 days for subjects who require repeat testing of the 
HIV-1 genotype.


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Amendment 6
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Subjects with exclusionary screening laboratory results due to an acute clinical condition which 
resolves can be re-screened within 3 months of initial Screening. The decision to re-screen the 
subject will be made in consultation with the Medical Monitor, and written notice of eligibility 
from the Sponsor is required before a re-screened subject can be enrolled.
For each screened subject, complete an eligibility worksheet and submit to Sponsor for review 
prior to assignment of subject number. The subject number assignment may be performed up to 
7 days prior to the in-clinic Baseline visit provided that all other Screening procedures havebeen 
completed and subject eligibility has been confirmed.
6.3.
Treatment Assessments
6.3.1.
Baseline/Day 1 Assessments
The following evaluations are to be completed at the Baseline/Day 1 visit. The subject must 
complete all Baseline procedures before being dispensed the study drug. Initiation of treatment 
with the study drug must take place within 24 hours after the Baseline visit. For Cohort 1, the 
Investigator must have received the results from the screening genotype report before proceeding 
with the Baseline/Day 1 visit.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Height and weight

Tanner Stage assessments (≥ 6 years of age)

DXA Scan (lumbar spine and total body)
The DXA scan will be performed on subjects once eligibility is confirmed and prior to 
study drug administration at the Baseline/Day 1 visit. The scan may be performed on the 
morning of the Baseline/Day 1 visit as long as it occurs beforedosing.

Urine collection for the following laboratory procedures:
Urinalysis
For Cohorts 1 and 2, urine renal safety including: urine chemistry, retinol binding protein 
and beta-2-microglobulin. 
For Cohorts 1 and 2, urine bone safety including: bicarbonate, N-telopeptide


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
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Final 
Amendment6 
I 
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive at Baseline, study dmg will not be dispensed. The positive result will be 
confmned with a sernm pregnancy test. If the sennn pregnancy test is positive, the 
subject will not be able to paiticipate. 
• 
Blood sample collection for the following laborato1y analyses: 
I 
Chemistiy profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect 
bilirnbin, cystatin C for Coho1ts 1 and 2, total protein, albumin, bicai·bonate, BUN, 
calcium, chloride, creatinine, phosphorns, magnesium, potassium, sodium, CPK, and uric 
acid 
For Cohorts 1 and 2, metabolic assessments: Fasting (no food or drinks, except water, at 
least 8 hours prior to blood collection) glucose and lipid panel (total cholesterol, HDL, 
direct LDL, and ti·iglycerides). If the subject has not fasted prior to the visit, the visit may 
proceed, but the subject must return within 72 hours in a fasted state to draw blood for the 
metabolic assessments. 
Hematology profile: CBC with differential and platelet count 
Plasma HIV-1 RNA (Roche COBAS TaqMan® v2.0) 
Full flow cytometiy panel testing 
For Coho1ts 1 and 2, senun bone safety including: Bicai·bonate, N-telopeptide, C-
telopeptide (CTX), osteocalcin, procollagen type 1 N-tenninal propeptide (Pl NP), bone 
specific alkaline phosphatase, pai·athyroid honnone (PTH), 25OH Vitainin D, and 
1,25OH Vitainin D 
Estimated glomernlar filu-ation rate according to Schwa1tz fonnula 
• 
Study diug dispensation. Subjects should initiate dosing of study diug along with food 
in-clinic the day of the Baseline visit. 
• 
Subjects should be instiucted to take study mugs with food. The subject should be counseled 
regarding the impo1tance of adherence and taking their study medication at approximately 
the same time each day as directed by the Investigator. Sites should consider individual 
subject study diug dosing schedule while scheduling study visits requiring collection of 
ti·ough PK sainples. 
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Amendment 6
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The PK study of Part A (inclusive of Cohort 3) is designed to assess the PK of and 
confirm the doses of E/C/F/TAF STR. Therefore, all subjects must take their dose of 
study medication with food at approximately the same time every morning at all visits 
prior to the Intensive PK visit.

Palatability and Acceptability assessment (Cohorts 2 and 3)
The Investigator will ask if the study drug was palatable and if the subject was able to 
take the dosage form.

Subjects should be reminded to bring the required drug bottles of the E/C/F/TAF STR with 
them for in-clinic dosing and drug accountability at the Week 1/(Day 7) visit.
6.3.2.
Treatment Assessments through 48 Weeks (Weeks 1 (Day 7) – 48)
The following evaluations are to be completed at the end of Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40 
and 48 unless otherwise specified.
All study visits are to be scheduled relative to the Baseline/Day 1 visit date. The Week 1 
(Day 7) visit should occur on the protocol-specified visit date based on the Baseline/Day 1 visit. 
Study visits at Weeks 2 through 8 are to be completed within ± 2 days of the protocol-specified 
visit date based on the Baseline/Day 1 visit and completed within ± 4 days of the
protocol-specified visit date at Weeks 12 through Week 48, unless otherwise specified.
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study drug.

Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24 and 48) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator) or symptom-directed physical examination as 
needed (all other visits)

Vital signs (blood pressure, pulse, respiration rate, and temperature)

Height and Weight

Tanner Stage assessments for ≥ 6 years of age (Weeks 24 and 48 − except for subjects 
documented to have achieved Tanner Stage 5)

DXA scan (lumbar spine and total body) (Weeks 24 and 48 ± 10 days)

Urine collection for the following laboratory procedures:
Urinalysis and urine chemistry


EVG/COBI/FfCffAF 
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Urine renal safety including: urine chemistry, retinol binding protein and 
beta-2-microglobulin (Weeks 8, 12, 24 and 48) 
For Coho1ts 1 and 2, urine bone safety including: bicarbonate, N-telopeptide (Weeks 8, 
12, 24 and 48) 
Urine pregnancy test (females of childbearing potential only). If the urine pregnancy test 
is positive, study drng will not be dispensed. The positive result will be confnmed with a 
sernm pregnancy test. If the sennn pregnancy test is positive, the subject will be 
discontinued 
• 
Blood sample collection for the following laborato1y analyses: 
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect 
bilirnbin, cystatin C (Weeks 2 [Cohort 1 only], 4, 24, and 48 [Cohorts 1 and 2 only]. 
Cystatin C will not be done for Cohort 3 to reduce blood draw volumes), total protein, 
albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorns, 
magnesium, potassium, and sodium, CPK, and uric acid. At Weeks 24 and 48, analyses of 
glucose will be done as pait of the fasting metabolic assessments and not as pa1t of the 
chemistry profile. 
Metabolic assessments: Fasting (no food or drinks, except water, at least 8 hours prior to 
blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, and 
tr·iglycerides). If the subject has not fasted prior to the visit, the visit may proceed, but the 
subject must return within 72 hours in a fasted state to draw blood for the metabolic 
assessments (Weeks 24 and 48 only). 
Hematology profile: CBC with differential and platelet count 
Plasma HIV-1 RNA (Roche COBAS TaqMan v2.0) 
Full flow cytometiy panel testing (Weeks 2 - 48) 
Sernm bone safety including: 
Coho1ts 1 and 2: bicarbonate, N-telopeptide, CTX, osteocalcin, PlNP 
For all coho1ts: bone specific alkaline phosphatase, PTH, 25OH Vitamin D, and 1,25OH 
Vitamin D (Weeks 8 [Cohort 1 only], 12, 24 and 48) 
CONFIDENTIAL 
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EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 61
21 February 2020
Estimated glomerular filtration rate according to Schwartz formula
HIV-1 genotype/phenotype testing for subjects with suboptimal virologic response or 
virologic rebound (as needed)

Pharmacokinetic (PK) blood collection:
Cohort 1
Trough PK sample (20 to 24 hours post-dose) (Weeks 1 (Day 7), 2, 24 and 48).*
Timed Single PK sample collected between 0.25 to 4 hours post-dose (Week 4 [Part B 
subjects only] and at Week 12 only)*
Random Single PK sample taken anytime in relationship to last dose of study drug (all 
other visits)*
Cohort 2
Trough PK sample (20 to 24 hours post-dose) (Weeks 1, 2, and 24)
Timed Single PK sample collected between 0.25 to 4 hours post-dose (Week 12 only)*
Random Single PK sample taken anytime in relationship to last dose of study drug 
(Weeks 8 and 16)
Cohort 3
Timed Single PK sample collected between 0.25 to 4 hours post-dose (Weeks 8, 12, and 
16)*
Trough PK sample (20 to 24 hours post-dose). Subjects should be reminded not to take 
their study medication on the morning of these visits. The time of last dose prior to the 
PK draw should be documented. (Weeks 4 and 24)
*
For subjects who take their medication in the evening, a Random Single PK sample taken 
at any time in relationship to last dose of study drug will be collected in lieu of the 
Trough or Timed Single PK collected between 0.25 to 4 hours post-dose. The time of last 
dose prior to the PK draw should be documented. (For Uganda only)

Subjects who meet the criteria for suboptimal virologic response or rebound should be 
managed according to Management Virologic Failure Section 6.8.1.

Subjects should be reminded not to take their study medication on the morning of their 
Week 1 (Day 7), 2, 4, 12, 24, and 48 clinic visits and the visits during which PK troughor 
intensive samples will be collected.


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 62
21 February 2020

Document study drug dispensation and accountability for all study drugs dispensed. No study 
drug will be dispensed at the Week 2 visit.

Subject dosing diaries should be dispensed at the Week 1 (Cohort 3) or Week 2 (Cohort 1 
and 2) visit (depending upon the timing of the intensive PK visit) to subjects in Part A 
(inclusiveof Cohort 3) to capture study drug information prior to the Intensive PK study visit.

Palatability and Acceptability Assessment
For Cohort 1, at the next scheduled visit, the investigator will ask if the study drug was 
palatable and if the subject was able to take the dosage form. If the subject has passed the 
Week 48 visit, the assessment will be performed during the next scheduled post Week 48 
visit. If the subject discontinues prior to the Week 48 visit, this assessment will be 
captured at the ESDD visit.
For Cohort 2, the same questions asked at Baseline will be asked at Week 4 or if the 
subject discontinues prior to the Week 4 visit, this assessment will be captured at the 
ESDD visit.
For Cohort 3, the same questions asked at Baseline will be asked at Week 4, Week 24, 
and Week 48. If the subject discontinues prior to the Week 4 visit, this assessment will be 
captured at the ESDD visit.
6.3.3.
Intensive PK Evaluation (Part A subjects only, inclusive of Cohort 3)
The Intensive PK evaluation will occur at the Week 4 (Cohorts 1 and 2) or Week 2 (Cohort 3) 
visit. For the purpose of scheduling the Intensive PK visit, a + 7 days window may be used.
Subjects should come in a fasted state (i.e. no food or drink except water at least 8 hours prior). 
Subjects should be instructed that on the day of the Intensive PK evaluation the dose of 
E/C/F/TAF STR must not be taken prior to the visit.
If the subject has already dosed prior to the Intensive PK evaluation visit or is not in a fasted 
state, the Intensive PK assessments must not be completed. The subject should be instructed to 
return in a fasted state within 7 days of their Week 4 (Cohorts 1 and 2) or Week 2 (Cohort 3) 
visit for the Intensive PK assessments.
If dosing non-compliance not related to AEs is identified on or prior to the Intensive PK 
evaluation visit, the Intensive PK assessments must not be completed. The subject should be 
counseled regarding proper dosing and be scheduled to return for the Intensive PK evaluation 
visit no sooner than three days following compliant dosing and no later than Week 4 (Cohorts 1 
and 2) + 7 days or Week 2 (Cohort 3) + 7 days.
In both scenarios described above, the subject should be reminded to not take the E/C/F/TAF 
STR prior to arriving at the clinic on the day of the re-scheduled Intensive PK visit. All Intensive 
PK assessments listed below should be completed when the subject returns:


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
• 
Subject dosing diaries will be collected and reviewed. 
Final 
Amendment6 
• 
For Coho1t 1 subjects, blood samples will be collected at 0 (pre-dose, ::; 30 minutes prior to 
dosing). After collection of the pre-dose sample, subjects will be provided a standardized 
meal. Within five minutes after consuming the standardized meal, subjects will be dosed 
with the E/C/F/TAF STR. Intensive PK sampling at the following time-points will occur: 
5 minutes, 0.25, 0.5, 1, 1.5, 2, 4, 5, 8 and 24 hours post-dose. 
• 
For Coho1t 2 subjects, blood samples will be collected ::; 30 minutes prior to dosing. After 
collection of the pre-dose sample, subjects will be provided a meal. Within five minutes after 
consuming the meal, subjects will be dosed with the E/C/F/fAF STR. Intensive PK sampling 
at the following time-points will occur: 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours post-dose. 
Subjects will be restricted from fiuther food intake until after the 4-hour PK blood draw. 
• 
For Cohort 3 subjects, blood samples will be collected ::; 30 minutes prior to dosing. After 
collection of the pre-dose sample, subjects will be provided a meal. Within five minutes 
after consuming the meal, subjects will be dosed with the E/C/F/fAF STR. Intensive PK 
sampling at the following time-points will occur: 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 8 hours 
post-dose. Subjects will be restricted from fiuther food intake until after the 4-hour PK blood 
draw. -
-
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Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
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Final 
Amendment6 
21 Febrna1y 2020 


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Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
I 
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6.3.6. 
Early Study Drug Discontinuation (ESDD) 
Final 
Amendment6 
If a subject in the treatment phase of the study discontinues study diug prior to Week 48, the 
subject will be asked to return to the clinic within 72 hours of stopping study diu s for an ESDD 
Visit. Sub· ects will then be asked to continue attendin all scheduled stud visits. 
At the ESDD Visit, any evaluations showing abnormal results for which there is a possible 
or probable causal relationship with the study drug, should be repeated weekly ( or as often 
as deemed prudent by the investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained. 
The following evaluations are to be completed at the ESDD visit: 
• 
Review of AEs and concomitant medications 
• 
Complete physical examination (urogenital/anorectal exams will be perfonned at the 
discretion of the Investigator) 
• 
Vital signs (blood pressure, pulse, respiration rate, and temperature) 
• 
Height and Weight 
• 
Urine collection for the followingprocedures: 
Urinalysis 
Urine pregnancy test (females of childbearing potential only). The positive result will be 
confmned with a sernm pregnancy test. 
CONFIDENTIAL 
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21 Febrna1y 2020 


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
I 
• 
Blood sample collection for the following laborato1y analyses: 
Final 
Amendment6 
Chemistiy profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect 
bilirnbin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorns, magnesium, potassium, and sodium, CPK, and mic acid 
Estimated glomernlar filu-ation rate according to Schwa1tz fonnula 
Hematology profile: CBC with differential and platelet count 
Full flow cytometiy panel testing 
Plasma HIV-I RNA (Roche COBAS TaqMan v2.0) 
Plasma storage samples for virology testing, safety or phaimacokinetic testing 
I 
HIV-I genotype/phenotype testing for subjects with suboptimal virologic response or 
virologic rebound 
Single plasma PK sainple taken anytime in relationship to last dose of study diug 
• 
Drng accountability 
• 
Palatability and Acceptability assessment (if applicable) 
6.3.7. 
30-Day Follow-Up Visit 
Subjects who discontinue study diug prior to Week 48 will be required to return to the clinic 
30 days after completion of an Early Study Drng Discontinuation visit for a 30-DayFollow-Up 
visit. Those subjects who pennanently discontinue study diug and continue in the study through 
at least one subsequent visit after the Eai·ly Study Drng Discontinuation visit will not be required 
to complete the 30-Day Follow-Up visit. 
Subjects who complete 48 weeks on study diug will be required to return to the clinic 30 da s 
after com letion of the Week 48 visit for a 30-Day Follow-Up visit 
For the pmpose of scheduling a 30-Day Follow-Up Visit, a± 6 days window may be used. The 
following evaluations are to be completed at the 30-Day Follow-Up Visit: 
• 
Review of AEs and concomitant medications 
• 
Symptom-directed physical exainination 
CONFIDENTIAL 
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21 Febrna1y 2020 


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
• 
Vital signs (blood pressure, pulse, respiration rate, and temperature) 
• 
Height and Weight 
• 
Urine collection for the followingprocedures: Urinalysis 
Final 
Amendment6 
Urine pregnancy test (females of childbearing potential only). A positive result will be 
confmned with a sernm pregnancy test. 
• 
Blood sample collection for the following laborato1y analyses: 
Chemistiy profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect 
bilirnbin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorns, magnesium, potassium, and sodium, CPK, and uric acid 
Estimated glomernlar filu-ation rate according to Schwa1tz fo1mula 
Hematology profile: CBC with differential and platelet count 
Full flow cytometiy panel testing 
Plasma HIV-I RNA (Roche COBAS TaqMan v2.0) 
• 
Palatability and Acceptability assessment (if applicable) 
At the 30-Day Follow-Up visit, any evaluations showing abnonnal results for which there is a 
possible or probable causal relationship with the study diug, should be repeated weekly ( or as 
often as deemed prndent by the investigator) until the abno1mality is resolved, returns to 
baseline, or is othe1wise explained. 
6.4. 
Bone Evaluations 
Dual energy x-ray abso1ptiometiy (DXA) scans of the lumbar spine and total body will be 
perfo1med prior to study diug adininisti·ation at the Baseline/Day 1, and Weeks 24, 48 and 
applicable post-Week 48 visits (±10 days). Scans will measure changes in lumbar spine bone 
mineral density (BMD) and total BMD. DXA scan results will be provided to study sites. 
A complete description of the procedures perfo1med for the DXA scans will be provided in a 
DXAmanual. 
CONFIDENTIAL 
Page 67 
21 Febrna1y 2020 


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
6.5. 
Bone and Renal Safety 
Final 
Amendment6 
The following semm bone safety parameters will be collected at Screening (Cohort 3) or 
Baseline (Coho1is 1 and 2) and Weeks 8 (Coho1i 1 only), 12, 24, and 48 and applicable 
post-Week 48 visits (±6 days): Senun: For Coho1is 1 and 2 only: bicarbonate, N-telopeptide, 
C-telopeptide (CTX), osteocalcin, and procollagen type 1 N-tenninal propeptide (PlNP). For all 
coho1is: bone specific alkaline phosphatase, parathyroid honnone (PTH), 250H Vitamin D, and 
1,250H Vitamin D. 
For Coho1is 1 and 2, the following urine bone safety parameters will be collected at Baseline, 
Weeks 8, 12, 24, 48: Urine: bicarbonate, N-telopeptide. 
For all subjects, urine will also be collected for selected renal safety, including urine chemistry, 
retinol binding protein, and beta-2-microglobulin at the Screening (Coho1i 3) or Baseline 
(Coho1is 1 and 2) visit, and Weeks 8, 12, 24, 48. 
6.7. 
Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject's best interest 
• 
Lack of efficacy (virologic failure) 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study 
• 
Discontinuation of the study at the request of Gilead, a regulato1y agency, or an IRB/IEC 
CONFIDENTIAL 
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EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 69
21 February 2020
6.8.
Virologic Failure
Subjects in Cohort 1 who experience suboptimal virologic response (SVR) or subjects in 
Cohorts 1, 2, or 3 who experience virologic rebound (VR), as defined below, will be considered 
to have virologic failure.
Upon confirmation of virologic failure, potential causes should be documented. Assessments 
should include:

Adherence

Concomitant medication

Comorbidities (eg active substance abuse, depression, other intercurrent illnesses)
If virologic failure is confirmed and the HIV-1 RNA value is ≥ 400 copies/mL, the blood 
samples from the confirmation visit will be used for HIV-1 genotype/phenotype testing.
Genotype/phenotype resistance testing will be performed using the RT/PR PhenoSense GT 
assay, the IN GeneSeq assay, and the IN PhenoSense assay (Monogram Biosciences, Inc.) in 
subjects who experience suboptimal virologic response or virologic rebound, if HIV-1 RNA is 
≥400 copies/mL.
If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued.
If no resistance is detected from genotype/phenotype testing, the subject may remain on study 
drug and an HIV-1 RNA test should be repeated (3-6 weeks after date of test with HIV-1 RNA
≥50 copies/mL). Investigators should carefully evaluate the benefits and risks of remaining on 
study drug for each individual subject and document this assessment in the on-site medical 
record. Investigators who opt to discontinue study drugs for an individual subject must discuss 
with the Medical Monitor prior to study drug discontinuation.
6.8.1.
Management of Suboptimal Virologic Response (Cohort 1 only)
Subjects who meet the criteria listed below will be considered to have suboptimal virologic 
response:

HIV-1 RNA is < 1 log10 reduction from Baseline and ≥ 50 copies/mL at the Week 8 visit, 
confirmed at Week 12 or Unscheduled visit following Week 8.
Following the unconfirmed suboptimal virologic response at Week 8, HIV-1 RNA should be 
repeated at a scheduled or Unscheduled visit (3-6 weeks after the date of the original test with 
HIV-1 RNA to ≥ 50 copies/mL). If suboptimal virologic response is confirmed, the samples from 
the confirmation visit will be used for HIV-1 genotype/phenotype testing if HIV-1 RNA is
≥400 copies/mL.


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 70
21 February 2020
Please refer to Figure 6-1 for the management of subjects who meet the criteria for suboptimal 
virologic response.
Figure 6-1.
Suboptimal Virologic Response Schema (Cohort 1 only)
a
If suboptimal virologic response is confirmed and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype 
(reverse transcriptase, protease and integrase) will be analyzed.
b
If genotype/phenotype results are not available by the Week 12 visit, an unscheduled visit should be performed when the 
laboratory results are available.
c
Based on the results of the genotype/phenotype assays, the subject will remain on study drug or study drug will be 
discontinued at the next scheduled or unscheduled visit, whichever occurs first. If genotyping/phenotyping fails, a repeat 
specimen will be sent for analysis. If repeat genotyping/phenotyping subsequently fails, study medications can be continued 
or a new ARV regimen can be configured at the discretion of the Investigator, in consultation with the Medical Monitor.
d
If no resistance is detected, HIV-1 RNA will be repeated within 3-6 weeks. Investigator reviews and document study drug 
continuation/discontinuation options. Investigator must discuss with the Medical Monitor prior to study drug discontinuation
e
A new ARV regimen will be configured, at the Investigator’s discretion, and the subject will remain in the study.
6.8.2.
Management of Virologic Rebound
Subjects who meet the criteria listed below will be considered to have virologic rebound:

At any visit, after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA to

≥ 50 copies/mL, which is subsequently confirmed (two consecutive tests) at the following 
scheduled or Unscheduled visit (3-6 weeks after the date of the original test with HIV-1 RNA 
to ≥ 50 copies/mL) (Cohorts 1, 2, and 3); OR
Figmie 6-1. 
Suboptimal Virologi.c Re-sp-0D1se Sdiem.a ,{Cohm·,t 1 oruy) 
Screenrng 
I 
Baiselm Day 1 
BIV-1!:NA < l loglli redud:i:-0 . 
fn>m l:Jas:eline 311.d 
50 ,c;o,pi~iml. 
U11c"Oafimted 
sul:Jo:plliimai 
mologiic: 
r,espo11Se-: i:-tmaia 
oa !fudJ d!m( 
; 
I' 
.,. 
.f 
I' 
.f 
.f 
I' 
I 
Tre.atment Pel'iod 
i 
r 
\\i,eel Uo.-
lm.St.hedu!ed i;:isit 
Repeal Hn'-1 RNA 
ed pote.atw 
geiti!l};p,l!lphmo~ 
, 3,-(i 'l{et!lu :alur W,etik3) 
Confum!d 
mboptim.a] 
. lo • 
!J 
Dl'O ~cnspoase 
HIV-l ·goiolypeiph.eaolJpt 
if 
~00 copn'inL ill 
t 
30-Da,y ·F,U 
I 
Unscheduled 
vis:if 
Geaotype,'pllea.otn,e malrsi! 
r.esollic.d . 
. 
f ao :r,e>fl"Se o:a:as;aiip last 
- or iu:ttgn5e reistaaoe-
d.etected,, ,c;ontiJJ11f o study 
dnige 
' l"l!TI!TS:e 
Ill" 
· 
u!istaaoe 
mded, ,~ontiJJ11(! study 
mgs aod «nstmd a :ae:w 
"·"'. . . 
f 
:u,.· r,epm,e,.n 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 71
21 February 2020

At any visit, a >1 log10 increase in HIV-1 RNA from the nadir which is subsequently
confirmed (two consecutive tests) at the following scheduled or Unscheduled visit
(3-6 weeks after the date of the original test with HIV-1 RNA to ≥ 50 copies/mL) (Cohort 1
only)
Following the unconfirmed virologic rebound, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (3-6 weeks after the date of the original test with VL ≥50 copies/mL). If 
virologic rebound is confirmed, the samples from the confirmation visit will be used for HIV-1 
genotype/phenotype testing if HIV-1 RNA is ≥ 400 copies/mL.
Please refer to Figure 6-2 for the management of subjects who meet the criteria for virologic 
rebound.
Figure 6-2.
Virologic Rebound Schema
a
If virologic rebound is not confirmed, the subject will remain on their current regimen.
b
If virologic rebound is confirmed, and the HIV-1 RNA is ≥ 400 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, protease and integrase) will be analyzed.
c
Based on the results of the genotype/phenotype assays, the subject will remain on study drug or study drug will be 
discontinued. If genotyping/phenotyping fails, a repeat specimen will be sent for analysis. If repeat genotyping/phenotyping 
subsequently fails, study medication can be continued or a new ARV regimen can be configured at the discretion of the 
Investigator, in consultation with the Medical Monitor.
d
If no resistance is detected. Investigator reviews study drug continuation/discontinuation options and discuss with the 
Medical Monitor prior to study drug discontinuation
e
A new ARV regimen will be configured, at the Investigator’s discretion, and the subject will remain in the study
Screemng 
Treaitment Period 
Follow-u_p 
BaseilmeiD.ay 
.~f au.~-risit, a.fter .a.duniug BIV-1 RNA < 50 CAJPieslmL, a, ubllllll.d lo ~ 50 copies.imL 
(Oiboot s l Hli 2} OR> [ log., DICUISf! m HIV--] RNIA fr.om lheir nlllfu- (Cdhort I ) 
Unconfirmed 
Tif,lllll<gic 
r,ebo1111.-d: 
.r,ellWl!< ooi 
CIIITffLt 
~1!11 
Iii 1111, nnrse 0-3.lll5cripla.slf or 
iDugra,se, n silstance defecied, 
C.GDU!llll! OIi sbldJ d!r11gs. d 
Remm for sd1.edaled.(11.11<sd1ed.aled 
iEln'-1 !R,'lf..'\ and potaitial 
i:e110.type,'pht:11~-pe (3-6 \liffl.:s htK) 
Coomrmedl .irologic 
i:eboud • 
Remam 
,o.a. stud)" 
Hu.e-rse• lra!IS(ripfMP or 
intep35e i-esmance 1btfd:ed, 
1limmtinue stod~• d111~ ad 
r,onstruct a ntw .UV r•e~11 ·0 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 72
21 February 2020
6.8.3.
Subjects with ≥ 400 copies/mL of HIV-1 in Absence of SVR or VR
Subjects may have an antiviral response that is sustained at ≥ 400 copies/mL but do not meet 
either SVR or VR criteria. Subjects in that category could have an antiviral response that was
1 log10 HIV-1 RNA reduction from baseline (and therefore did not meet SVR criteria), but did 
not show > 1 log10 increase from nadir. These subjects will be analyzed for resistance at Week 48
or their last time point on study. Subjects who have achieved HIV-1 RNA < 50 copies/mL could 
subsequently experience unconfirmed blips ≥ 400 copies/mL of HIV-1 RNA. Such subjects will 
be analyzed for resistance if the unconfirmed rebound happens at Week 48 or last visit while 
receiving study drugs (or within 72 hours of discontinuation of study treatment). Subjects with
≥400 copies/mL of HIV-1 RNA at study discontinuation (after Week 8) while receiving study 
drugs (or within 72 hours of discontinuation of study treatment) will be analyzed for resistance.


EVG/COBI/FTC/TAF
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Final
Gilead Sciences, Inc.
Amendment 6
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7.
ADVERSE EVENTS AND TOXICITYMANAGEMENT
7.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
AEs also include the following:

Pre- or post-treatment complications that occur as a result of protocol mandated procedure 
(e.g. such as venipuncture, biopsy) during or after Screening (before the administration of 
study investigational medicinal product).

Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study investigational medicinal product phase of a human clinical trial, 
will also be considered an AE.

Complications and termination of pregnancy (see Section 7.4 for additional information)

All AEs that occur from the Screening visit onwards and throughout the duration of the 
study, including the follow-up off study medication period should be recorded as an AE.
An AE does not include the following:

Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that leads to the procedure is an adverse event

Pre-existing diseases or conditions or laboratory abnormalities present or detected beforethe 
Screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.4)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.

Uncomplicated pregnancy.

An induced elective abortion to terminate a pregnancy without medical reason.


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Gilead Sciences, Inc.
Amendment 6
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7.2.
Assessment of Adverse Events
All AEs will be assessed by the investigator or qualified designee and recorded on the AE CRF 
page. The AE entry should indicate whether or not the AE was serious, the start date (AE onset), 
the stop date (date of AE resolution), whether or not the AE was related to investigational 
medicinal product or to a study procedure, the action taken with investigational medicinal 
product due to the AE, and the severity of the AE. The investigator is responsible for final 
review and confirmation of accuracy of events, relationship and severity confirmed by the 
signature on the CRF book. The relationship to investigational medicinal product therapy should 
be assessed using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the investigational 
medicinal product. For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication).

Yes: A temporal relationship exists between the AE onset and administration of the 
investigational medicinal product that cannot be readily explained by the subject’s clinical 
state or concomitant therapies. Furthermore, the AE appears with some degree of certainty to 
be related, based on the known therapeutic and pharmacologic actions or adverse event 
profile of the investigational medicinal product. In case of cessation or reduction of the dose, 
the AE abates or resolves and reappears upon rechallenge.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol-mandated procedures such as 
venipuncture or biopsy.
7.3.
Serious Adverse Events
A serious adverse event (SAE) is defined as follows:
Any adverse drug experience occurring at any dose that results in any of the following outcomes:

Death

Life-threatening situation (subject is at immediate risk of death)

In-patient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other SAEs)


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Amendment 6
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
Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a subject who received investigational 
medicinal product

Other: medically significant events that may not be immediately life-threatening or result in 
death or hospitalization, but based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above
Examples of such events are as follows:
Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias or convulsions that do not result in hospitalization
Development of drug dependency or drug abuse
Clarification of Serious Adverse Events

Death is an outcome of an AE, and not an adverse event in itself. In reports of death due to 
“Disease Progression,” where no other information is provided, the death will be assumed to 
have resulted from progression of the disease being treated with the investigational medicinal 
product(s).

The subject may not have been on investigational medicinal product at the occurrence of the 
event. Dosing may have been given as treatment cycles or interrupted temporarily beforethe 
onset of the SAE, but may have contributed to the event.

“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity.

Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE.

“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department.

The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms.


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Amendment 6
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A distinction should be drawn between seriousness and severity of AEs. An AE that is assessed 
as Grade 4 (potentially life-threatening) should not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
Grade 4. An event is defined as “serious” when it meets one of the predefined outcomes 
described above in Section 7.3.
7.4.
Special Situations
7.4.1.
Definitions of Special Situations
Special situation reports include pregnancy reports, reports of medication error, abuse, misuse, or 
overdose, reports of adverse reactions in infants following exposure from breastfeeding, 
occupational exposure with an AE, and reports of adverse reactions associated with product 
complaints.
A pregnancy report is used to report any pregnancy that occurs during the study, whether or not 
maternal exposure to the product occurred.
Medication error is any unintentional error in the prescribing, dispensing or administration of a 
medicinal product while in the control of the HCP, patient or consumer.
Abuse is defined as persistent, sporadic or intentional excessive use of a medicinal product by a 
patient.
Misuse is defined as any use of a medicinal product in a way that the product is intentionally and 
inappropriately used not in accordance with the protocol instructions or the local prescribing 
information.
An overdose is defined as a dose taken (accidentally or intentionally) exceeding the dose as 
prescribed by the protocol or the maximal recommended daily dose as stated in the Product 
Labeling (as it applies to the daily dose for the subject/patient in question). In cases of a 
discrepancy in drug accountability, overdose will be established only when it is clear that the 
subject has taken the excess dose(s). Overdose cannot be established when the subject cannot 
account for the discrepancy except in cases in which the investigator has reason to suspect that 
the subject has taken the additional dose(s)
Product complaint is defined as any written or verbal report arising from potential deviations in 
the manufacture, packaging or distribution of the product.
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
7.4.2. 
7.4.2.1. 
Instructions for Reporting Special Situations 
Instrnctions for Repo1t ing Pregnancies 
Final 
Amendment6 
The Investigator should repo1t all pregnancies occuning in female subjects that are identified 
after the subject first consents to pa1ticipate in the study (ie, signing the info1m ed consent) and 
throughout the study, including the post-study diug follow-up period, to Gilead PVE (fonnerly 
DSPH) using the Pregnancy Repo1t fo1m within 24 hours of becoming aware of the pregnancy. 
Refer to Section 7.5 and the CRF/eCRF completion guidelines for full instrnctions on the 
mechanism of pregnancy repo1ting. 
The pregnancy itself is not considered an AE nor is an induced elective abo1tion to te1minate a 
pregnancy without medical reasons. 
Any premature te1mination of pregnancy ( eg, a spontaneous abo1tion, an induced therapeutic 
abo1tion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the adverse event 
tenn. 
A spontaneous abo1tion is always considered to be an SAE and will be repo1ted as described in 
the Adverse and Serious Adverse Events section. Fmt he1more, any SAE occuning as an adverse 
pregnancy outcome post-study must be repo1ted to Gilead Sciences. 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. If the conclusion of the pregnancy occurs after the post-study di11g follow up period, 
then the outcome should be repo1ted to Gilead PVE (fo1merly DSPH) using the Pregnancy 
Outcome Repo1t fonn. Gilead PVE (formerly DSPH) contact info1mation is as follows: 
Email:IPPD 
andfax: PD 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations. 
7.4.2.2. 
Instrnctions for Repo1ting Other Special Situations 
All other Special Situation repo1ts must be repo1ted on the Special Situations Repo1t Fo1m and 
fo1warded to Gilead PVE (fonnerly DSPH) within 24 hours. 
These repo1ts must consist of situations that involve study investigational medicinal products 
(IMPs), but do not apply to conc01nitant medications (i.e., except for situations that result in 
adverse events, special situations involving conc01nitant medications will not be repo1ted). Any 
inappropriate use of non-protocol approved medications should not be repo1ted as "inisuse" but 
may be more appropriately documented as a protocol deviation if applicable. 
Refer to Section 7.5 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations repo1ting. 
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Gilead Sciences, Inc. 
Final 
Amendment6 
All clinical sequelae in relation to these special situation repo1is will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE repo1i fonn. Details of the symptoms and 
signs, clinical management and outcome will be repo1ied, when available. 
7.5. 
7.5.1. 
Serious Adverse Event Reporting Requirements 
All Serious Adverse Events 
Gilead Sciences is required to expedite to worldwide regulato1y authorities repo1is of Serious 
Adverse Dmg Reactions or Suspected Unexpected Serious Adverse Reactions (SUSARs); 
therefore, Gilead Sciences ( or the CRO on the behalf of Gilead Sciences) must be notified 
immediately regarding the occmTence of any SAE that occurs after the subject consents to 
paiiicipate in the study, including SAEs resulting from protocol-associated procedures perfo1med 
from Screening onwai·ds. The procedures for reporting all SAEs, regardless of causal 
relationship, ai·e as follows: 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
• 
At the time of study start, SAEs will be reported using a paper serious adverse event 
repo1iing fo1m (see following bullet). During the study conduct sites may transition to an 
electronic SAE ( eSAE) system. Gilead will notify sites in writing and provide training and 
account infonnation prior to implementing an eSAE system. 
Serious Adverse Event Paper Reporting Process 
All SAEs will be recorded on the serious adverse event repo1i fonn and subinitted by faxing the 
repo1i fonn within 24 hours of the investigator's knowledge of the event to the attention of 
Gilead PVE (fo1merly DSPH). Contact info1mation is as follows: 
Gilead PVE (fo1merly DSPH): 
Gilead Sciences Medical Monitor: 
Fax: 
E-mail: 
IPIPD 
IPIPD 
The medical monitor name and contact 
infonnation will be provided on the Key Study 
T earn Contact List. 
For fatal or life-threatening events, also e-mail or fax copies of hospital case repo1is, autopsy 
repo1is, and other documents when requested and applicable. Transmission of such documents 
should occur with Personal Subject Details de-identified, without losing the traceability of a 
document to the Subject Identifiers. 
Gilead Sciences may request additional info1mation from the investigator to ensure the timely 
completion of accurate safety repo1is. 
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Amendment 6
CONFIDENTIAL
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The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF and the event description section of the SAE form.
Follow-up of adverse events will continue through the last day on study (including the follow-up 
off-study medication period of the study) and/or until the investigator and/or Gilead Sciences 
determine that the subject’s condition is stable. Gilead Sciences may request that certain adverse 
events be followed until resolution.
Electronic Serious Adverse Event (eSAE) Reporting Process
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead PVE (formerly DSPH) within 24 hours of the investigator’s knowledgeof 
the event. Detailed instructions can be found in the eCRF completion guidelines.
If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting form 
and submit within 24 hours to Gilead PVE (formerly DSPH) as described above.
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
7.5.2.
Investigator and Sponsor Reporting Requirements for SAEs
An SAE may qualify for reporting to regulatory authorities. Expectedness of SAEs will be 
determined by Gilead Sciences using reference safety information specified in the Investigator’s 
Brochure.
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
Investigator should notify the IRB or IEC as soon as is practical, of serious events in writing 
where this is required by local regulatory authorities, and in accordance with the local 
institutional policy.
In accordance with the EU Clinical Trials Directive (2001/20/EC), the Sponsor or specified 
designee will notify worldwide regulatory authorities and the relevant Ethics Committees in 
concerned Member States of applicable SUSARs.
7.5.3.
Post-Study Reporting Requirements
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol-required post-treatment follow-up).
Any SAEs and deaths that occur after the post-treatment follow-up visit but within 30 days of the 
last dose of investigational medical product, regardless of causality, should also be reported.


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Amendment 6
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Investigators are not obligated to actively seek SAEs after the protocol-required post-treatment 
follow-up; however, if the Investigator learns of any SAEs that occur after study participation 
and the event is deemed relevant to the use of investigational medicinal products, he/she should 
promptly document and report the event to Gilead PVE (formerly DSPH).
7.6.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., electrocardiogram,
X-rays, vital signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Sections 7.1 and 7.3. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (i.e., anemia) not 
the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 4). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
7.7.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3.
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal product 
discontinuation, unless such a delay is not consistent with good medical practice.
Clinical events and clinically significant laboratory abnormalities will be graded according to the 
Table for GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(Appendix 4).
When restarting investigational medicinal product following resolution of the adverse event, the 
investigational medicinal product should be restarted at full dose upon discussion with the 
Medical Monitor.
Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or clinically 
significant laboratory adverse event following dose interruption mandates permanent 
discontinuation of investigational medicinal product.
Any questions regarding toxicity management should be directed to the Medical Monitor.


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Amendment 6
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7.7.1.
Management of Changes in Estimated Glomerular Filtration Rate
Estimated glomerular filtration rate (GFR), according to the Schwartz formula, will be followed 
post-baseline during the study. All subjects with estimated GFR < 50 mL/min must have serum 
creatinine and subject’s height and weight measured again within 3 calendar days of receipt of 
results. If a subject has confirmed estimated GFR < 50 mL/min, the Medical Monitor should be 
notified and investigational medicinal product discontinued.
7.7.2.
Management of Posterior Uveitis Cases
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18 mg/kg) had minimal mononuclear cell infiltration in the posterior uvea, 
considered secondary to general debilitation; this finding did not occur in animals given lower 
doses and it has not occurred in other animal studies. This pre-clinical finding has also not been 
observed in humans where the dose is much lower, nor have there been reports of posterior 
uveitis in human clinical studies.
Across all ongoing Phase 2 and Phase 3 studies in which 2,394 subjects have received E/C/F/TAF 
STR for up to 96 weeks, eye disorders were uncommon, generally unrelated to treatment, and 
balanced between treatment arms. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drugs. One subject in Study GS-US-292-0106 had an AE of 
intermediate uveitis that was considered related to study drug by the investigator but resolved 
while the subject continued on study drug withoutinterruption.
Nonetheless, if any subjects develop signs or symptoms of posterior uveitis, investigators should 
contact the Gilead Medical Monitor to discuss the need for additional ophthalmologic evaluation 
including dilated fundoscopy and optical coherence tomography (OCT).
7.7.3.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.
7.7.4.
Grade 3 Laboratory Abnormality or Clinical Event
For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to investigational 
medicinal product.
For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by repeat 
testing, that is considered to be related to investigational medicinal product, investigational 
medicinal product should be withheld until the toxicity returns to ≤ Grade 2.
If a laboratory abnormality recurs to ≥ Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject managed 
according to local practice. Recurrence of laboratory abnormalities considered unrelated to 
investigational medicinal product may not require permanent discontinuation.


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Amendment 6
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7.7.5.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality confirmed 
by repeat testing that is considered related to investigational medicinal product, investigational 
medicinal product should be permanently discontinued and the subject managed according to 
local practice. The subject 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.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.


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Amendment 6
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
Cohort 1
The primary analysis objectives are:
Part A:

To evaluate the steady state PK for EVG and TAF and confirm the dose of theE/C/F/TAF 
STR in HIV-1 infected, ARV treatment-naive adolescents
Part B:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 24 in HIV-1 
infected, ARV treatment-naive adolescents
The secondary analysis objectives are:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 48 in HIV-1 
infected, ARV treatment-naive adolescents

To evaluate the antiviral activity of the E/C/F/TAF STR through Week 48 in HIV-1infected, 
ARV treatment-naive adolescents
Cohort 2
The primary analysis objectives are:
Part A

To evaluate the PK of EVG and TAF in virologically suppressed HIV-1 infected children 
6 to < 12 years of age, weighing ≥ 25 kg, administered E/C/F/TAF STR
Part B

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 24 in virologically 
suppressed HIV-1 infected children 6 to < 12 years of age
The secondary analysis objectives are:

To evaluate the antiviral activity of switching to E/C/F/TAF STR through Week 48 in 
virologically suppressed HIV-1 infected children 6 to < 12 years of age, weighing ≥25 kg.

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 48 in virologically 
suppressed HIV-1 infected children 6 to < 12 years of age, weighing ≥25 kg


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Cohort 3 
The prima1y analysis objectives are: 
Final 
Amendment6 
• 
To evaluate the PK of EVG and TAF and confnm the dose of the STR in virologically 
suppressed HIV-I infected children 
2 years of age weighing 
14 to < 25 kg administered 
E/C/F/TAF LD STR 
• 
To evaluate the safety and tolerability ofE/C/F/TAF LD STR through Week 24 in 
virologically suppressed HIV-I infected children ~ 2 years of age and weighing~ 14 to 
< 25 kg 
The secondaiy analysis objectives are: 
• 
To evaluate the antiviral activity of switching to E/C/FffAF LD STR through Week 48 in 
virologically suppressed HIV-I infected children ~ 2 years of age and weighing~ 14 to 
< 25 kg 
• 
To evaluate the safety and tolerability ofE/C/F/TAF LD STR through Week 48 in 
virologically suppressed HIV-I infected children ~ 2 yeai·s of age, weighing~ 14 to < 25 kg 
All Cohorts 
I 
8.1.2. 
Primary Endpoints. 
Cohort 1 
In Pait A the prima1y endpoints ai·e PK pai·ameter of AUC1aufor EVG and AUC1astfor TAF and 
in Pait B the primaiy endpoints include incidence of treatment-emergent SAEs and all 
treatment-emergent adverse events. 
Cohort 2 
In Pait A the prima1y endpoints include PK parameter of AUC1aufor EVG and AUC1astfor TAF, 
and in Pait B the prima1y endpoints include incidence of treatment-emergent SAEs and all 
treatment-emergent adverse events. 
Cohort 3 
The prima1y endpoints include PK pai·ameter of AUCtau for EVG and TAF, incidence of 
treatment-emergent SAEs, and all treatment-emergent adverse events. 
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Amendment 6
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8.1.3.
Secondary Endpoints
Cohort 1
For Part A, the secondary endpoints include:

PK parameters of Ctau, Cmax, apparent CL and apparent Vz for EVG, Cmax, apparent CL and 
apparent Vz for TAF, AUCtau, Cmax, and Ctau for FTC, TFV and COBI.
For Part B, the secondary endpoints include:

The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as 
defined by the FDA snapshot analysis

The percentage of subjects with plasma HIV-1 RNA < 400 copies/mL at Weeks 24 and 48 as 
defined by the FDA snapshot analysis

The change from baseline in plasma log10 HIV-1 RNA (copies/mL) and in CD4+ cell count
(cells/μL) and percentage at Weeks 24 and 48
Cohort 2
For Part A, the secondary endpoints include:

PK parameters of Ctau, Cmax, apparent CL and apparent Vz for EVG, Cmax, apparent CL and 
apparent Vz for TAF, AUCtau, Cmax, and Ctau for FTC, TFV and COBI.
For Part B, the secondary endpoints include:

The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as 
defined by the FDA snapshot analysis

The percentage of subjects with plasma HIV-1 RNA < 400 copies/mL at Weeks 24 and 48as 
defined by the FDA snapshot analysis.

The change from baseline in CD4+ cell count (cells/μL) and percentage at Weeks 24 and 48
Cohort 3
The secondary endpoints include:

PK parameters of Ctau, Cmax, apparent CL and apparent Vz for EVG, Cmax, apparent CL and 
apparent Vz for TAF, AUCtau, Cmax, and Ctau, for FTC, TFV andCOBI.

The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as 
defined by the FDA snapshot analysis.


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Amendment 6
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
The percentage of subjects with plasma HIV-1 RNA < 400 copies/mL at Weeks 24 and 48as 
defined by the FDA snapshot analysis.

The change from baseline in CD4+ cell count (cells/μL) and percentage at Weeks 24 and48
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
The full analysis set will include all subjects who received at least one dose of study drug.
8.2.1.2.
Safety Analysis Set
The safety analysis set will include all subjects who received at least one dose of study drug.
All the data collected up to 30 days after subjects permanently discontinue their study regimen 
will be included in the safety summaries.
8.2.1.3.
BMD Analysis Sets
8.2.1.3.1.
Spine BMD Analysis Set
The spine BMD analysis set will include all subjects who received at least one dose of study
drug, had nonmissing spine BMD value for the Baseline visit and at least one postbaseline visit.
8.2.1.3.2.
Total Body Analysis Set
The total body less head BMD analysis set will include all subjects who received at least one 
dose of study drug, had nonmissing total body less head BMD value for the Baseline visit and at 
least one postbaseline visit.
8.2.1.4.
Pharmacokinetics (PK) Analysis Sets
8.2.1.4.1.
Intensive PK Analysis Set
The Intensive PK analysis set will include all subjects who received at least one dose of study 
drug and for whom steady-state pharmacokinetic profiles at Intensive PK visit are evaluable. The 
Intensive PK analysis set will be used for detailed PK analysis of EVG, COBI, FTC, TAF, and 
TFV by cohort.
8.2.1.4.2.
PK Analysis Set
The PK analysis set will include all subjects who received at least one dose of study drug and for 
whom at least one observed concentration data of any analyte of interest is available. The PK 
analysis set will be used for analysis of general PK and trough blood concentrations by cohort.


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
8.2.2. 
Data Handling Conventions 
Final 
Amendment6 
Natural logarithm trnnsfo1m ation for key PK parameters, such as Cmax, Ctau and AUCtau, will be 
applied for phaimacokinetic analysis. 
8.3. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized using standard descriptive 
methods. Demographic summaries will include sex, race/ethnicity, and age. 
Baseline data including body weight, height, body mass index, HIV-1 infection, and emolhnent 
distribution will be summarized. 
8.4. 
Efficacy Analysis 
The percentage of subjects with HIV-1 RNA < 50 copies/mL at Week 24 (Windows: Study 
Days 140-195) as defined by the FDA-defined snapshot algorithms ai·e described below. 
Virologic outcome at Week 24 for the Cohort 1 (treatment-na'ive) subjects will be defined into 
the following 3 categories: 
• 
HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the Week 24 analysis window; 
• 
HIV-1 RNA::::: 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA::::: 50 copies/mL in the Week 24 analysis window, or who do not have 
on-treatment HIV-1 RNA data in the Week 24 analysis window and who discontinue study 
drng prior to or in the Week 24 analysis window due to lack of efficacy, or who discontinue 
study drng prior to or in the Week 24 analysis window due to reasons other than AE, death, 
or lack of efficacy and have the last available on-treatment HIV-1 RNA ::::: 50 copies/mL; 
• 
No Virologic Data in the Week 24 Analysis Window: this includes subjects who do not have 
on-treatment HIV-1 RNA at Week 24 window because of the following: 
Discontinuation of study diug prior to or in the Week 24 analysis window due to AE or 
death; or 
Discontinuation of study diug prior to or in the Week 24 analysis window due to reasons 
other than AE, death, or lack of efficacy and the last available on-treatment HIV-1 RNA 
< 50 copies/mL; or 
Missing data in the Week 24 window but on study diug 
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Virologic outcome at Week 24 for the Cohort 2 and Cohort 3 (treatment suppressed) subjects 
will be defined similarly with the exception of classifying subjects who discontinue study drug 
due to AE or death and have the last available on-treatment HIV-1 RNA ≥50 copies/mL into the 
“HIV-1 RNA ≥ 50 copies/mL” category.
Virologic outcomes will be summarized using frequency counts and percentages based on the 
Full analysis set.
The percentage of subjects with HIV-1 RNA < 50 copies/mL at Week 48 (Windows: Study 
Days 308-377) and the percentage of subjects with HIV-1 RNA < 400 copies/mL at Weeks 24 
and 48 will be summarized in the same manner as described above.
The changes from baseline in plasma log10 HIV-1 RNA (Cohort 1 only) and in CD4+ cell count 
will be summarized using descriptive statistics.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
8.5.1.
Extent of Exposure
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study regimen, inclusive, regardless of temporary interruptions in study 
regimen administration.
Dosing information for individual subjects will be listed.
8.5.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Adverse events meeting the following criteria are defined as treatment-emergent AEs.
1) Any AEs with onset date of on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug
2) Any AEs leading to premature discontinuation of study drug.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and PT) will be provided. Additional summaries will include summaries for adverse events by 
grade, Investigator’s assessment of relationship to study drug, and effect on study drug dosing.


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8.5.3.
Laboratory Evaluations
Laboratory results will be expressed both in the original measurement and in terms of the 
toxicity grade according to toxicity grading table attached in Appendix 4. Changes from baseline 
in quantitative laboratory tests will be summarized by visit (including eGFR estimated by 
cystatin C clearance for Cohorts 1 and 2). Cystatin C will not be collected for Cohort 3. The 
maximum toxicity grade will be summarized by laboratory parameter. The post-baseline 
laboratory measurements obtained up to 30 days after the last dose date of the study drug will be 
included in the quantitative and qualitative summaries.
8.5.4.
Bone Safety
Selected bone safety, including:
Cohorts 1 and 2: serum bicarbonate, N-telopeptide, C-telopeptide, osteocalcin, procollagen type 
1 N-terminal propeptide (P1NP), and urine bicarbonate and N-telopeptide
For all cohorts: bone specific alkaline phosphatase, parathyroid hormone (PTH), 25OH 
Vitamin D, and 1,25OH Vitamin D
All the above will be summarized by visit using descriptive statistics.
8.5.5.
Renal Safety
Selected renal safety, including urine chemistry, retinol binding protein, and 
beta-2-microglobulin, will be summarized by visit using descriptive statistics.
8.5.6.
Spine and Total Body Less Head Bone Mineral Density
For all cohorts, the percentage change from baseline in spine and total body less head BMD will 
be summarized by study visit. BMD z-score will be derived for each BMD measurement if the 
corresponding reference population is available. Z-scores for spine and total body less head 
BMD and change from baseline in z-scores will also be summarized by visit.
8.5.7.
Tanner Stage Assessment
The Tanner stage score will be summarized by study visit.
8.5.8.
Palatability
Palatability will be summarized using descriptive statistics by cohort.
8.5.9.
Acceptability
Acceptability will be summarized using descriptive statistics.


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8.6.
Pharmacokinetic Analysis
The concentration data of EVG, COBI, FTC, TAF, and TFV over sampling time will be listed 
and summarized. Pharmacokinetic parameters (e.g., AUCtau, AUClast, Cmax, Tmax, Clast, Tlast, Ctau, 
λz, apparent CL, apparent Vz and T½) will be listed and summarized for analytes EVG, COBI, 
FTC, TAF, and TFV using descriptive statistics (e.g., sample size, arithmetic mean, geometric 
mean, coefficient of variation %, standard deviation, median, Q1, Q3, minimum, and maximum).
To determine whether the adult dose of TAF in adolescents (Cohort 1) and children (Cohort 2 
and 3), respectively, achieves similar TAF systemic exposures to that in adults, an analysis of 
variance will be carried out for log-transformed AUC as a primary parameter while other 
pharmacokinetic parameters such as Cmax will be explored. TAF data from the current study will 
be compared to the integrated historical control data using pharmacokinetic equivalence testing 
with an equivalency boundary of 70% - 143% for the 90% confidence interval. In addition, the 
95% confidence interval of the geometric mean estimate of apparent CL and Vz of TAF will be
provided.
Similar analysis will be done for log-transformed AUCtau as a primary parameter to determine 
whether the adult dose of EVG in adolescents and children, respectively, achieves similar EVG 
systemic exposures to that in adults. Other pharmacokinetic parameters such as Cmax and Ctau will 
be explored. EVG data from the current study will be compared to the integrated historical 
control data using pharmacokinetic equivalence testing with an equivalency boundary of 70% -
143% for the 90% confidence interval. The 95% confidence interval of the geometric mean 
estimate of apparent CL and Vz of EVG will also be provided.
Pharmacokinetic parameters of COBI, FTC, and TFV will be summarized using descriptive 
statistics.
8.7.
Independent Data Monitoring Committee
An external Independent Data Monitoring Committee (IDMC) will review the progress, efficacy, 
and safety data of this study while the study is ongoing. No formal stopping rules will be used by 
the IDMC for safety outcomes. Rather, a clinical assessment will be made to determine if the
nature, frequency, and severity of adverse events associated with a study regimen warrant the 
early termination of the study in the best interest of the participants. A separate IDMC charter 
will be finalized prior to initiation of dosing.
8.8.
Analysis Schedule
Cohort 1
A PK analysis will be performed after the first 18 subjects (regardless of age distribution) 
complete the Intensive PK portion of the study (Part A). With confirmation of TAF exposure 
from the first 18 subjects, screening in Part B will be initiated. If more than 18 subjects are 
enrolled in Part A, the final PK analysis will be performed after all subjects complete the 
Intensive PK portion of the study. The Week 24 analysis of efficacy and safety will be conducted 
after the last subject completes 24 weeks on study. The Week 48 analysis of efficacy and safety 
will be conducted after the last subject completes 48 weeks on study.


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Cohort 2
A PK analysis will be performed after all subjects complete the Intensive PK portion of the study 
(Part A). The Week 24 analysis of efficacy and safety will be conducted after the last Part A 
subject completes 24 weeks on study and also after all subjects complete 24 weeks on study. The 
Week 48 analysis of efficacy and safety will be conducted after the last subject completes
48 weeks on study.
Cohort 3
A PK analysis will be performed after all subjects complete the Intensive PK portion of the 
study. The Week 24 analysis of efficacy and safety will be conducted after all subjects complete 
24 weeks on study. The Week 48 analysis of efficacy and safety may be conducted after the last 
subject completes 48 weeks on study.
8.9.
Sample Size and Power
Cohort 1 and 2
A minimum of 18 Part A subjects from each cohort will receive E/C/F/TAF STR in this study. 
PK data from these subjects will have 92% power to conclude exposure equivalence of TAF 
AUClast in adolescents and children, respectively vs. 51 HIV-1 infected and HIV-negative adults 
(GS-US-292-0102 and GS-US-292-0103 combined) using two one-sided tests with each 
performed at an alpha level of 0.05. In this power analysis, it is assumed that the expected 
geometric mean ratios of TAF AUClast between adolescent group and adult group are equal to 1, 
and the inter-subject standard deviation (natural log scale) of TAF AUClast is 0.37 ng•hr/mL, and 
the equivalency boundary is 70% to 143%.
A minimum of 18 Part A subjects from each cohort will also provide > 99% power to target a 
95% confidence interval within 60% and 140% of the geometric mean estimate of apparent CL 
and Vz of TAF respectively, assuming a coefficient of variation (CV) of 38% for CL and 42% for 
Vz (GS-US-292-0102 and GS-US-292-0103 combined).
For each cohort, a total of 50 subjects (subjects from Part A and subjects from Part B combined) 
is planned to study the safety of the E/C/F/TAF STR. With this sample size, the present study 
will have 92% chance to observe at least 1 SAE, assuming the SAE incidence rate is 5% 
(observed in GS-US-292-0102).
After amendment 2 of the study protocol was finalized, the adult data included in Genvoya label 
have become available and will be used as historical control for comparison for Cohort2
(ie, intensive PK data from 19 HIV-1 infected adults in Study GS-US-292-0102 for EVG AUCtau 
and population PK data from 539 HIV-1 infected adults in Studies GS-US-292-0104 and
GS-US-292-0111 combined for TAF AUClast). Given the actual number of enrollments in 
Cohort 2 Part A is 23, a total of 23 subjects will provide 90% power for EVG AUCtau and 88% 
power for TAF AUClast to conclude exposure equivalence between adults and children. In this 
power analysis, it is assumed that the expected geometric mean ratios are equal to 1, the 
intersubject standard deviation (natural log scale) of EVG AUCtau and TAF AUClast is
0.34 ng•hr/mL and 0.52 ng•hr/mL, respectively, 2 one-sided statistical tests are done at an alpha 
level of 0.05, and the equivalency boundary is 70% to 143%.


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A total of 23 subjects will also provide > 86% power to target a 95% confidence interval within 
60% and 140% of the geometric mean estimate of CL and Vz of TAF respectively, assuming a 
coefficient of variation (CV) of 53% for CL and 76% for Vz (based on population PK data from 
GS-US-292-0104 and GS-US-292-0111 combined).
Cohort 3
Twenty-five evaluable subjects compared to historical adult data will provide 90% power for 
each of EVG AUCtau and TAF AUCtau to conclude exposure equivalence between children and 
adults. In this power analysis, it is assumed that the expected geometric mean ratios is 1, 
equivalency boundary is 70% to 143%, two one-sided tests are each performed at an alpha level 
of 0.05, and the intersubject standard deviations (natural log scale) of EVG AUCtau and TAF 
AUCtau are 0.34 ng•hr/mL and 0.52 ng•hr/mL. For historical adult data, we used intensive PK data 
from 19 HIV-1 infected adults in Study GS-US-292-0102 for EVG AUCtau and population PK 
data from Studies GS-US-292-0104 and GS-US-292-0111 combined for TAF AUCtau.
Twenty-five evaluable subjects will also provide > 99% power to target a 95% confidence 
interval within 60% and 140% of the geometric mean estimate of apparent CL and Vz of TAF 
respectively, assuming the standard deviation in natural log scale is 0.51 for CL and 0.54 for Vz 
(based on population PK data from Studies GS-US-292-0104 and GS-US-292-0111 combined).
Sample size and power calculations were made using the software package nQuery Advisor 
(Version 6.0) and R.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, Washington, 
Seoul, and South Africa), International Conference on Harmonisation (ICH) guidelines, or with 
the laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the study subject. For studies conducted under a United States IND, the 
Investigator will ensure that the basic principles of “Good Clinical Practice,” as outlined in
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 
”Protection of Human Subjects”, and 21 CFR, part 56, ”Institutional Review Boards”, are 
adhered to. These standards are consistent with the requirements of the European Community 
Directive 2001/20/EC.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all subinvestigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
subinvestigator. The investigator and subinvestigator agree to notify Gilead Sciences of any 
change reportable interests during the study and for one year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol defined 
activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Research Ethics Board (REB) Approval
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB/EC/REB. Approval from the 
IRB/EC/REB must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol after receipt of IRB/EC/REB approval must also be 
submitted to the IRB/EC/REB for approval before implementation.


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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must utilize an IRB/EC/REB-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the subject 
or the subject’s legally authorized representative and the person obtaining consent.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB/EC/REB, or laboratory. The investigator must keep a Screening 
log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in 
the trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, the investigational new drug, and any 
other study information, remain the sole and exclusive property of Gilead Sciences during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Gilead Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/EC/REB approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include, but is not limited to sequential notes containing at least 
the following information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Participation in trial (including trial number);


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• 
Trial discussed and date of info1med consent; 
• 
Dates of all visits; 
• 
Documentation that protocol specific procedures were perfo1med; 
• 
Results of efficacy parameters, as required by the protocol; 
Final 
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• 
Staii and end date (including dose regimen) of trial medication (preferably drng dispensing 
and return should be documented as well); 
• 
Record of all adverse events and other safety pai·ameters (staii and end date, and preferably 
including causality and intensity); 
• 
Concomitant medication (including staii and end date, dose if relevant; dose changes should 
be motivated); 
• 
Date of trial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the investigator until at least 2 yeai·s after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated mai·keting applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulato1y authorities have been notified. Investigators may be 
required to retain documents longer if required by applicable regulato1y requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences before destroying any clinical study records. 
Should the investigator wish to assign the study records to another paiiy or move them to another 
location, Gilead Sciences must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special an angements must be made between the investigator and Gilead Sciences 
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulato1y audit. When source documents ai·e required for the continued 
cai·e of the subject, appropriate copies should be made for storage outside of the site. 
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9.1.6.
Electronic Case Report Forms (eCRFs)
For each subject enrolled, an eCRF must be completed and signed by the principal investigator 
or subinvestigator (as appropriate) within a reasonable time period after data collection. This also 
applies to records for those subjects who fail to complete the study (even during a 
prerandomization screening period if an eCRF was initiated). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because of 
a treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
9.1.7.
Drug Accountability
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug kit. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug kits dispensed to subjects must be returned to the site.
Each study site must keep accountability records that capture:

The date received and quantity of study drug kits 

The date, subject number, and the study drug kit number dispensed.

The date, quantity of used and unused study drug kits returned, along with the initials of the 
person recording the information.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
9.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRB/EC/REBs, or to regulatory authority or health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/EC/REB 
in accordance with local requirements. Approval must be obtained before changes can be 
implemented.


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9.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies).
Gilead Sciences will ensure that the report meets the standards set out in the ICH Guideline for 
Structure and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may 
be prepared in certain cases.
After conclusion of the study and without prior written approval from Gilead Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead Sciences in an abstract, manuscript, or presentation form; or

The study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 9.1.4).
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with Gilead Sciences’ request to delete references to 
its confidential information (other than the study results) in any paper or presentation and agrees 
to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol (eg, attendance at Investigator Meetings). If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.


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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10. 
REFERENCES 
Airoldi M, Zaccarelli M, Bisi L, Bini T, Antinori A, Mussini C, et al. One-pill once-a-day 
HAART: a simplification strategy that improves adherence and quality of life of 
HIV-infected subjects. Patient preference and adherence 2010;4:115-25. 
Bangsberg DR, Ragland K, Monk A, Deeks SG. A one-pill, once-daily, fixed-dose combination 
(FDC) of efavirenz, emti·icitabine, and tenofovir disoproxil fumarate 
(EFV /FTCffDF) regimen is associated with higher unannounced pill count 
adherence than non-one pill, once-daily [Poster]. 17th Conference on Reti·ovirnses 
and Opportunistic Infections (CROI); 2010 Febrnaiy 16-19; San Francisco, CA. 
Capeau J. Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: 
Facts and Hypotheses. Clin Infect Dis 2011;53 (11):1127-9. 
Dejesus E, Young B, Morales-Ramirez JO, Sloan L, Wai·d DJ, Flaherty JF, et al. Simplification 
of antireh'oviral therapy to a single-tablet regimen consisting of efavirenz, 
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therapy in virologically suppressed HIV-I-infected patients. J Acquit· hnmune 
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Depaiiment of Health and Human Services (DHHS), Panel on AntiI·eu-oviI·al Therapy and 
Medical Management of HIV-Infected Chilch·en. Guidelines for the Use of 
Antireti·oviral Agents in Pediati-ic HIV Infection. Available at 
https://aidsinfo.nih.gov/guidelines. [Repo1i] Last Updated: May 22. 2018. 
EMTRIV A®, Gilead Sciences Inc. EMTRIV A® ( emu-icitabine) capsule, for oral use. 
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City, CA. Revised November. 2012: 
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US Prescribing Info1mation. Foster City, CA. Revised August 2012: 
Hodder SL, Mounzer K, Dejesus E, Ebrahimi R, Grimm K, Esker S, et al. Patient-Repo1ied 
Outcomes in Vii·ologically Suppressed, HIV-I-Infected Subjects After Switching 
to a Simplified, Single-Tablet Regimen of Efavii·enz, Emu-icitabine, and 
Tenofovii· DF. AIDS Patient Cai·e STDS 2010;24 (2):87-96. 
Joint United Nations Programme on HIV/AIDS (UNAIDS). Fact Sheet 2016. Available at: 
http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf . 
2016. 
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gai·galianos P, et al. Changing patterns of 
mo1iality across Europe in patients infected with HIV-1. EuroSIDA Study Group. 
Lancet 1998;352 (9142):1725-30. 
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Palella FJ, Delaney KM, Moo1man AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining 
Morbidity and Mortality Among Patients With Advanced Human 
Immunodeficiency Vims Infection. N Eng J Med 1998;338 (13):853-60. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
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Health and Human Services. 1-239. Available at 
http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Accessed 
August 22. 2012. 
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http://aidsinfo.nih.gov/ContentFiles/PediactricGuidelines.pdf. Accessed 
September 9, 2012. 2011:1-279. 
Prejean J, Song R, Hernandez A, Ziebell R, Green T, Walker F, et al. Estimated HIV incidence 
in the United States, 2006-2009. PLoS ONE 2011;6 (8):el 7502. 
Sax PE, Meyers J, Mugavero M, Davis KL. Adherence to Antiretroviral Treatment Regimens 
and Co1Telation with Risk of Hospitalization Among Commercially Insmed HIV 
Patients in the United States [Poster 0113]. 10th International Congress on Dmg 
Therapy in HIV Infection; 2010 November 7-11; Glasgow, UK. 
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
tenofovir disoproxil fumai·ate, cofonnulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-
blind, phase 3, non-inferiority trials. Lancet 2015;385:2606-15. 
Sterne J, Heman M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-te1m effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
coho1i study. Lancet 2005;366 (9483):378-84. 
World Health Organization (WHO). Developing Dosing Guidance For New And Upcoming 
Fonnulations Of Paediatric Antiretrovirals In Line With Treatment 2.0 Priorities. 
Presented at: Paediatric Antiretroviral Working Group.; 2011 25-26 October; 
Geneva, Switzerland. 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Stage-3-Defining Opportunistic Illnesses in HIV Infection
Appendix 7.
Tanner Stages


EVG/COBJ/FTC/f AF 
Protocol GS-US-292-0106 
Final 
Gilead Sciences, Inc. 
Amendment 6 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral Activity of 
the Elvitegravir/Cobicistat/Emtricitabine/fenofovir Alafenamide (E/C/F/TAF) Single Tablet 
Regimen (STR) in HIV-1 Infected Antiretroviral Treatment-Naive Adolescents and 
Virologically Suppressed Children 
GS-US-292-0106, Amendment 6, 21 February 2020 
This protocol bas been approved by Gilead Sciences, lnc. The following signature 
documents this approval. 
PD 
Name (Printed) 
PD 
Date 
PPD 
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 
CONFIDENTIAL 
Page 102 
21 February 2020 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 103
21 February 2020
Appendix 2.
Study Procedures Table
Study Procedures
Screeninga
Baseline 
(Day 1)
Week 1
(Day 7) Week 2b
Intensive 
PKc
End of Weekb
30-Day 
Follow-upd ESDDe
4
8
12
16
24
32
40
48
Assent/Informed 
Consent
X
Medical History
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Exam
X
X
X
X
X
Symptom-Directed 
Physical Examg
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tanner Stage 
Evaluationsh
X
X
X
12-lead ECG -
performed supine
X
HIV-1 Genotypei
X
Hematology Profilej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Profilek
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full flow cytometry 
panel testing
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic 
Assessmentsl
Xff
Xee
X
X
Plasma HIV-1 RNAm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Serologies 
X 
Urinalysis 
X 
Estimated Glomemlar 
X 
X 
Urine Pregnancy Testq 
Dispense Dosing Diaty 
(for Patt A subjects, 
inclusive of Cohott 3) 
Review Dosing Diaty 
(For Patt A subjects, 
inclusive of Cohott 3) 
Single PK Sampling1' 
Trough PK Samples 
CONFIDENTIAL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xff 
X 
X 
xee 
xee 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xz 
X 
X 
X 
xff 
X 
Page 104 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xdd 
xdd 
X 
Final 
Amendment6 
X 
X 
X 
X 
X 
X 
X 
21 Febrna1y 2020 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 105
21 February 2020
Study Procedures
Screeninga
Baseline 
(Day 1)
Week 1
(Day 7) Week 2b
Intensive 
PKc
End of Weekb
30-Day 
Follow-upd ESDDe
4
8
12
16
24
32
40
48
DXA Scan (Lumbar 
spine & Total Body)v
X
X
X
Bone Safetyw
Xff
Xee
Xdd
X
X
X
Urine Renal Safetyx
Xff
Xee
X
X
X
X
Study Drug 
Dispensation
X
X
X
X
X
X
X
X
X
In-clinic Dosingy
X
X
X
X
X
X
X
Drug Accountability
X
X
X
X
X
X
X
X
X
X
X
X
Palatability and 
Acceptability 
Assessment
Xbb
Xbb
Xaa, bb
Xaa
Xaa
Xaa, bb
Xcc
Xcc
a
Evaluations to be completed within 35 days prior to Baseline (or 42 days for subjects who require repeat testing of the HIV-1genotype).
b
All study visits are to be scheduled relative to the Baseline/Day 1 visit date. Visit windows are ± 2 days of the protocol-specified visit date from Week 2 through Week 8, 
± 4 days of the protocol-specified visit date from Week 12 through Week 48, 
, unless otherwisespecified.
c
Part A subjects only, inclusive of Cohort 3. The Intensive PK evaluation will occur at the Week 4 (Cohorts 1 and 2) or Week 2 (Cohort 3) visit. For the purpose of scheduling 
the Intensive PK visit, a + 7 days window may be used. If the subject has already dosed prior to the Intensive PK evaluation visit or is not in a fasted state, the Intensive PK 
assessments must not be completed. The subject should be instructed to return in a fasted state within 7 days of their Week 4 (Cohorts 1 and 2) or Week 2 (Cohort 3) visit for 
the Intensive PKvisit.
d
Only required for those subjects not enrolling in the 
 phase of the study or those subjects who permanently discontinue study drug and do not continue in the study 
through at least one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6 days window may be used.
e
ESDD visit should occur within 72 hours of last dose of study drug.
f
Vital signs include blood pressure, pulse, respiration rate, and temperature.
g
Symptom-directed physical examinations performed as needed.
h
Tanner assessments will be performed on subjects ≥ 6 years of age and no longer be performed once a subject has been documented as Tanner Stage 5. Tanner stage 
assessments will be performed 
 until subjects reach Tanner Stage 5, after which point Tanner assessments will no longer 
be performed.
i
Analysis for reverse transcriptase, protease and integrase resistance will be done at Screening. The investigator must have received the results from the Screening genotype 
before proceeding with the Baseline visit. (Cohort 1 only)
j
CBC with differential and platelet count.
k
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, cystatin C (Cohorts 1 and 2; Baseline, Weeks 2 [Cohort 1 only], 4, 24, and 
48), total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, CPK, and uric acid
l
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides).
If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted state to draw blood for the metabolic assessments.
CCI
CCI
CCI
CCI
CCI-


EVG/COBI/FfCffAF 
Protocol GS-US-292-0106 
Gilead Sciences, Inc. 
Final 
Amendment6 
m 
For Part A subjects (inclusive of Cohort 3), back-up samples will not be collected at Weeks I, 2, and 4 visits for Cohort I and at Weeks I through 16 for Cohorts 2 and 3. For 
Pait B sub' ects back-u sam !es will be collected at all visits. 
r 
0 I' 
q 
ema es o c 11 
eanng potenba on y. os,tive unne pregnancy tests w, 
e con ume wi a semm test at any VlSlt. 
r 
Cohoit I: a timed random PK sample collected at Week 4 (Part B subjects only) and Week 12 between 0.25-4 hours post-dose. A random PK sample collected at Week 8, 
Week 16, and Week 32. Cohoit 2: a timed PK at Week 12 between 0.25-4 hom·s post-dose. A random PK samples at Week 8 and Week 16. Cohoit 3: a timed PK sample 
collected between 0.25 and 4 hom·s post-dose at Week 8, 12, and 16. 
s 
Subjects must come into the clinic without taking their dose ofE/C/F/fAF STR and subjects should fast ovemight (a minimum of8 hotu-s). A trough (20 to 24 hours post-dose) 
plasma PK sample will be collected at Weeks 1, 2, and 24 for subjects in Cohort I and 2 and Week 48 for Cohoit I only. For subjects in Cohoit 3, a trough sample will be 
collected at Weeks 4 and 24. 
Pait A subjects only, inclusive of Cohoit 3. Intensive PK sampling will be peifonued on Week 4 (Cohoits 1 and 2) or Week 2 (Cohoit 3). For the ptupose of scheduling the 
Intensive PK visit a + 7 days window may be used. If the subject has already dosed prior to the Intensive PK visit or is not in a fasted state, the Intensive PK assessments must 
not be completed. The subject should be instmcted to rettun within fotu· days for the Intensive PK visit. If dosing non-compliance is identified on or prior to the Intensive PK 
visit, the Intensive PK assessments must not be completed. The subject should be counseled regarding proper dosing and asked to rettun for the Intensive PK visit no sooner 
than three da s followin com liant dosin and no later than Week 4 + 7 da s. Please refer to the PK/PBMC manual for sam le collection and rocessino details. 
r 
V 
w 
or o oits an 
, one sa ety mc u mg: 
Senllll: bicarbonate, N-telopeptide, C-telopeptide (CDC), osteocalcin, procollagen type 1 N-terminal propeptide (PINP) 
Urine: bicarbonate, N-telopeptide 
For all cohoits, bone safety including: 
Senllll: bone specific alkaline phosphatase, parathyroid hormone (PTH), 25OH Vitaniin D and 1, 25OH Vitaniin D 
x 
Urine Renal Safety including: m-ine chemistry, retinol binding protein, and beta-2-microglobulin. 
4 and 48 (± IO days).-
y 
All subjects will be given their dose ofE/C/F/fAF STR with food. For those subjects that take their medication in the evening, the in-clinic dosing will not be pe1foimed. 
z 
Cohoit I Pait B subjects only 
aa 
To be pe1foimed for all Cohoit 1 subjects ctm·ently on stt1dy at their next scheduled visit. 
bb To be peifoimed at Baseline and Week 4 for all Cohoit 2 subjects and at Baseline, Weeks 4, 24, and 48 for all Cohort 3 subjects enrolled. 
cc To be peifoimed at ESDD or 30-Day Follow-Up visit for either Cohort 1 or 2, as applicable. 
dd Cohoit I subjects only 
Cohoit I and 2 subjects only 
Cohoit 3 sub'ects 
CONFIDENTIAL 
Page 106 
21 Febrna1y 2020 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 107
21 February 2020
Appendix 3.
Management of Clinical and Laboratory Adverse Events
'f 
l\:la..- COil'DDUf 
dosing at th:e 
discretion of die 
inn:stig, to 
Grade . 
H confi1,ne,d and poss.ib111.,- au ot probably reb1ted! to 
in'loies:rigatiou,'ll ml'dkiinal p1roouc,5: 
Repeat fab t,o 
confirm tm:ici.n· 
grade 
• 
l. \'\iit:hhoM im.-e-stigational medir.inall p1·oduets UIJrtil •Gt·.:1de • 
' 
Restm.1 al] inwsrn:ganou.,~ tnedicinai pl'Oducts at full d'O&e 
H Grade J, or 4 t'ecunenee that i.~ confirmed and. po~ ilily 01· 
pll!ibably 1-d:ited fu i.m·e.srtigntion:iil mediri.nal p1roducts,. dm:-on:tinue 
all m\'·~tigational mem.ci.rutl produr~ dosing petil!lllmenth· 
Gnule3 
,. 
Repe, t Jnb to 
con.firm tm:k:it'> 
g1·ade 
· 
If ,tonfi.nm-d au.d um.\fbU,ed to 
i.nn-sn;gational mtsdicin:al. prmb1tis, 
dosing may,c,ontinuts ,a,t tihe 
dhtntion of the in11"e:stigat,or 
ff c.onfumed aml 
possih,~- or pmbab~· 
I_. nL,ted ro 
im,<' ligati-on,d 
mt'.dici.na:t pt"Oducts 
distmuinue 
iu. w liga.ti-onall 
mt'mdnaJ prnduc s 
dosing pe1110m1enrtly 
and follow at pe1riodic 
inren-als at i1east 
weekh' unfil a, trefurn 
to bas~line or is 
otil'mwe npbined 
li Grad1e 3 01· 41·ecun1ence ~il'm.t is ,i:rnns.iderod um·efoted 1to 
inn-stigationru medicinal p1"0d11ct continue all! ioxes·tigati.on.,~ 
lllfldicmal products ar the _ ,m.e dose at thi' disere,ti,ou. of the 
im-estigator 


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 108
21 February 2020
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 85 to 100 g/L
7.5 to 8.5 g/dL 75 to 85 
g/L
6.5 to 7.5 g/dL 65 to 75 
g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL 100 to 109 
g/L OR
Any decrease from Baseline
2.5 to 3.5 g/dL 25 to 35 
g/L
9.0 to 10.0 g/dL 90 to 100 
g/L OR
Any decrease from Baseline
3.5 to 4.5 g/dL 35 to 45 
g/L
7.0 to 9.0 g/dL 70 to 90 
g/L OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days (HIV 
POSITIVE OR NEGATIVE)
8.5 to 9.4 g/dL 85 to 94 g/L
7.0 to 8.5 g/dL 70 to 85 
g/L
6.0 to 7.0 g/dL 60 to < 70 
g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days (HIV 
POSITIVE OR NEGATIVE)
9.5 to 10.5 g/dL 95 to 105 g/L
8.0 to 9.5 g/dL 80 to 95 
g/L
7.0 to 8.0 g/dL 70 to 80 
g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days (HIV 
POSITIVE OR NEGATIVE)
12.0 to 13.0 g/dL 120 to 130 
g/L
10.0 to 12.0 g/dL 100 to 
120 g/L
9.0 to 10.0 g/dL 90 to 100 
g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric,
7 Days
1000 to 1300/mm3
1.00 to 1.30 GI/L
750 to 1000/mm3
0.75 to 1.00 GI/L
500 to 750/mm3
0.50 to 0.75 GI/L
500/mm3
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 109
21 February 2020
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric
300 to 400/mm3
200 to 300/mm3
100 to 200/mm3
100/mm3
13 Years
300 to 400/μL
200 to 300/μL
100 to 200/μL
100/μL
Absolute Lymphocyte Count 
HIV NEGATIVE ONLY
Adult and Pediatric
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs
2000/mm3 to 2500/mm3
2.00 GI/L to 2.50 GI/L
1,500 to 2,000/mm3
1.50 to 2.00 GI/L
1000 to 1,500/mm3
1.00 to 1.50 GI/L
1000/mm3
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
1.00 to 2.00 g/L
75 to 100 mg/dL
0.75 to 1.00 g/L
50 to 75 mg/dL
0.50 to 0.75 g/L
50 mg/dL
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product
20 to 40 μg/mL
20 to 40 mg/L
40 to 50 μg/mL
40 to 50 mg/L
50 to 60 μg/mL
50 to 60 mg/L
60 μg/mL
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN
1.50 to 3.00 ULN
3.00 ULN
International Normalized 
Ratio of prothrombin time 
(INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial 
Thromboplastin Time (APTT) 1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 110
21 February 2020
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to <LLN mEq/L
130 to <LLN mmol/L
125 to 130 mEq/L
125 to 130 mmol/L
121 to 125 mEq/L
121 to 125 mmol/L
121 mEq/L
121 mmol/L
Hypernatremia
146 to 150 mEq/L
146 to 150 mmol/L
150 to 154 mEq/L
150 to 154 mmol/L
154 to 159 mEq/L
154 to 159 mmol/L
159 mEq/L
159 mmol/L
Hypokalemia
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mEq/L
2.0 to 2.5 mmol/L
2.0 mEq/L
2.0 mmol/L
Hyperkalemia
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting
116 to 160 mg/dL
6.42 to 8.91 mmol/L
160 to 250 mg/dL
8.91 to 13.90 mmol/L
250 to 500 mg/dL
13.90 to 27.79 mmol/L
500 mg/dL
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric
7 Days Infant, 7 Days
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L
6.1 mg/dL
1.51 mmol/L
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected for 
albumin if appropriate*) 
Adult and Pediatric 7 Days
>ULN to 11.5 mg/dL
>ULN to 2.88 mmol/L
11.5 to 12.5 mg/dL
2.88 to 3.13 mmol/L
12.5 to 13.5 mg/dL
3.13 to 3.38 mmol/L
13.5 mg/dL
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
3.23 to 3.38 mmol/L
13.5 mg/dL
3.38 mmol/L


EVG/COBI/FTC/TAF
Protocol GS-US-292-0106
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 111
21 February 2020
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia (ionized)
3.0 mg/dL to LLN
0.74 mmol/L to LLN
2.5 to < 3.0 mg/dL
0.62 to 0.74 mmol/L
2.0 to 2.5 mg/dL
0.49 to 0.62 mmol/L
2.0 mg/dL
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
ULN to 1.50 mmol/L
6.0 to 6.5 mg/dL
1.50 to 1.63 mmol/L
6.5 to 7.0 mg/dL
1.63 to 1.75 mmol/L
7.0 mg/dL
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
0.58 to <LLN mmol/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.43 to 0.58 mmol/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.28 to 0.43 mmol/L
0.67 mg/dL
0.6 mEq/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
Pediatric 1 Year–14 Years
Pediatric 1 Year
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.0 mg/dL
0.31 mmol/L
1.5 mg/dL
< 0.47 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia
Adult and Pediatric
14 Days
1.0 to 1.5 ULN
1.5 to 2.5 ULN
2.5 to 5.0 ULN
5.0 ULN
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL 342 to 428 
μmol/L
25.0 to 30.0 mg/dL
428 to 513 μmol/L
30.0 mg/dL
513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL 342 to 428 
μmol/L
25.0 mg/dL
428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL
>ULN to 597 μmol/L
10.0 to 12.0 mg/dL
597 to 716 μmol/L
12.0 to 15.0 mg/dL
716 to 895 μmol/L
15.0 mg/dL
895 μmol/L


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CONFIDENTIAL
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypouricemia
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN
16.0 mmol/L to LLN
11.0 to 16.0 mEq/L
11.0 to 16.0 mmol/L
8.0 to 11.0 mEq/L
8.0 to 11.0 mmol/L
8.0 mEq/L
8.0 mmol/L
Triglycerides (Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
3.35 to 4.15 mmol/L
>160 to 190 mg/dL
>4.15 to 4.92 mmol/L
190 mg/dL
>4.92 mmol/L
NA
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia (Fasting) 200 to 239 mg/dL
5.16 to 6.19 mmol/L
239 to 300 mg/dL
6.19 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL


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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
3.0 g/dL to LLN 30 g/L to 
LLN
2.0 to 3.0 g/dL 20 to 30 
g/L
2.0 g/dL
20 g/L
NA


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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick)
1
2
3-4+
NA
Hematuria (Quantitative) See 
Note below
Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
75 RBC/HPF
NA
Males
6-10 RBC/HPF
10-75 RBC/HPF
75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes:
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to Dipstick 
Hematuria.
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the 
AE.


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
Asymptomatic AND No
Asymptomatic AND Non-
Symptomatic, non-life-
Life-threatening arrhythmia
(By ECG or physical exam)
intervention indicated
urgent medical intervention
threatening AND Non-urgent
OR Urgent intervention
indicated
medical intervention
indicated
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing consistent 
with ischemia
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant
NA
Symptomatic AND No
Symptomatic AND
Life-threatening hypotension
acute blood loss)
transfusion indicated
Transfusion of 2 units
OR Transfusion of 2 units
packed RBCs (for children
packed RBCs indicated (for
10 cc/kg) indicated
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic OR
90–99 mmHg diastolic
159–179 mmHg systolic OR
99–109 mmHg diastolic
179 mmHg systolic OR
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other 
than ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥ 95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences
(eg, tamponade) OR Urgent 
intervention indicated


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV block 
OR Ventricular pause
3.0 sec
Complete AV block
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block
Type II 2nd degree AV block
Complete AV block
Prolonged QTc
Pediatric 16 Years
Asymptomatic, QTc interval
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval
0.450 to 0.464 sec
Asymptomatic, QTc interval
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval
0.465 to 0.479 sec
Asymptomatic, QTc interval
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Asymptomatic, QTc interval
0.480 sec
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)
Embolic event (eg, pulmonary 
embolism, life- threatening 
thrombus)
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms OR 
Worsening symptomatic CHF
Life-threatening CHF


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


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


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


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CONFIDENTIAL
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis (clinical 
exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (eg, aspiration, 
choking)
Nausea
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with oral
intake
Persistent nausea resulting in 
decreased oral intake for 24–
48 hours
Persistent nausea resulting in 
minimal oral intake for
48 hours OR Aggressive 
rehydration indicated
(eg, IV fluids)
Life-threatening consequences
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis
(functional- symptomatic) 
Also see Mucositis/Stomatitis 
for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences
(eg, hypotensive shock)


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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic self-
care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy)
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weak- ness causing no 
or minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or 
minimal interference with 
usual social & functional 
activities
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & functional 
activities
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic self-
care functions
Seizure: (new onset)
NA
1 seizure
2–4 seizures
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)


EVG/COBI/FTC/TAF
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing)
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase from 
Previous Level of Control to 
Any of These Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality)
Seizures of any kind that are 
prolonged, repetitive (eg, 
status epilepticus), or difficult 
to control (eg, refractory 
epilepsy)
Seizure
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 5–20 
minutes with
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting
20 minutes
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated with 
a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or minimal 
interference with usual social 
& functional activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic self-
care functions


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
Joint pain causing no or
Joint pain causing greater
Joint pain causing inability to
Disabling joint pain causing
See also Arthritis
minimal interference with
than minimal interference
perform usual social &
inability to perform basic
usual social & functional
with usual social & functional
functional activities
self-care functions
activities
activities
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing greater than minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0
BMD t-score or z-score
–2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences
Pediatric 21 Years
BMD z-score
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater 
than minimal interference 
with usual social & functional 
activities
Muscle pain causing inability 
to perform usual social & 
functional activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND 
No operative intervention 
indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic
self-care functions


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


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


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


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


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 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 subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of E/C/F/TAF STR have demonstrated 
that a clinically relevant interaction with contraceptive steroids was observed or suspected. If 
used, a hormonal contraceptive should contain at least 30 mcg of ethinyl estradiol. In addition, 
non-clinical toxicity studies of E/C/F/TAF STR have demonstrated no adverse effect on fertility 
or embryo-fetal development. However, there is no clinical data of E/C/F/TAF STR in pregnant 
women. Please refer to the latest version of the investigator’s brochure for additional 
information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable 
effective contraceptive measure. They must have a negative serum pregnancy test at Screening 
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. In the event of 
a delayed menstrual period (over one month between menstruations), a pregnancy test must be 
performed to rule out pregnancy. This is applicable also for women of childbearing potential 
with infrequent or irregular periods. They must also agree to one of the following Screening until 
the last dose of study drug.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or


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
Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure® micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods (including Intrauterine hormone-releasing system (IUS)) must be 
used with barrier methods described above. The hormonal contraceptive should contain at
least 30 mcg of ethinyl estradiol.
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until the last study drug dose. 
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use
condoms when engaging in intercourse of reproductive potential. Male subjects must also refrain
from sperm donation during treatment and until at least the end of the protocol-defined
posttreatment period.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). A female condom and a male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.4.2.1.


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Appendix 6.
Stage-3-Defining Opportunistic Illnesses in HIV Infection
Bacterial infections, multiple or recurrent* Candidiasis of bronchi, trachea, or lungs Candidiasis 
of esophagus
Cervical cancer, invasive†
Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV§
Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumonitis, or esophagitis 
(onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s 
duration) Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) 
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary 
Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary 
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary 
Pneumocystis jirovecii (previously known as “Pneumocystis carinii”) pneumonia 
Pneumonia, recurrent†
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age >1 month 
Wasting syndrome attributed to HIV§
*
Only among children aged <6 years.
†
Only among adults, adolescents, and children aged ≥6 years.
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy and HIV 
wasting syndrome, are described in the following references: CDC. 1994 Revised classificationsystem for human 
immunodeficiency virus infection in children less than 13 years of age.
MMWR 1994;43(No. RR-12). CDC. 1993 Revised classification system for HIV infection and expanded surveillance case 
definition for AIDS among adolescents and adults. MMWR 1992;41(No. RR-17).


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Appendix 7.
Tanner Stages
1.
Pubic hair (male and female)
Tanner I
no pubic hair at all (prepubertal Dominic state)
Tanner II
small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum 
(males) or on the labia majora (females)
Tanner III
hair becomes more coarse and curly, and begins to extend laterally
Tanner IV
adult-like hair quality, extending across pubis but sparing medial thighs
Tanner V
hair extends to medial surface of the thighs
2.
Genitals (male) (One standard deviation around mean age)
Tanner I
Testes, scrotum, and penis about same size and proportion as in early childhood
Tanner II
Enlargement of scrotum and testes; skin of scrotum reddens and changes in texture; little or no 
enlargement of penis (10.5-12.5)
Tanner III
Enlargement of penis, first mainly in length; further growth of testes and scrotum (11.5-14)
Tanner IV
Increased size of penis with growth in breadth and development of glans; further enlargement of 
testes and scrotum and increased darkening of scrotal skin (13.5-15)
Tanner V
Genitalia adult in size and shape
3.
Breasts (female)
Tanner I
no glandular tissue: areola follows the skin contours of the chest
Tanner II
breast bud forms, with small area of surrounding glandular tissue; areola begins to widen
Tanner III
breast begins to become more elevated, and extends beyond the borders of the areola, which 
continues to widen but remains in contour with surrounding breast
Tanner IV
increased breast size and elevation; areola and papilla form a secondary mound projecting from 
the contour of the surrounding breast
Tanner V
breast reaches final adult size; areola returns to contour of the surrounding breast, with a 
projecting central papilla.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, 
and Antiviral Activity of the Elvitegravir/Cobicistat/Emtricitabine/
Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen 
(STR) in HIV-1 Infected Antiretroviral Treatment-Naive 
Adolescents and Virologically Suppressed Children
Name of Test Drug:
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) STR
Study Number:
GS-US-292-0106
Protocol Version:
Amendment 3
Protocol Date:
11 August 2016
Analysis Type:
Interim 4 Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
12 October 2018
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD 
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives of Cohorts 1 and 2........................................................................................................7
1.2.
Study Design of Cohorts 1 and 2..............................................................................................................8
1.2.1.
Design Configuration .............................................................................................................8
1.2.2.
Subject Population..................................................................................................................9
1.2.3.
Treatment Group ....................................................................................................................9
1.2.4.
Study Schema (Main Phase)...................................................................................................9
1.2.5.
Key Eligibility Criteria.........................................................................................................10
1.2.6.
Study Periods/Phases and Duration......................................................................................11
1.2.7.
Pharmacokinetic Evaluation.................................................................................................11
1.2.9.
Schedule of Assessments......................................................................................................12
1.3.
Sample Size and Power of Cohorts 1 and 2 ...........................................................................................12
2.
PLANNED ANALYSES ....................................................................................................................................13
2.1.
Cohort 1 Part A Week 4 Independent Data Monitoring Committee Analysis .......................................13
2.2.
Cohort 1 Part A Final PK Analysis ........................................................................................................13
2.3.
Cohort 1 Interim Week 24 Analysis.......................................................................................................13
2.4.
Cohort 1 Week 24 Analysis (All Subjects Included) .............................................................................13
2.5.
Cohort 1 Week 48 Analysis ...................................................................................................................13
2.6.
Cohort 2 Part A Week 4 Independent Data Monitoring Committee Analysis .......................................14
2.7.
Cohort 2 Part A Week 24 Analysis ........................................................................................................14
2.8.
Interim 4 Analysis..................................................................................................................................14
2.9.
Final Analysis ........................................................................................................................................14
2.10.
Changes from Protocol-Specified Analysis............................................................................................14
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSIS .............................................................................15
3.1.
Analysis Sets..........................................................................................................................................15
3.1.1.
All Enrolled Analysis Set.....................................................................................................15
3.1.2.
Full Analysis Set ..................................................................................................................15
3.1.3.
Safety Analysis Set...............................................................................................................15
3.1.4.
DXA Analysis Set ................................................................................................................15
3.1.5.
PK Analysis Sets ..................................................................................................................16
3.2.
Subject Grouping ...................................................................................................................................16
3.3.
Strata and Covariates..............................................................................................................................16
3.4.
Multiple Comparisons............................................................................................................................16
3.5.
Missing Data and Outliers......................................................................................................................16
3.5.1.
Missing Data ........................................................................................................................16
3.5.2.
Outliers.................................................................................................................................16
3.6.
Data Handling Conventions and Transformed Data...............................................................................17
3.7.
Visit Windows........................................................................................................................................17
3.7.1.
Key Definitions ....................................................................................................................17
3.7.2.
Analysis Windows................................................................................................................18
3.7.3.
Selection of Data in the Event of Multiple Records in a Window .......................................21
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment.................................................................................................................................22
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4.2.
Disposition of Subjects ..........................................................................................................................22
4.3.
Extent of Exposure.................................................................................................................................23
4.3.1.
Duration of Exposure to Study Drug....................................................................................23
4.3.2.
Adherence with Study Drug.................................................................................................24
4.4.
Protocol Deviations................................................................................................................................24
5.
BASELINE CHARACTERISTICS....................................................................................................................25
5.1.
Demographics and Baseline Characteristics ..........................................................................................25
5.2.
Medical History......................................................................................................................................25
6.
EFFICACY ANALYSES ...................................................................................................................................26
6.1.
Definition of the Efficacy Endpoints......................................................................................................26
6.1.1.
Efficacy Endpoints ...............................................................................................................26
6.1.2.
US FDA-Defined Snapshot Algorithm ................................................................................26
6.1.3.
Missing = Failure and Missing = Excluded Analyses ..........................................................27
6.2.
Analysis Methods for Efficacy Endpoints..............................................................................................28
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................28
7.
SAFETY ANALYSES........................................................................................................................................29
7.1.
Adverse Events.......................................................................................................................................29
7.1.1.
Adverse Event Dictionary ....................................................................................................29
7.1.2.
Adverse Event Severity........................................................................................................29
7.1.3.
Relationship of AEs to Study Drug......................................................................................29
7.1.4.
Relationship of AEs to Study Procedure..............................................................................29
7.1.5.
Serious AEs..........................................................................................................................29
7.1.6.
Treatment Emergent AEs .....................................................................................................30
7.1.7.
Summaries of AEs and Deaths.............................................................................................30
7.1.8.
Stage 3 Opportunistic Illnesses in HIV ................................................................................31
7.2.
Laboratory Evaluations ..........................................................................................................................31
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................31
7.2.2.
Graded Laboratory Values ...................................................................................................32
7.3.
Bone Safety Analyses ............................................................................................................................33
7.3.1.
Bone Mineral Density ..........................................................................................................33
7.3.2.
Bone Safety Assessments.....................................................................................................34
7.3.3.
Fracture Events.....................................................................................................................34
7.4.
Renal Safety Analyses............................................................................................................................34
7.4.1.
Serum Creatinine..................................................................................................................34
7.4.2.
Estimated Glomerular Filtration Rate ..................................................................................35
7.4.3.
Urine Retinol Binding Protein to Creatinine Ratio and 
Beta-2-Microglobulin to Creatinine Ratio............................................................................35
7.4.4.
Proteinuria by Quantitative Assessment...............................................................................35
7.5.
Tanner Stage Assessment.......................................................................................................................36
7.6.
Palatability/Acceptability Assessment ...................................................................................................36
7.7.
Body Weight, Height, and Vital Signs...................................................................................................36
7.8.
Nonstudy-Drug Antiretroviral Medications ...........................................................................................36
7.9.
Concomitant Non-ARV Medications.....................................................................................................37
7.10.
Electrocardiogram Results .....................................................................................................................37
7.11.
Other Safety Measures ...........................................................................................................................37
7.12.
Changes from Protocol-Specified Safety Analysis ................................................................................37
8.
PHARMACOKINETICS ANALYSIS ...............................................................................................................38
8.1.
Analysis Methods for Anytime PK ........................................................................................................38
8.2.1.
Statistical Comparative Analysis..........................................................................................38
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8.3.
Changes from Protocol-Specified PK Analysis .....................................................................................38
9.
REFERENCES ...................................................................................................................................................39
10.
SOFTWARE.......................................................................................................................................................40
11.
SAP REVISION..................................................................................................................................................41
12.
APPENDICES ....................................................................................................................................................42
Appendix 1.
Study Procedure Table ...........................................................................................................43
Appendix 2.
Flowchart of US FDA-Defined Snapshot Algorithm .............................................................46
Appendix 3.
Fracture Events.......................................................................................................................47
Appendix 4.
Programming Specifications...................................................................................................50
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for Vital Signs, Weight, Height, and Laboratory Testsa..........................19
Table 3-2.
Analysis Windows for Metabolic Assessmentsa.....................................................................19
Table 3-3.
Analysis Windows for Fasting Glucose .................................................................................19
Table 3-4.
Analysis Windows for Tanner Stage and BMD Assessments................................................20
Table 3-5.
Analysis Windows for Bone Safety Assessmentsa .................................................................20
Table 3-6.
Analysis Windows for Cystatin Ca .........................................................................................20
Table 3-7.
Analysis Windows for Urine Renal Safety Assessmentsa,b ....................................................20


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LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
ARV 
antiretroviral 
BLQ
below limit of quantitation
BMD
bone mineral density
BMI
body mass index
BSA
body surface area
CDER
Center for Drug Evaluation and Research
CI
confidence interval 
COBI
cobicistat (GS-9350)
CPK
creatine phosphokinase
CRF
case report form
CV
coefficient of variation
DC
study drug discontinuation
DEXA
dual-energy x-ray absorptiometry
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EVG
elvitegravir
EVG/COBI/FTC/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
FDA
Food and Drug Administration
FEPO4
urine fractional excretion of phosphate
FTC
emtricitabine
GFR
glomerular filtration rate
GSI
Gilead Sciences, Inc.
HIV-1
human immunodeficiency virus (Type 1) 
HLGT
high-level group term
IDMC
independent data monitoring committee
MedDRA
Medical Dictionary for Regulatory Activities
NCEP
National Cholesterol Education Program
PBMC
peripheral blood mononuclear cell
PT
preferred term
PK
pharmacokinetic
PR
pulse rate
PVF
pure virologic failure
Q
Quartile
QD
once daily


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RNA
ribonucleic acid
SAP
statistical analysis plan
SD
standard deviation
SMQ
standardized MedDRA query
SOC
system organ class
STB
Stribild®
STR
single-tablet regimen
TDF
tenofovir disoproxil fumarate, Viread®
TFL
tables, figures, and listings
TFV
tenofovir
WHO
World Health Organization


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1.
INTRODUCTION
GS-US-292-0106 is a Phase 2/3, open-label, multicenter, multicohort, single-arm study of the 
pharmacokinetics (PK), safety, tolerability, and antiviral activity of elvitegravir/cobicistat/
emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen (STR) in HIV-1 infected, 
antiretroviral (ARV) treatment-naive adolescents and virologically suppressed children. 
This document describes the statistical analysis methods and data presentations to be used in the 
summary and analysis of data for Study GS-US-292-0106 Interim 4 Analysis. This analysis will 
include data collected from Cohort 1 (treatment-naïve adolescents 12 to < 18 years of age and 
weight ≥ 35 kg) and Cohort 2 (virologically suppressed children 6 to < 12 years of age and 
weight ≥ 25 kg) of the study. 
1.1.
Study Objectives of Cohorts 1 and 2
Cohort 1
The primary objectives of Cohort 1 are:
Part A:

To evaluate the steady state pharmacokinetics (PK) for elvitegravir (EVG) and tenofovir 
alafenamide (TAF) and confirm the dose of the elvitegravir/cobicistat/emtricitabine/ 
tenofovir alafenamide (E/C/F/TAF) single tablet regimen (STR) in HIV-1 infected, 
antiretroviral (ARV) treatment-naive adolescents
Part B:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 24 in HIV-1 
infected, ARV treatment-naive adolescents
The secondary objectives of Cohort 1 are:

To evaluate the safety and tolerability of the E/C/F/TAF STR through Week 48 in HIV-1 
infected, ARV treatment-naive adolescents

To evaluate the antiviral activity of the E/C/F/TAF STR through Week 48 in HIV-1 infected, 
ARV treatment-naive adolescents


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Cohort 2
The primary objectives of Cohort 2 are:
Part A:

To evaluate the PK of EVG and TAF in virologically suppressed HIV-1 infected children 6 
to < 12 years of age weighing ≥ 25 kg administered E/C/F/TAF STR
Part B:

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 24 in virologically 
suppressed HIV-1 infected children 6 to < 12 years of age weighing ≥25 kg
The secondary objectives of Cohort 2 are:

To evaluate the antiviral activity of switching to E/C/F/TAF STR through Week 48 in 
virologically suppressed HIV-1 infected children 6 to < 12 years of age weighing ≥25 kg

To evaluate the safety and tolerability of E/C/F/TAF STR through Week 48 in virologically 
suppressed HIV-1 infected children 6 to < 12 years of age, weighing ≥25 kg
1.2.
Study Design of Cohorts 1 and 2
1.2.1.
Design Configuration
Each cohort contains 2 parts (Part A and Part B) and 2 phases (main phase 
). 
The “main phase” in this document refers the safety and efficacy evaluation phase through 
Week 48. For each cohort, 18 to 24 eligible subjects will be enrolled into Part A to evaluate the 
EVG and TAF plasma PK and confirm the dose of EVG and TAF. The Week 4 intensive PK 
samples will be analyzed after 18 subjects (regardless of age distribution) complete the Week 4 
intensive PK portion of the study. Following completion of the intensive PK visit, subjects will 
continue to receive the E/C/F/TAF STR and return for scheduled study visits through Week 48.
Screening will be initiated into Part B following confirmation of EVG and TAF exposure in at 
least 18 subjects from Part A. An additional 26 to 32 subjects will be enrolled in Part B to 
evaluate the safety, tolerability and antiviral activity of the E/C/F/TAF STR in at least 
50 subjects, including all subjects enrolled in Parts A and B combined. 
CCI 


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1.2.2. 
Subject Population 
Cohort 1 
Final 
Version 1.0 
Antiretrnviral treatment-naive, HIV-1 infected adolescents (12 to < 18 years of age) of either sex 
with plasma HIV-1 RNA levels :::: 1,000 copies/mL 
Cohort 2 
Virologically suppressed, HIV-1 infected children ( 6 to < 12 years of age and screening weight 
:::: 25 kg) of either sex with plasma HIV-1 RNA levels < 50 copies/mL) for :::: 6 consecutive 
months prior to screening on a stable antiretrnviral regimen, with no documented histo1y of 
resistance to any component of E/C/FffAF STR. 
1.2.3. 
Treatment Group 
This is an open-label, single-aim study. All subjects in Coho1ts 1 and 2 will be enrolled and 
treated with the E/C/F/TAF 150/150/200/10 mg STR. 
1.2.4. 
Study Schema (Main Phase) 
Cohort 1 (N = 50): 
'.:o 35 days prior 
Baseline 
PK 
to Baseline 
(Day 1) 
Week24 
Week48 
30 DayF/U 
( ScreeningH Pait B: E~~1{_,/;AF QD ~
I 
'.:o 35 days prior 
Baseline 
Week24 
Week 48 
30 Day F/U 
to Baseline 
(Day 1) 
a 
Screening for Pait B will commence after the PK data from Part A confirms the adolescent dose of the E/C/F/TAF STR 
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Cohort 2 (N = 50): 
( ScreeningH~ __ P_ru_t_A_: -~-~c_1s_~-~-T_AF_Q_D_~l~~ ~~~j 
35 days prior 
Baseline 
to Baseline 
(Day 1) 
PK 
Week24 
Week48 
30 DayF/U 
Final 
Version 1.0 
( ScreeningH.__P_rut_
B:_~=-~i_3
~T_
AF_QD_..._.l~-~ -"-"-'
~ '-"-'"'
~ I 
3 5 days prior 
Baseline 
Week24 
to Baseline 
(Day 1) 
Week48 
30 DayF/U 
1.2.5. 
Key Eligibility Criteria 
HIV-1 infected subjects who meet the following criteria: 
Cohort 1 
• 
Age at Baseline: 12 to < 18 yeru·s old 
• 
Weight at Screening: ~ 35 kg (77 lbs) 
• 
Plasma HIV-1 RNA ~ 1,000 copies/mL at Screening (Roche COBAS TaqMan v2.0) 
• 
Screening genotype repo1t shows sensitivity to EVG, FTC and TFV (Monogram Biosciences, 
fuc.) 
-
Subjects with HIV subtype AE who meet all inclusion/exclusion criteria and who have a 
non-repo1table integrase genotype result may proceed with study emollment. 
(For Thailand only) 
• 
No prior use of any approved or experimental anti-HIV-I dmg for any length of time 
( other than that given for prevention of mother-to-child transmission) 
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Cohort 2 
• 
Age at Baseline: 6 to < 12 years old 
• 
Weight at Screening: ~ 25 kg (55 lbs) 
Final 
Version 1.0 
• 
Plasma HIV-1 RNA: < 50 copies/mL for ( or undetectable HIV-1 RNA level according to the 
local assay being used if the limit of detection is > 50 copies/mL) 
6 months prior to 
screening on a stable antiretrnviral regimen, without prior histo1y of resistance to any 
component of E/C/FffAF STR 
-
Unconfomed HIV-1 RNA 
50 copies/mL after previously reaching virologic 
suppression (transient detectable viremia, or "blip") and prior to screening is acceptable 
• 
Cunently receiving an antiretroviral regimen that has been stable for at least 6 months or has 
been newly initiated within 6 months for reasons other than virologic failure. 
1.2.6. 
Study Periods/Phases and Duration 
futensive PK evaluation occurs at Week 4 for subjects in Paii A, a 48-week safety and efficacy 
evaluation phase occurs for all subjects, and a 30-day follow up phase occurs for subjects who 
are pe1manently discontinued from the study before Week 48 and for subjects who do not choose 
to continue on the study after completing Week 48. 
1.2.7. 
Pharmacokinetic Evaluation 
Subjects emolled in Paii A will participate in an intensive PK evaluation at Week 4. Samples 
will be collected at O (predose, 
30 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 4, 5, 8, and 
24 hours postdose. 
A trough PK sample (20 to 24 hours postdose) will be collected at Weeks 1, 2, and 24. 
A random single plasma PK sample will be collected between 0.25 to 4 hours postdose at 
Week 12, and another random single plasma will be collected anytime in relationship to last dose 
of study drng between Weeks 8 and 16. 
The PK ofEVG, COBI, FTC, TAF, and tenofovir (TFV) will be evaluated. 
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1.2.9. 
Schedule of Assessments 
Final 
Version 1.0 
Study procedures at screening, baseline, and during the study are outlined in the protocol and 
presented in Appendix 1 of the Statistical Analysis Plan (SAP). 
1.3. 
Sample Size and Power of Cohorts 1 and 2 
A minimum of 18 Paii A subjects from each cohort will receive E/C/F/TAF STR in this study. 
PK data from these subjects will have 92% power to conclude exposure equivalence of T AF 
AUC1ast in adolescents and children, respectively vs. 51 HIV-1 infected and HIV-negative adults 
(GS-US-292-0102 and GS-US-292-0103 combined) using two one-sided tests with each 
perfo1med at an alpha level of 0.05. In this power analysis, it is assumed that the expected 
geometric mean ratios of TAF AUC1ast between adolescent group and adult group ai·e equal to 1, 
and the inter-subject standai·d deviation (natural log scale) ofTAF AUC1ast is 0.37 ng•hr/mL, and 
the equivalency boundaiy is 70% to 143%. 
A minimum of 18 Paii A subjects from each coho1i will also provide > 99% power to tai·get a 
95% confidence interval within 60% and 140% of the geometric mean estimate of appai·ent CL 
and Vz ofTAF respectively, assuming a coefficient of vai·iation (CV) of 38% for CL and 42% 
for Vz (GS-US-292-0102 and GS-US-292-0103 combined). 
After protocol Amendment 2 was finalized, adult data included in Genvoya label became 
available. This data will be used as historical control for Coho1i 2 (ie, intensive PK data from 19 
HIV-1 infected adults in Study GS-US-292-0102 for EVG AUCiau and population PK data from 
539 HIV-1 infected adults in Studies GS-US-292 0104 and GS-US-292-0111 combined for TAF 
AUC1ast) as compai·ison for Coho1i 1 has been perfonned. The actual em olled number of subjects 
in Coho1i 2 Pa1i A is 23, which will provide 90% power for EVG AUCiau and 88% power for 
TAF AUC1ast to conclude exposure equivalence between adults and children. In this power 
analysis, it is assumed that the expected geometric mean ratios are equal to 1, the intersubject 
standai·d deviation (natural log scale) ofEVG AUCiau and TAF AUC1ast is 0.34 ng•hr/mL and 
0.52 ng•hr/mL, respectively, 2 one-sided statistical tests ai·e done at an alpha level of 0.05, and 
the equivalency boundaiy is 70% to 143%. 
The total of 23 subjects em olled in Coho1i 2 Pa1i A also provides > 86% power to target a 95% 
confidence interval within 60% and 140% of the geometric mean estimate of CL and Vz ofTAF 
respectively, assuming a coefficient of vai·iation (CV) of 53% for CL and 76% for Vz (based on 
population PK data from GS-US-292-0104 and GS-US-292-0111 combined). 
Sainple size and power calculations were made using the software package nQue1y Advisor 
(Version 6.0) and R. 
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2.
PLANNED ANALYSES
2.1.
Cohort 1 Part A Week 4 Independent Data Monitoring Committee Analysis 
Analyses of safety, PK, and efficacy data were performed after 18 subjects (regardless of age 
distribution) from Cohort 1 Part A completed the Week 4 intensive PK portion of the study. The
purpose of this interim analysis was to provide the Independent Data Monitoring Committee 
(IDMC) with a statistical report for review and to determine whether screening for Cohort 1 
Part B would be initiated. More details are documented in the IDMC charter. 
2.2.
Cohort 1 Part A Final PK Analysis 
A Cohort 1 Part A final PK analysis was scheduled to be performed after all subjects in Cohort 1 
Part A either completed the Week 4 intensive PK portion of the study or permanently 
discontinued the study. This analysis was performed as part of the Cohort 1 Interim Week 24 
Analysis (see the next section) and the results were included in the Interim 1 clinical study report 
(CSR).
2.3.
Cohort 1 Interim Week 24 Analysis
An unplanned Cohort 1 interim Week 24 analysis was conducted after 23 subjects enrolled by 
11 February 2014 from both Part A and Part B of Cohort 1 completed the Week 24 visit or 
prematurely discontinued study drug. The date of 11 February 2014 was selected for the purpose 
of ensuring all subjects enrolled by that date would have the chance to reach Week 24 visit by 
the data cut date. Results of this analysis were included in the interim 1 CSR. 
2.4.
Cohort 1 Week 24 Analysis (All Subjects Included)
A Cohort 1 Week 24 analysis was conducted after all subjects from both Part A and Part B of 
Cohort 1 completed their Week 24 visit or prematurely discontinued study drug.
The Cohort 1 Week 24 analysis was the primary analysis for the study objectives in Cohort 1
Part B. The purpose of this interim analysis was to provide the IDMC with a statistical report for 
review.
2.5.
Cohort 1 Week 48 Analysis 
A Cohort 1 Week 48 analysis was conducted after all subjects from both Part A and Part B of 
Cohort 1 completed their Week 48 visit or prematurely discontinued study drug. Results of this 
analysis were included in the interim 2 CSR.


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2.6.
Cohort 2 Part A Week 4 Independent Data Monitoring Committee Analysis
Analyses of safety, PK, and efficacy data were performed after 18 subjects (regardless of age 
distribution) from Cohort 2 Part A completed the Week 4 intensive PK portion of the study. The
purpose of this interim analysis was to provide the IDMC with a statistical report for review. 
More details are documented in the IDMC charter. 
2.7.
Cohort 2 Part A Week 24 Analysis
A Cohort 2 Part A Week 24 analysis was conducted after all subjects in Cohort 2 Part A 
completed their Week 24 visit or prematurely discontinued study drug. Results of this analysis
were included in the interim 3 CSR.
2.8.
Interim 4 Analysis
An Interim 4 Analysis will be conducted after all subjects in Cohort
2 have completed their
 or Week 48 visit (for Cohort 2), or prematurely discontinued study 
drug. This SAP describes the analysis plan for the Interim 4 Analysis. Results of this analysis 
will be included in the interim 4 CSR.
2.9.
Final Analysis
A final statistical analysis will be conducted after all subjects have completed the study.
2.10.
Changes from Protocol-Specified Analysis
The Cohort 1 Interim Week 24 analysis and Cohort 2 Part A Week 24 analysis were added. The 
rationale for performing these analysis was to include the most current Week 24 data from
treatment-naïve adolescents and virologically suppressed children in the supplemental 
E/C/F/TAF marketing application.
A Cohort 1 Week 12 IDMC analysis was planned after the first 18 subjects from Cohort 1 Part A 
have either completed the Week 12 visit or prematurely discontinued study drug. This analysis 
was not done, as the Cohort 1 Interim Week 24 analysis results were presented to the IDMC 
instead.
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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSIS
Only Cohorts 1 and 2 data will be included for this Interim 4 Analysis.
3.1.
Analysis Sets
Analysis sets define which subjects are included in an analysis. A summary of the number and 
percentage of subjects in each analysis set will be provided. A listing will be provided for each
analysis set.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set will include all subjects who are enrolled in this study. This is the 
primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) will include all subjects who are enrolled in the study and have 
received at least 1 dose of study drug. For FAS analysis, all efficacy data, including data 
collected after the last dose date of study drug, will be included, unless specified otherwise. This 
is the primary analysis set for efficacy analyses. 
3.1.3.
Safety Analysis Set
The Safety Analysis Set will include all subjects who have received at least 1 dose of study drug.
All data collected from the first dose date up to 30 days after subjects permanently discontinue 
their study drug will be included in the safety summaries. This is the primary analysis set for 
safety analyses.
3.1.4.
DXA Analysis Set
3.1.4.1.
Spine DXA Analysis Set
The Spine DXA Analysis Set will include all subjects who are enrolled in the study, have 
received at least 1 dose of study drug, and have a nonmissing baseline and at least 
1 postbaseline spine bone mineral density (BMD) value.
3.1.4.2.
Total Body Less Head DXA Analysis Set
The Total Body Less Head DXA analysis set will include all subjects who are enrolled in the 
study, have received at least 1 dose of study drug, and have a nonmissing baseline and at least 
one postbaseline total body less head BMD value.


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3.1.5. 
3.1.5.1. 
PK Analysis Sets 
PK Analysis Set 
Final 
Version 1.0 
A PK analysis set will be defined separately for each of the 5 analytes (EVG, COBI, FTC, TAF, 
and TFV). The 5 PK analysis sets will include all enrolled and treated subjects from both Paii A 
and Paii B who have at least one observed concentration data of the respective analyte. The PK 
analysis sets will be used for analysis of single and trnugh blood concentrations. 
-
3.2. 
Subject Grouping 
The subjects will be grouped by coho1i (ie, Coho1i 1 and Coho1i 2) for efficacy and safety 
analyses. 
3.3. 
Strata and Covariates 
Not applicable. 
3.4. 
Multiple Comparisons 
Not applicable. 
3.5. 
3.5.1. 
Missing Data and Outliers 
Missing Data 
A missing datum for a given study visit window may be due to any of the following reasons: 
• 
A visit occuned in the window but data were not collected or were unusable. 
• 
A visit did not occur in the window. 
• 
A subject pe1manently discontinued from the study before reaching the window. 
In general, values for missing data will not be imputed, unless specified othe1wise. 
3.5.2. 
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be done to evaluate the impact of outliers on PK, efficacy, or safety 
outcomes, unless specified othe1wise. All data will be included in the analysis. 
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3.6.
Data Handling Conventions and Transformed Data
Logarithm (base 10) will be used to transform HIV-1 RNA data. Natural logarithm 
transformation will be applied to the PK concentrations for the PK analysis.
The PK concentration values below the lower limit of quantitation (BLQ) will be treated as zero
for the determination of summary and order statistics. Individual values that are BLQ will be 
presented as “BLQ” in the concentration data listing. For the presentation of summary and order 
statistics, if at least one subject has a concentration value of BLQ for the time point, then the 
minimum value will be displayed as “BLQ”. If more than 50% of the subjects have a 
concentration data value of BLQ for the time point, then the minimum and median values will be 
displayed as “BLQ”. If all subjects have concentration data values BLQ for the time point, then 
all order statistics (minimum, first quartile [Q1], median, third quartile [Q3], maximum) will be 
displayed as “BLQ”.
Data (eg, HIV-1 RNA data) that are continuous in nature but are less than the lower limit of 
quantitation or above the upper limit of quantitation will be imputed as follows: 

A value that is 1 unit less than the limit of quantification will be used for calculation of 
descriptive statistics if the datum is reported in the form of “< x”. For example, if the values 
are reported as < 50 and < 5.0, then values of 49 and 4.9 will be used for calculation of 
summary statistics, respectively. 

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the datum is reported in the form of “> x” (x is considered as the 
limit of quantitation). Values with decimal points will follow the same logic as above.

The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the form of “≤ x” or “≥ x” (x is considered as the limit of quantitation).

For direct bilirubin, a value of “< 0.1” is imputed as 0.09. For urine creatinine, a value of 
“< 1” is handled as a missing value in the calculation of related ratios.
3.7.
Visit Windows
3.7.1.
Key Definitions
Study Day 1 is defined as the day when the first dose of study drug E/C/F/TAF was taken, as 
recorded on the study drug administration electronic case report form (eCRF).
Study Day is calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1, Study Day is calculated as (visit date minus date of the first dose plus 1). For 
events that occurred prior to Study Day 1, Study Day is calculated as (visit date minus date of the 
first dose).


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Last Dose Date is defined as the maximum and nonmissing end date of study drng E/C/F /T AF 
on the study drng administrntion eCRF fonn with "Study Drng Pennanently Discontinued" box 
checked for sub· ects a who premature! 
· 
· 
· 
If the date oflast dose is incomplete or missing (eg, due to lost to follow-up), the last dose date 
will be imputed using the instruction described in Appendix 4. 
Last Study Date is the maximum of the nonmissing study drng staii dates, study drng end dates, 
and the clinic visit and laborato1y visit dates, includin the 30-da follow-u visit date for 
subjects 
· 
e 
Baseline Value is defined as the last nonmissing value obtained on or prior to Study Day 1. 
The baseline BMD value and Tanner Stage is defined as the last nonmissing value obtained prior 
to or up to Study Day 21 (inclusive). 
3.7.2. 
Analysis Windows 
Subject visits might not occm on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. 
The analysis windows for vital signs, weight, height, laboratory tests, and mine chemistry ai·e 
presented in Table 3-1. 
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Table 3-1.
Analysis Windows for Vital Signs, Weight, Height, and Laboratory 
Testsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 1
7
[2,9] (NPa)
Week 2
14
[10, 20] ([2,20]a)
Week 4
28
[21, 41]
Week 8
56
[42, 69]
Week 12
84
[70, 97]
Week 16
112
[98, 139]
Week 24
168
[140, 195]
Week 32
224
[196, 251]
Week 40
280
[252, 307]
Week 48
336
[308, 377]
NP = Not planned by the protocol.
a
Laboratory tests include HIV-1 RNA, CD4 cell counts, CD4%, hematology and chemistry. For CD4 cell count and CD4 %, 
Week 1 is not applicable and the study day range for Week 2 is [2, 20].
The analysis windows for metabolic assessments are presented in Table 3-2.
Table 3-2.
Analysis Windows for Metabolic Assessmentsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 24
168
[2, 251]
Week 48
336
[252, 503]
a
Metabolic assessments include lipid panel (total cholesterol, high-density lipoprotein [HDL], direct low-density lipoprotein 
[LDL], and triglycerides).
The analysis windows for fasting glucose are presented in Table 3-3.
Table 3-3.
Analysis Windows for Fasting Glucose
Nominal Day
Visit Window
Baseline
≤ 1
Week 8
56
[2, 69]
Week 12
84
[70, 125]
Week 24
168
[126, 251]
Week 48
336
[252, 503]
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The analysis windows for tanner stage and BMD assessments are presented in Table 3-4.
Table 3-4.
Analysis Windows for Tanner Stage and BMD Assessments
Nominal Day
Visit Window
Baseline
≤ 21
Week 24
168
[22, 251]
Week 48
336
[252, 503]
The analysis windows for serum bone safety assessments are presented in Table 3-5.
Table 3-5.
Analysis Windows for Bone Safety Assessmentsa
Nominal Day
Visit Window
Baseline
≤ 1
Week 12
84
[2, 125]
Week 24
168
[126, 251]
Week 24*k, k = 2, 
168*k
[168*k-84, 168*k+83]
a
Bone safety assessments include N-Telopeptide, CTx, bone specific alkaline phosphatase, P1NP, PTH, 25-hydroxy vitamin D, 
1,25-dihydroxyvitamin D. Urine bone assessments include bicarbonate, N-telopeptide.
The analysis windows for cystatin C are presented in Table 3-6.
Table 3-6.
Analysis Windows for Cystatin Ca
Nominal Day
Visit Window
Baseline
≤ 1
Week 4
28
[2, 97]
Week 24
168
[98, 251]
Week 48
336
[252, 419]
a
Only collected up to Week 48.
The analysis windows for urine renal safety assessments are presented in Table 3-7.
Table 3-7.
Analysis Windows for Urine Renal Safety Assessmentsa,b
Nominal Day
Visit Window
Baseline
≤ 1
Week 8
56
[2, 69]
Week 12
84
[70, 125]
Week 24
168
[126, 251]
Week 48
336
[252, 503]
a
Urine Renal Safety including: retinol binding protein, and beta-2-microglobulin.
b
Only collected up to Week 48.
CCI 
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3.7.3.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time to event analysis would not require one value per analysis window. When multiple valid 
and nonmissing observations fall within the bounds of a visit window and a single value is 
needed, the following rule(s) will be used. 
3.7.3.1.
Numeric Observations

For efficacy data (ie, HIV-1 RNA level, CD4 cell count, and CD4%) and BMD data, the 
latest record within the window will be selected. 

For other numeric observations, the record closest to the nominal day for that visit within the 
window will be selected. If there are 2 records equidistant from the nominal day, the latest 
will be selected.

If there is more than one record on the selected day, the average will be taken 
(geometric mean for HIV-1 RNA and arithmetic mean for others).
3.7.3.2.
Categorical Observations

For baseline, the last available record prior to the date of the first dose of the study drug will 
be selected. If there are multiple values recorded on the same day with the same time or 
missing time, select the value with the lowest severity.

For postdose visits, the most conservative value (eg, abnormal will be selected over normal, 
or the value with the highest severity) within the window will be selected.


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment 
Final 
Version 1.0 
The number and percentage of subjects enrolled will be summarized by each country and by 
each investigator within a country. The denominator for this calculation will be the number of all 
enrolled subjects. 
info1med consent date, enrollment status for the main phase 
will be provided. 
Screen failure subjects will be listed, including screening number, inclusion criteria not met, and 
exclusion criteria met. 
4.2. 
Disposition of Subjects 
A summaiy of subject disposition will be provided for all screened subjects. This SllilllllaIY will 
include the number of subjects screened, screened subjects who were not enrolled, screen failure 
subjects who were not enrolled, subjects enrolled, subjects in the Safety Analysis Set, and 
subjects in the FAS. 
In addition, the number and percentage of the subjects in the following categories will be 
smnmai·ized: 
a) Prematurely discontinued study tr·eatment in the main phase (with smnmaiy of reasons for 
discontinuing h'eatment) 
b) Completed study tr·eatment in the main phase 
c) Prematurely discontinued study in the main phase (with summaiy ofreasons for 
discontinuing study). 
d) Completed study in the main phase 
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The denominator for the percentages of subjects in each cate 
in the safet anal sis set for items a through 
Final 
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No inferential statistics will be generated. Subject dispositions will also be listed. Data listings of 
reasons for premature study drng/study discontinuation will be provided. 
4.3. 
4.3.1. 
Extent of Exposure 
Duration of Exposure to Study Drug 
Duration of exposure will be calculated in the Safety Analysis Set for exposure during the entire 
study for all subjects. 
Duration of exposure during the entire study will be expressed in weeks (recorded to 1 decimal 
place for week, eg, 4.5 weeks), and calculated as (Date oflast dose - Date of first dose+ 1) / 7, 
regardless of tempora1y intenuptions in study dmg administration. If subjects are still on study 
diug, the last dose date will be imputed for the calculation of study diug exposure using 
instructions provided in Appendix 4. 
Duration of exposure to study diug will be summarized using descriptive statistics (sample size, 
mean, SD, median, first quartile [Ql], third quaiiile [Q3], minimum, and maximum) and as the 
number and percentage of subjects exposed for specified periods, eg, 
1 week (7 days), 
2 weeks (14 days), ~ 4 weeks (28 days),~ 8 weeks (56 days), ~ 12 weeks (84 days). 
Summaries will be provided using the Safety Analysis set. 
Time to premature discontinuation of stud drug will be analyzed usin 
· 
imputed last dose date. 
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4.3.2.
Adherence with Study Drug
Study drug adherence will be computed based on pill counts. The numbers of pills of study drug 
dispensed and returned are captured on the study drug accountability eCRF.
Adherence (%) to the study drug will be calculated as follows:
Adherence (%) = 100 ×
Number of pills taken
Number of pills prescribed
= 100 ×
Sum of Number of pills taken at each dispensing period [1]
Sum of Number of pills prescribed at each dispensing period [2]
[1]
Number of pills taken at each distinct dispensing period is calculated as the minimum of a) the daily number of pills 
prescribed multiplied by the duration of treatment at each dispensing period, and b) number of pills taken (number of 
pills dispensed minus the number of pills returned). Total number of pills taken is determined by summing the number of 
pills taken from all evaluable dispensing periods.
[2]
Number of pills prescribed at each distinct dispensing period is calculated as the daily number of pills prescribed 
multiplied by the duration of treatment at each dispensing period. Total number of pills prescribed is determined by 
summing the number of pills prescribed from all evaluable dispensing periods.
The duration of treatment at each dispensing period is calculated as the minimum of (the last 
returned date of the same dispensing period, the date of permanent discontinuation of study drug, 
and next pill dispensing date) minus the dispensing date. The next pill dispensing date is the 
following dispensing date of the study drug regardless of the bottle return date.
For a record where the number of pills returned was missing (with “Yes” answered for 
“Was Bottle returned?” question), it is assumed the number of pills returned was 0. If the number 
of pills dispensed was missing or any study drug bottle was not returned or the bottle return 
status was unknown for the same dispensing date, all records for the same dispensing date will 
be excluded from both denominator and numerator calculations.
Overall adherence will be calculated for each subject either up to the date of permanent 
discontinuation of the study drug for subjects who permanently discontinued study drug or 
completed study drug or using all data available for subjects ongoing on study drug.
Descriptive statistics for overall adherence with the study drug (sample size, mean, SD, median, 
Q1, Q3, minimum, and maximum) together with the number and percentage of subjects in
adherence categories (eg, < 80%, ≥80% to < 90%, ≥90% to < 95%, ≥95%) will be provided for 
the Safety Analysis Set. No inferential statistics will be provided.
Drug accountability and adherence data will be listed.
4.4.
Protocol Deviations
A listing will be provided for subjects in the Safety Analysis Set who violate at least 
1 inclusion or exclusion criteria. The listing will include the eligibility criteria not met.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex, race, and ethnicity) and baseline characteristics 
(eg, body weight, weight Z-score, height, height Z-score, body surface area [BSA],
body mass index [BMI], and Tanner Stage) will be summarized using descriptive statistics for all 
subjects in the safety analysis set. The BSA will be calculated using the formula,
BSA (m2) = SQRT([Height(cm) × Weight(kg)] / 3600). The percentage of subjects who reach 
Tanner Stage 4 or 5 (defined as the maximum stage of public hair and genitalia/breasts) will also 
be summarized. The sample size, mean, SD, median, Q1, Q3, minimum, and maximum will be 
provided for continuous data, and the number and percentage of subjects will be provided for 
categorical data. Age is calculated as age in years at first dose of study drug. The definition of 
baseline value is provided in Section 3.7.1.
In addition, the following baseline disease characteristics will be summarized:

HIV-1 RNA (log10 copies/mL)

HIV-1 RNA categories (copies/mL): 100,000 and 100,000

HIV-1 RNA categories (copies/mL): ≤50 and > 50 

CD4 cell count (cells/µL) 

CD4 cell count categories (cells/µL): a) < 199, b) 200 to < 349, c) 350 to < 499, and d) ≥500

CD4 percentage (%)

HIV disease status

Mode of infection (HIV risk factor)

Years diagnosed with HIV (to be calculated as time prior to first dose date)

HBV surface antigen 

HCV antibody 

eGFR calculated by the Schwartz Formula (Section 7.4.2)

eGFR calculated by the modified Schwartz Formula (Section 7.4.2)

Proteinuria by urinalysis (dipstick)
Demographic, baseline characteristics, and baseline disease characteristics data will be listed for 
all enrolled subjects.
5.2.
Medical History
The HIV/AIDS-specific medical history and general medical history (ie, conditions not specific 
to the disease being studied) data will be listed only. Medical history data will not be coded.


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6.
EFFICACY ANALYSES
6.1.
Definition of the Efficacy Endpoints
6.1.1.
Efficacy Endpoints
The efficacy endpoints include:

The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL at Weeks 24 and 48 as 
defined by the United States (US) FDA-defined snapshot algorithm {U. S. Department of 
Health and Human Services 2015}

The change from baseline in CD4 cell count (cells/µL) and percentage at Weeks 24 and 48

The percentage of subjects with HIV-1 RNA < 50 copies/mL and < 400 copies/mL at 
Weeks 24 and 48 (Missing = Failure and Missing = Excluded analyses) 

The change from baseline in plasma log10 HIV-1 RNA (copies/mL) at Weeks 24 and 48
(Cohort 1 only)

The percentage of subjects with plasma HIV-1 RNA 400 copies/mL at Weeks 24 and 48 as 
defined by the FDA snapshot analysis (Cohort 1 only)
The percentage of subjects with plasma HIV-1 RNA < 50 copies/mL and < 400 copies/mL 
(based on the US FDA-defined snapshot) at Weeks 24 and 48 for Cohort 1 were performed as 
part of the interim 2 CSR and will not be repeated in this analysis. 
The change from baseline in CD4 cell counts and percentages at Weeks 24 and 48 and the 
percentage of subjects with HIV-1 RNA < 50 copies/mL or < 400 copies/mL at Weeks 24 and 48 
(based on the Missing = Failure and Missing = Excluded analyses) were performed as part of the 
interim 2 CSR for Cohort 1 and will be repeated using data from this analysis.
6.1.2.
US FDA-Defined Snapshot Algorithm
The analysis window at Week 24 is defined as from Study Day 140 to Study Day 195, inclusive. 
All HIV-1 RNA data collected on-treatment (eg, data collected from Study Day 1 up to 1 day 
after the last dose date of study drug) will be used in the US FDA-defined snapshot algorithm. 
Virologic outcome will be defined as the following categories:

HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the Week 24 analysis window

HIV-1 RNA ≥ 50 copies/mL: this include subjects:
1) Who have the last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the Week 24 
analysis window, or
2) Who do not have on-treatment HIV-1 RNA data in the Week 24 analysis window and
a) Who discontinue study drug prior to or in the Week 24 analysis window due to lack 
of efficacy, or


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b) Who discontinue study drug prior to or in the Week 24 analysis window due to AE or 
death and have the last available on-treatment HIV-1 RNA ≥50 copies/mL, or
c) Who discontinue study drug prior to or in the Week 24 analysis window due to 
reasons other than AE, death, or lack of efficacy and have the last available 
on-treatment HIV-1 RNA ≥50 copies/mL.

No Virologic Data in Week 24 Window: this includes subjects who do not have 
on-treatment HIV-1 RNA data in the Week 24 analysis window because of the following:
1) Discontinuation of study drug prior to or in the Week 24 analysis window due to AE or 
death and the last available on-treatment HIV-1 RNA < 50 copies/mL, or
2) Discontinuation of study drug prior to or in the Week 24 analysis window due to reasons 
other than AE, death, or lack of efficacy and the last available on-treatment HIV-1 RNA 
is < 50 copies/mL, or
3) Missing data during the window but on study drug.
The flowchart of the snapshot algorithm is provided in Appendix 2.
The snapshot algorithm for the percentage of subjects with HIV-1 RNA < 50 copies/mL at 
Week 48 will be defined similarly. The Week 48 analysis window for snapshot algorithm will be 
from Study Day 308 to Day 377. The analysis based on the snapshot algorithm will be performed 
for Cohort 2 subjects only.
6.1.3.
Missing = Failure and Missing = Excluded Analyses
Virologic response, defined as HIV-1 RNA < 50 copies/mL, will also be analyzed using the 
following 2 methods for imputing missing HIV-1 RNA values:

Missing = Failure (M = F)
In this approach, all missing data will be treated as virologic failure (ie, HIV-1 RNA 
≥50 copies/mL). This analysis will be done using the FAS.

Missing = Excluded (M = E) 
In this approach, all missing data will be excluded in the computation of virologic response 
(ie, missing data points excluded from both the numerator and denominator in 
response rate computation).


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6.2.
Analysis Methods for Efficacy Endpoints
The analyses for all the efficacy endpoints will be conducted using the FAS. 
The numbers and percentages of subjects with HIV-1 RNA < 50 copies/mL or < 400 copies/mL
based on the US FDA-defined snapshot algorithm, M = F analysis, and M = E analysis, will be 
summarized. The 95% CI for the percentage estimate in the snapshot algorithm analysis, M = F 
analysis, and M = E analysis will be constructed using the Clopper-Pearson exact method. For 
the snapshot algorithm, the numbers and percentages of subjects with HIV-1 RNA 
< 50 copies/mL, HIV-1 RNA ≥ 50 copies/mL (including subcategories), and no virological data 
(including reasons) will be summarized. For the M = F analysis, results will be summarized for 
all visits up to Week 48. For the M = E analysis, results will be summarized at all visits through 
the data cut date for the FAS.
The log10 HIV-1 RNA data will be summarized for Cohort 1 only, using observed data. The CD4 
cell count and CD4% data will be summarized using observed, on-treatment data (ie, up to 1 day 
after the last dose date of study drug). The baseline values and changes from baseline in CD4 cell 
count (cells/μL), and CD4% at each visit will be summarized descriptively (sample size, mean, 
SD, 95% CI, median, Q1, Q3, minimum, and maximum). The mean and 95% CI of change from 
baseline over time will be plotted.
A listing for plasma HIV-1 RNA, CD4 cell count, CD4%, and a listing for snapshot outcome 
will be provided.
6.3.
Changes From Protocol-Specified Efficacy Analyses
For Cohort 2, the percentage of subjects with plasma HIV-1 RNA < 400 copies/mL using 
snapshot algorithm was removed, because Cohort 2 is comprised of suppressed subjects and this 
endpoint does not apply.


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7.
SAFETY ANALYSES
Safety data will be summarized for the subjects in the Safety Analysis Set. All safety data 
collected on or after the date of the first dose of study drug up to the last dose date of study drug 
plus 30 days will be summarized, unless specified otherwise. All safety data will be included in 
data listings.
7.1.
Adverse Events
7.1.1.
Adverse Event Dictionary
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). System organ class (SOC), high-level group terms (HLGT), high-level 
term, preferred term (PT), and lower-level term will be attached to the clinical database.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe) or Grade 4 (life threatening) according to toxicity criteria specified in
Appendix 4 of the study protocol. The severity grade of events for which the investigator did not 
record severity will be left as “missing” for data listings.
7.1.3.
Relationship of AEs to Study Drug
Related AEs are those for which the investigator answers ‘Related’ to the question 
‘Related to Study Treatment?’ in the eCRF. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. Data 
listings will show relationship as missing.
7.1.4.
Relationship of AEs to Study Procedure
Adverse events for which “Yes” is marked for the question “Related to Study Procedures?” in 
the eCRF will be identified and included in the AE listing.
7.1.5.
Serious AEs
Serious AEs are those identified in the eCRF, where “Yes” was marked for “AE serious”. The 
clinical database will be reconciled with the SAE database (from the Pharmacovigilance and 
Epidemiology Department) before database finalization.


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7.1.6.
Treatment Emergent AEs
7.1.6.1.
Definition of Treatment Emergent
Treatment-emergent AEs (TEAEs) are events that meet one of the following criteria up to 
30 days after the permanent discontinuation of the study drug:

Events with onset dates on or after the first dose date of study drug 

Events that result in permanent study drug discontinuation
7.1.6.2.
Incomplete Dates
If the date of onset is incomplete or completely missing, the detailed definition of TEAE is 
specified in Appendix 4.
7.1.7.
Summaries of AEs and Deaths
A brief summary of AEs will show the number and percentage of subjects who a) had any 
treatment-emergent AE, b) had any Grade 3 or 4 treatment-emergent AE, c) had any 
Grade 2, 3, or 4 treatment-emergent AE, d) had any treatment-emergent study-drug-related AE, 
e) had any Grade 3 or 4 treatment-emergent study-drug-related AE, f) had any Grade 2, 3, or 4 
treatment-emergent study-drug-related AE, g) had any treatment-emergent SAE, h) had any 
treatment-emergent study-drug-related SAE, i) had any treatment-emergent AE leading to 
premature study-drug discontinuation, and j) had treatment-emergent death.
Treatment-emergent death refers to a death that occurred between the first dose date and the last 
dose date plus 30 days (inclusive).
Summaries (number and percentage of subjects) of AEs (by SOC and PT) will be provided using 
the safety analysis set as follows:

All treatment-emergent AEs 

Grade 3 or 4 treatment-emergent AEs

Grade 2, 3, or 4 treatment-emergent AEs

All treatment-emergent study-drug-related AEs 

Any Grade 3 or 4 treatment-emergent study-drug-related AEs 

Any Grade 2, 3, or 4 treatment-emergent study-drug-related AEs

All treatment-emergent SAEs

All treatment-emergent study-drug-related SAEs

All treatment-emergent AEs that caused premature discontinuation from study drug


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Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC will be ordered alphabetically, with PT sorted by decreasing total frequency. For 
summaries by severity grade, the most severe event will be selected.
In addition to the summaries, data listings will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Study-drug related SAEs

Death report

Pregnancy report

AEs leading to premature discontinuation of study drug
7.1.8.
Stage 3 Opportunistic Illnesses in HIV
On an ongoing basis, AEs will be reviewed for events that might meet the definition of stage 3 
opportunistic illnesses that are indicative of an AIDS-Defining Diagnosis 
(see Protocol Appendix 5). Gilead medical personnel will review the possible stage 3 
opportunistic illnesses and approve the events that meet the definition. Events that meet the 
stage 3 opportunistic illnesses definition of an AIDS-Defining Diagnosis will be listed.
7.2.
Laboratory Evaluations
Summaries of laboratory data will be provided for the Safety Analysis Set. Analysis will be 
based on values reported in conventional units. 
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided for each laboratory test specified in the study protocol as follows: 

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window

Percentage change from baseline to each postbaseline analysis window (if specified)
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.


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7.2.1.1.
Metabolic Assessments
For the lipid panel and glucose, only those measurements under fasting status will be 
summarized.
7.2.1.2.
Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized for the study. The following 
formula will be used when both serum calcium and albumin results for a given blood draw are 
available and serum albumin value is < 4.0 g/dL:
Calcium corrected for albumin (mg/dL) = serum calcium (mg/dL) + 0.8 × (4.0 – albumin [g/dL])
Toxicity grading for calcium will be applied based on the corrected values.
7.2.2.
Graded Laboratory Values
The criteria specified in the protocol will be used to grade laboratory results as Grade 0, 
mild (Grade 1), moderate (Grade 2), severe (Grade 3) or life-threatening (Grade 4). Grade 0 
includes all values that do not meet criteria for an abnormality of at least Grade 1. Some 
laboratory tests have criteria for both increased and decreased levels; analyses for each direction 
(ie, increased, decreased) will be presented separately.
Maximum postbaseline grade, instead of treatment-emergent grade, for nonfasting glucose will 
be summarized, as nonfasting glucose was not assessed at the baseline visit.
For triglycerides and cholesterol, the protocol-specified toxicity grading scale is for fasting test 
values, so nonfasting lipid results (or lipid results without known fasting status) will not be 
graded or summarized by toxicity grades.
If there is any laboratory toxicity grading scale overlapping with normal reference ranges 
(eg, Grade 1 scale overlaps with normal reference ranges), laboratory values within normal range 
will not be graded, except lipid tests.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
one toxicity grade from baseline at any time postbaseline up to and including the date of 
last dose of study drug plus 30 days. If the relevant baseline laboratory data are missing, any
laboratory abnormality of at least Grade 1 is considered treatment-emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) of laboratory abnormalities will 
be provided (subjects categorized according to most severe abnormality grade):

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 or 4 laboratory abnormalities


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For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values in the given study period. Listings will be provided for 
treatment-emergent laboratory abnormalities and treatment-emergent Grade 3 or Grade 4 
laboratory abnormalities.
7.2.2.3.
Liver-Related Laboratory Test 
The number and percentage of subjects will be summarized for the following liver-related 
laboratory tests and categories:

Aspartate aminotransferase (AST): (a) > 3 × upper limit of normal (ULN), (b) > 5 × ULN, 
(c) > 10 × ULN, (d) > 20 × ULN

Alanine aminotransferase (ALT): (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, 
(d) > 20 × ULN

AST or ALT: (a) > 3 × ULN, (b) > 5 × ULN, (c) > 10 × ULN, (d) > 20 × ULN

Total bilirubin: (a) > 1 × ULN, (b) > 2 × ULN

Alkaline phosphatase (ALP) > 1.5 × ULN

AST or ALT > 3 × ULN and total bilirubin: (a) > 1.5 × ULN, (b) > 2 × ULN

AST or ALT > 3 × ULN and total bilirubin > 2 × ULN and ALP < 2 × ULN
The summary will use data from all the postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For the composite endpoint of AST or ALT and total bilirubin, and 
the composite endpoint of AST or ALT, total bilirubin, and ALP, subjects will be counted once
when the criteria are met at the same postbaseline visit date. The denominator is the number of 
subjects in the Safety Analysis Set with nonmissing postbaseline values of the tests in evaluation 
at the same postbaseline visit date. 
Subjects with AST or ALT > 3 × ULN will be listed. 
7.3.
Bone Safety Analyses
7.3.1.
Bone Mineral Density
The BMD will be evaluated in 2 body sites: spine and total body less head. BMD standard
Z-score will be computed based on the chronological age-matched population of the same sex 
and ethnicity. BMD height-age Z-score will be generated by substituting height-age for 
chronological age, where height-age will be determined as the age at which the child’s height is 
the median on the stature-for-age Centers for Disease Control (CDC) Year 2000 growth chart
published on the following CDC website: 
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm


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If a subject’s height was greater than the median height for a 20-year-old according to the growth 
chart, both height-age and height-age Z-score will not be calculated. The BMD Z-scores 
(standard Z-score and height-age Z-score) will be calculated for the 2 body sites (ie, spine and
total body less head).
Percentage change from baseline in spine and total body less head BMD will be summarized by 
visit using descriptive statistics for subjects in the spine and total body less head DXA analysis 
sets, respectively.
Descriptive summaries for the BMD Z-scores (standard Z-score and height-age Z-score) and the 
change from baseline in Z-scores (standard Z-score and height-age Z-score) will be presented by 
visit for the spine and total body less head DXA Analysis Sets.
Shift tables of the clinical BMD status at baseline versus postbaseline visits will be presented for 
both spine and total body less head BMD. Clinical BMD status will be classified into 
2 categories using the BMD Z-scores (standard Z-score and height-age Z-score): Z-scores > −2
versus Z-scores ≤−2 {Gordon et al 2008}. The number and percentages of subjects with at least
4% decline in BMD from baseline to each postbaseline visit will be summarized by visit for the 
spine and total body less head DXA Analysis Sets.
A listing of subjects with at least 4% decline from baseline in BMD from at least one of the body 
sites (ie, spine and total body less head) at any postbaseline visit will be provided. The BMD 
values, standard BMD Z-score, height-age BMD Z-score, and height-age will be listed. Listings 
of subjects with baseline BMD Z-score > -2 and BMD Z-score ≤−2 at any postbaseline visit in 
spine and/or total body less head BMD based on standard Z-scores and height-age Z-scores, 
respectively, will also be provided. 
7.3.2.
Bone Safety Assessments
Bone safety assessments include the following in serum: bicarbonate, N-telopeptide, 
C-telopeptide, osteocalcin, bone-specific alkaline phosphatase, procollagen type 1 N-terminal 
propeptide [P1NP], parathyroid hormone [PTH], 25-OH vitamin D, and 1, 25-OH vitamin D; 
and in urine: bicarbonate and N-telopeptide.
Baseline, postbaseline, changes from baseline, and percentage change from baseline in bone 
safety assessments will be summarized by visit using descriptive statistics.
7.3.3.
Fracture Events
The preferred terms included in analysis for fracture events are defined based on the
Standardized MedDRA Query (SMQ) of osteoporosis/osteopenia of fractures and HLGT of 
fractures from MedDRA. The lists of PTs selected by clinical review from all the PT terms under 
SMQ of osteoporosis/osteopenia fractures and HLGT of fractures are presented in Appendix 3. 
Fracture events will be listed only.
7.4.
Renal Safety Analyses
7.4.1.
Serum Creatinine
The baseline and change from baseline in serum creatinine will be summarized by visit using 
descriptive statistics. 


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7.4.2.
Estimated Glomerular Filtration Rate
The following formulae will be used to calculate eGFR: 
Schwartz Formula: 
eGFR (ml/min/1.73m+) = k × L/SCr,
where 
k is the proportionality constant (0.55 for children [6-11 years old] or adolescent girls 
≥12 years old; 0.70 for adolescent boys ≥12 years old)
L is height (cm) 
SCr is serum creatinine (mg/dL)
Modified Schwartz Formula: 
eGFR (ml/min/1.73m+)
= 39.1[height (m) / SCr (mg/dl)]0.123
× [1.8 / cystatin C (mg/L)]0.+67 [30 / BUN (mg/dl)]0.236 × [1.099]:;<=
× [height (m) / 1.4]0.2??
where BUN is the blood urea nitrogen. The modified Schwartz formula incorporates additional 
laboratory assessments of renal function, specifically BUN and cystatin C, and may, therefore,
offer an alternative method of assessment of postbaseline changes in eGFR that is not as strongly 
affected by the changes in serum creatinine assay method {Schwartz et al 2009}.
Change from baseline in eGFR at each postbaseline visit will be provided.
7.4.3.
Urine Retinol Binding Protein to Creatinine Ratio and Beta-2-Microglobulin 
to Creatinine Ratio
Baseline, postbaseline, change from baseline, and percentage change from baseline in urine 
retinol binding protein (RBP) to creatinine ratio and beta-2-microglobulin to creatinine ratio will 
be summarized by visit using descriptive statistics.
7.4.4.
Proteinuria by Quantitative Assessment
The baseline, postbaseline, changes from baseline, and percentage change from baseline in urine 
protein to creatinine ratio (UPCR) will be summarized by visit using descriptive statistics.


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7.5.
Tanner Stage Assessment
The Tanner Stages will be used to evaluate the onset and progression of pubertal changes. 
Females will be rated for pubic hair growth and breast development, and males will be rated for
pubic hair growth and genitalia development. The Tanner Stages (Pubic Hair and Breasts for 
female; Pubic Hair and Genitalia for male) at each postbaseline visit will be summarized by 
baseline Tanner Stages using frequency count and percentage.
Tanner Stage results at screening and during the study will be listed.
7.6.
Palatability/Acceptability Assessment
Palatability and acceptability assessments were collected once (at a postbaseline visit) for 
Cohort 1 subjects, and were collected at baseline and Week 4 for Cohort 2 subjects. These 
assessments will be summarized using frequency count and percentage, as one group 
(for Cohort 1) or by visit (for Cohort 2).
Palatability and acceptability assessments will also be listed.
7.7.
Body Weight, Height, and Vital Signs
Body weight and height at each visit and change from baseline in body weight and height at each 
visit will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) by visit. 
An age- and sex-specific Z-score will be derived for each weight and height measurement 
according to the downloadable SAS program available on the Centers for Disease Control (CDC) 
website using the year 2000 growth charts. The methods and SAS program published on the 
following CDC websites will be applied to calculate the Z-score:
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/index.htm
http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm
Z-scores for body weight and height at each visit and change from baseline in Z-scores for 
postbaseline body weight and height will be summarized by visit. In the case of multiple values 
in an analysis window, data will be selected for analysis as described in Section 3.7.3. 
Body weight, weight Z-score, height, height Z-score, BMI, and BSA will be listed. Vital signs 
will be presented in data listings only.
7.8.
Nonstudy-Drug Antiretroviral Medications
Nonstudy-drug ARV medications used prior to the study (expected for Cohort 2 only), during 
study, and after study (if collected), will be coded using the GSI-modified World Health 
Organization (WHO) Drug Dictionary. The WHO preferred name and drug code will be attached 
to the clinical database. All nonstudy-drug ARV medications will be listed. 


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Nonstudy-drug ARV medication with an end date on or one day before the first dose date of 
study drug will be considered as nonstudy-drug ARV medication received immediately prior to 
the first dose date of study drug (or pre-switch ARV used).
Nonstudy-drug ARV medication received immediately prior to the first dose date of study drug 
will be summarized by ARV drug class and generic name for subjects in the Safety Analysis Set. 
Multiple drug use (by drug class or generic name) will be counted only once per subject. Drug 
classes were presented alphabetically and generic names within each drug class were presented 
by descending order of the total frequency. No inferential statistics will be provided.
7.9.
Concomitant Non-ARV Medications
Nonantiretroviral concomitant medications (ie, medications other than study drug that are taken 
while receiving study drug) will be coded using the WHO Drug Dictionary. The WHO preferred 
name and drug code will be attached to the clinical database. Use of concomitant medications 
from Study Day 1 up to the date of last dose of study drug will be summarized (number and 
percentage of subjects) by preferred name. Multiple drug use (by preferred name) will be 
counted once only per subject. The summary will be sorted alphabetically by drug class and then 
by decreasing total frequency within a class.
If the start or stop date of a nonantiretroviral medication is incomplete, the month and year 
(or year alone if month is not recorded) of the start or stop date will be used to determine 
whether the non-ARV is concomitant or not as follows. The medication is concomitant if the 
month and year of start or stop (or year of the start or stop) of the medication do not meet any of 
following criteria:

The month and year of start of the medication is after the date of the last dose of study drug

The month and year of stop of the medication is before the date of the first dose of study drug
If the start and stop date of a non-ARV medication is not missing, the start date is not after 
last dose date and the stop date is not before first dose date, or the non-ARV medication is
marked as ongoing and start date is on or before last dose date, the non-ARV medication is
concomitant.
Subjects with any non-ARV concomitant medications will be listed.
7.10.
Electrocardiogram Results
The ECG data collected at screening and early study drug discontinuation will be listed.
7.11.
Other Safety Measures
Hepatitis test results will be listed. A data listing will be provided for subjects experiencing 
pregnancy during the study.
7.12.
Changes from Protocol-Specified Safety Analysis
There is no change from protocol-specified safety analyses.


EICIFITAF 
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8. 
PHARMACOKINETICS ANALYSIS 
Final 
Version 1.0 
summa1y statistics on intensive PK data for both Coho1is 1 and 2-
have been perfo1med as aii of the interim 1 and interim 3 CS~ 
trough/single PK concentrations 
will be included in this 
analysis. 
8.1. 
Analysis Methods for Anytime PK 
Plasma concentration data for will be listed for all subjects. EVG, COB!, FTC, TFV trough 
samples, defined as the sainpling time within a range of [20.0, 28.0] homs after observed dosing 
time, will be mai·ked and included for summa1y statistics. Spare samples may be used for 
population PK assessment. Plasma concentrations for T AF will be listed only and will not be 
smnmai·ized. 
The following TFLs will be provided for the trough PK sampling: 
• 
Table with individual subject concentration data for EVG, COB!, FTC, TFV 
• 
Listing of PK sampling details 
• 
Listing of study diu g adininistration record for PK dosing. 
8.2.1. 
Statistical Comparative Analysis 
No statistical compai·ative analyses will be perfonned. 
8.3. 
Changes from Protocol-Specified PK Analysis 
No change from the protocol-specified PK analysis is planned. 
CONFIDENTIAL 
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9.
REFERENCES
Gordon CM, Bachrach LK, Carpenter TO, Crabtree N, El-Hajj Fuleihan G, Kutilek S, et al. Dual 
energy X-ray absorptiometry interpretation and reporting in children and 
adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 2008;11 
(1):43-58.
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4.
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to 
estimate GFR in children with CKD. J Am Soc Nephrol 2009;20 (3):629-37.
Smith F, Hammerstrom T, Soon G, Zhou S, Chen B, Mai Y, et al. A meta-analysis to assess the 
FDA DAVP's TLOVR algorithm in HIV submissions. Drug Information Journal 
2011;45:291-300.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Revision 1. November 2015.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence. January, 2001.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1). March, 2003.


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10.
SOFTWARE
nQuery Advisor® (Statistical Solutions Ltd., Version 6.0, Cork, Ireland) will be used for the 
sample size and power calculation.
SAS® (SAS Institute Inc., Version 9.2, Cary, NC) will be used for generating all TFLs. 
WinNonlin® (Pharsight Corporation Version 6.3, Mountain View, CA) will be used for all 
PK analyses.


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedure Table
Appendix 2.
Flowchart of US FDA-Defined Snapshot Algorithm
Appendix 3.
Fracture Events
Appendix 4.
Programming Specifications


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Appendix 1. 
Study Procedures 
Assent/lnfo1med Consent 
Medical Histo1y 
Adverse Events 
Concomitant Medications 
Vital Signsr 
Complete Physical Exam 
Symptom-Directed 
Physical Examg 
Height 
Weight 
Tanner Stage Evaluationsh 
12-lead ECG -
Pe1fo1med Supine 
HIV-1 Genotypei 
Hematology Profilei 
Chemistiy Profile" 
CD4+ Cell Count and 
Percentage 
Metabolic Assessments1 
Urinalysis 
Estimated Glomemlar 
Filti·ation Rate0 
CONFIDENTIAL 
Study Procedure Table 
Baseline 
Week i 
Screening" 
(Day 1) 
(Day7) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Week 2b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final 
Version 1.0 
End ofWeekb 
Intensive 
30-Day 
PK' 
4 
8 
12 
16 
24 
32 
40 
Follow-upd 
ESDD• 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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EICIFITAF 
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Statistical Analysis Plan (Interim 4 Analysis) 
Serum Pregnancy Test'l 
Urine Pregnancy Test'l 
X 
Dispense Dosing Dia1y 
(for Part A Subjects) 
Review Dosing Dia1y 
(For Part A subjects) 
Single PK Sampling' 
Trough PK Sample' 
X 
Bone Safety 
X 
Urine Renal Safety" 
X 
Study Dmg Dispensation 
X 
In-clinic DosingY 
X 
Drug Accountability 
Palatability and 
Xbb 
Acceptability Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
X 
X 
X 
Xdd 
Xdd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xbb 
xaa 
xaa 
xaa 
a 
Evaluations to be completed within 35 days prior to Baseline ( or 42 days for subjects who require repeat testing of the HIV-I genotype). 
X 
xcc 
Final 
Version 1.0 
X 
X 
X 
xcc 
b 
All study visits are to be scheduled relative to the Baseline/Da I visit date. Visit windows are± 2 days of the protocol specified date through Week 8, ± 4 days of the 
C 
d 
e 
f 
g 
protocol specified date through Week 48, 
, unless othe1w ise specified. 
Pait A subjects only. The Intensive PK eva nation w1 occm· at t 1e Wee 4 VlSlt. For t 1e pmpose of scheduling the Intensive PK visit, a + 7 days window may be used. If the 
subject has already dosed prior to the Intensive PK evaluation visit or is not in a fasted state, the Intensive PK assessments must not be completed. The subject should be 
insti·ucted to retmn in a fasted state anytime but not later than Week 4 + 7 days for the Intensive PK visit. 
Only required for those subjects not enrolling in the-
phase of the study or those subjects who pemianently discontinue study dmg and do not continue in the study 
through at least one subsequent visit after the Early Stu y Drug Discontinuation Visit. For the pmpose of scheduling a 30-Day Follow-Up Visit, a± 6 days window may be used. 
ESDD visit should occm· within 72 hours of last dose of study drug. 
Vital signs include blood pressm·e, pulse, respiration rate and temperature. 
Symptom-directed physical examinations performed as needed. 
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h 
J 
k 
m 
I 
0 
r 
Tanner assessments will no longer be pe1fo1med once a subject has been documented as Tanner Stage 5. Tanner stage assessments will be performed 
----until subjects reach Tanner Stage 5, after which point Tanner assessments will no longer be pe1fon11ed. 
~
e, prntease and integrase resistance will be done at Screening. The investigator must have received the results from the Screening genotype 
before proceeding with the Baseline visit. (Cohort 1 only). 
CBC w'ith differential and platelet count 
Chemistry prnfile: alkaline phosphatase, AST, ALT, total bilimbin, direct and indirect bilimbin, cystatin C (Baseline, Weeks 2 (Cohort 1 only), 4, 24, and 48), total prntein, 
albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, otassium, sodium, CPK and tu-ic acid 
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 
If the subject has not fasted prior to the visit, the visit may proceed, but the subject must rettun wit un 72 1otu-s m a aste state to 
w oo or e meta o c assessments. 
For, Pait A subjects, back-up samples not be collected at Week 1, 2 and 4 visits for Coho1t 1 and at Week 1- Week 16 for Cohort 2. For Part B subjects, back-up samples will 
be collected at all visits. 
Estimated Glomemlar Filtration Rate (GFR) using Schwa1tz Formula (mL/min/l .73m = k x UScr [(k is a proportionality constant, for females~ 6 yea1-s old is 0.55; and for 
ears old is 0.70 : Lis height in centimeters cm : and Ser is senun creatinine mo dL 
q 
Fema es o c I 
eanng potentia on y. Positive unne pregnancy tests w1 
e co ume w1 a senun test at any v1s1t. 
r 
At Week 4 (Cohort 1 Pait B subjects only) and Week 12 (all subjects), the random single plasma PK saiuple should be collected between 0.25 and 4 hotu-s post-dose. For Coho1t 1 
subjects, at all other visits, and for Coho1t 2, at Weeks 8 and 16 only. The random single PK sample can be taken anytime in relationship to last dose of study dmg. 
s 
Subjects must come into the clinic w'ithout taking their dose ofE/C/F/TAF STR. A trough (20 to 24 hotu-s post-dose) plasma PK sample will be collected at Weeks 1, 2, and 24 
for all subjects and Week 48 for Coho1t 1 only. 
Pait A subjects only. Intensive PK sampling will be performed on Week 4. For the ptupose of scheduling the Intensive PK visit a+ 7 days window may be used. If the subject 
has ah-eady dosed prior to the Intensive PK visit or is not in a fasted state, the Intensive PK assessments must not be completed. The subject should be instructed to return 
within fotu· days for the Intensive PK visit. If dosing non-compliance is identified on or prior to the Intensive PK visit, the Intensive PK assessments must not be completed. 
The subject should be cotmseled regarding proper dosing and asked to rettun for the Intensive PK visit no sooner than three days following compliant dosing and no later than 
Week 4 + 7 da s. Please refer to the PK and PBMC manual for saiu le collection and rocessino details. 
r 
V 
at Baseline. DXA scan also to be pe1fon11ed Weeks 24 and 48 (± 10 days).-
w 
Bone Sa ety mc u mg: Semm: 1car onate, N-te opepti e, C-te opepti e CTX , osteocalcin, bone specific alkaline phosphatase, procollagen type 1 N-tel1llinal prnpeptide 
(PlNP), senun parathyroid ho1mone (PTH), 25OH Vitamin D and 1, 25OH Vitamin D. U1me: bicarbonate, N-telopeptide. Specimens for bone safety should be taken when 
subjects are in a fasted state. If the sub· ect has not fasted rior to the visit, the visit ma 
roceed, but the subject must rettun within 72 hotu·s in a fasted state to draw blood for 
bone safety. 
x 
U1me Renal a ety mc u mg: tume c enustiy, retmo 
m mg prntem, an 
eta- -nucrog o u m. U1me for selected safety should be collected when subjects are in a fasted 
state. If the subject has not fasted prior to the visit, the visit may prnceed, but the subject must rettun within 72 hotu-s in a fasted state to collect tume for tu'ine renal safety. 
y 
All subjects will be given their dose ofE/C/F/TAF STR with food. 
z 
Coho1t 1 Pait B subjects only 
aa 
To be pe1fo1med for all Coho1t 1 subjects ctu1·ently on study at their next scheduled visit. 
bb To be pe1fo1med at Baseline and Week 4 for all Coho1t 2 subjects elll'olled. 
cc To be pe1fo1med at ESDD or 30-Day Follow-Up visit for either Cohort. 1 or 2, as applicable. 
dd Coho1t 1 subjects only 
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Appendix 2. 
Flowchart of US FDA-Defined Snapshot Algorithm 
The following flowchaii for US FDA-defined snapshot algorithm in switch trial is based on the 
US FDA Guidance on Human hnmunodeficiency Virns-1 Infection: Developing Antiretrnviral 
Drngs for Treatment {U. S. Depaiiment of Health and Human Services et al 2015}. 
Yes 
Is there at least 1 on-
treatment* HIV-1 RNA 
collected in the Snapshot 
window? 
ls the last available on-treatment* 
HIV- I RNA in the Snapshot 
window < 50 copies/ml? 
0 
Is study drug prematurely 
discontinued on or prior to the 
upper limit of the Snapshot 
window? 
Yes 
Yes 
ls discontinuation of the study 
drug due to Lack of Efficacy? 
HIV-1 RNA< 
50 copies/mL 
HIV-1 RNA 2:: 
50 copies/mL 
No 
ls discontinuation of the study 
drug due to AE/Death? 
Yes 
Is the last available on-
Is the last available on-
treatment* HIV-1 RNA < treatment* HIV- I RNA< 
50 copies/ml 
Yes 
No Virologic Data: 
iscontinued Study Drug 
Due to Other Reasons 
and Last HIV-I RNA< 
50 co1>ies/mL 
50 copies/mL 
No Virologic Data: 
Discontinued Study 
Drug Due to AE/Death 
and Last HIV-I RNA< 
50 copies/mL 
No 
No Virologic Data: 
Missing Data During 
Window but on Study 
Drug 
* On-Treatment HIV-I RNA data include all HIV- I RNA data from Study Day I for subjects who are on-going and HIV- I 
RNA data from Study Day I up to 1 day after the last dose date of study drug for subjects who prematurely discontinue or 
complete study drug. 
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Appendix 3.
Fracture Events
The selected PTs from the SMQ of osteoporosis/osteopenia and HLGT of fractures based on 
clinical review are listed as follows.
Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Acetabulum fracture
Ankle fracture
Atypical femur fracture
Atypical fracture
Avulsion fracture
Bone fissure
Bone fragmentation
Cervical vertebral fracture
Chance fracture
Clavicle fracture
Closed fracture manipulation
Comminuted fracture
Complicated fracture
Compression fracture
Craniofacial fracture
Epiphyseal fracture
External fixation of fracture
Facial bones fracture
Femoral neck fracture
Femur fracture
Fibula fracture
Flail chest
Foot fracture
Forearm fracture
Fracture
Fracture displacement
Fracture of clavicle due to birth trauma
Fracture treatment
Fractured coccyx


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Fractured ischium
Fractured sacrum
Fractured skull depressed
Greenstick fracture
Hand fracture
Hip fracture
Humerus fracture
Ilium fracture
Impacted fracture
Internal fixation of fracture
Jaw fracture
Limb fracture
Lisfranc fracture
Lower limb fracture
Lumbar vertebral fracture
Multiple fractures
Open fracture
Open reduction of fracture
Open reduction of spinal fracture
Osteochondral fracture
Osteoporotic fracture
Patella fracture
Pathological fracture
Pelvic fracture
Periprosthetic fracture
Pubis fracture
Radius fracture
Rib fracture
Sacroiliac fracture
Scapula fracture
Scapulothoracic dissociation
Skull fracture
Skull fractured base


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Spinal compression fracture
Spinal fracture
Sternal fracture
Stress fracture
Tartrate-resistant acid phosphatase decreased
Thoracic vertebral fracture
Tibia fracture
Torus fracture
Traumatic fracture
Ulna fracture
Upper limb fracture
Vertebroplasty
Wrist fracture
Vertebral body replacement
Note: AEs are coded by MedDRA 20.1.


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Appendix 4.
Programming Specifications
General Conventions
1) The standard mock tables 
(http://gnet/biometrics/stat/doc/Standard%20TFL_Final%20GNET%202009%2005%2015.doc)
are default outputs developed based on standard CRF and standard SAP template. Changes to 
the CRFs or SAP may warrant changes to these outputs.
2) Italicized text in the mocks indicates that the entry is either optional or can be replaced by a 
more suitable term depending on the content.
3) Whenever possible, do not reference footnote by symbol within the body of the table and 
table title unless it greatly improves the clarity.
4) Titles should not exceed 128 characters (including the word “table,” the table number, 
punctuation, and spaces). If a title must exceed 128 characters, key descriptive information 
should be presented in the first 128 characters.
5) For completeness, please always include all the possible categories on standard CRF, 
including those with zero counts.
6) Treatment groups will be ordered as Gilead product in the first and then the rest of active 
control groups in alphabetical order, and placebo in the last column. Within each treatment, 
dose level will be in ascending order. Separate column for total or subtotal are allowed if 
space permits depending on study design, eg, a subtotal column could combine dose levels 
within the same treatment.
7) The ordering of these mock tables is the default ordering in the TFLs, ie, enrollment, 
disposition, demographic, baseline data, efficacy, drug exposure, and safety. 
8) Number TFLs consecutively and do not use decimal numbering for unique items.
9) A maximum of three titles and seven footnotes is allowed. Additional lines document the date 
of date extraction, source of SAS program, output files, and date-time of outputs generated.
10) The precision in reporting numerical values should be as follows: 
a) Raw measurements will be reported the same as the data captured electronically or on the 
CRFs.
b) Standard deviation and stand error will be reported to one more significant decimal place 
than the raw measurement.
c) Mean, median, minimum, Q1, Q3, maximum, 95% CIs will be reported to the same 
number of decimal places of the raw measurements. 
d) Exceptions may be considered; for example if more than 4 significant digits are provided 
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11) The number of decimal places in reporting p-values should be as follows:
a) Values Less than 0.001 < 0.001
b) Values 0.001 to less than 0.10 round to 3 decimal places
c) Values 0.10 and greater round to 2 decimal places
12) For lab summaries, tests will be grouped as Chemistry, Hematology, and Urinalysis. 
Disease related biomarkers, eg, bone biomarkers, will be grouped separately. Summaries will 
be sorted alphabetically by test within group.
13) Study day calculation: if visit date ≥first dose date, study day = visit date – first dose date +1.
If visit date < first dose date, study day = visit date – first dose date.
Other Definitions
1) AGE is calculated as follows:
a) AGE (years) is calculated from the number of days between the date of birth (DOB) and 
Day 1 (first dose date),
b) Use the SAS INTCK function to determine the number of “1st-of-month days” 
(eg, January 1st, February 1st, March 1st) between DOB and Day 1 (inclusive),
c) Divide the result in (b) by 12,
d) AGE = the integer of the result in (c),
e) If the DOB and Day 1 have the month in common and the birthday is later in the month 
than the date of Study Day 1, then subtract one from the AGE result above.
For subjects who are enrolled and never dosed with study drug, AGE is calculated based on
the date of screened.
2) All screened subjects refer to all subjects who are screened and have a screening number. For 
summarization, same subject is counted only once. DOB and other demographic information 
such as gender, race, and ethnicity will be used for identifying unique screened subjects.
3) Screen failure subjects are the subjects who answered “Yes” to “Was subject a 
Screen Failure?” in informed consent and eligibility criteria eCRF.
4) BMI is calculated from height in meters (eg, height in cm/100) and weight in kilograms as:
BMI = (weight [kg]) / (height [meters]2)
5) For HIV test using HIV Taqman kit, if a value is reported as “< 20 cp/mL HIV-1 RNA 
Detected” or “No HIV-1 RNA detected”, a numeric value of 19 will be used for summary 
purpose.


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6) For direct bilirubin, a value of “< 0.1” will be treated as 0.09 for calculation of 
summary statistics {Nehls et al 1973}.
7) For serum Cystatin C test, a value of “< .10” is treated as missing in summary or in the
calculation of eGFR.
8) Generally for AE summary tables, SOC and PT will be included in all treatment-emergent 
AE tables.
9) Last Dose Date has been defined in Section 3.7.1.
Last Dose Date Imputation for Subjects Who Prematurely Discontinued Study or 
Completed Study

For subjects with a partial last dosing date (ie, month and year of last dose are known), 
use the maximum of the dispensing dates of study drug bottles, study drug start dates and 
end dates, the imputed last dose date (day imputed as 15) to impute the final last dose 
date. However if dispensing date’s month is after last dose date’s month, data query is 
needed.

If the date of last dose is missing (ie, only year of last dose is known or completely 
missing due to lost to follow-up), use the maximum of study drug start dates and end 
dates, clinical visit dates, and laboratory visit dates excluding the 30-day follow-up visit 
to impute the last dose date.
Last Dose Date Imputation for Ongoing Subjects (for the Purpose of Duration of 
Exposure)
If subjects are still on study drug (ie, defined as subjects who do not have study drug 
completion eCRF filled out), the last dose date will be estimated as follows:

If the last record in the study drug administration eCRF has a nonmissing study drug end
date, the estimated last dose date will be the last study drug end date.

If the last record in the study drug administration eCRF has a missing end date, the 
estimated last dose date will be the maximum of nonmissing study drug start dates and 
end dates, the clinical visit dates, and the laboratory visit dates excluding the date of 
30-day follow-up visit.
10) Last Study Date
Last Study Date is the maximum of nonmissing study drug start dates and end dates, clinic 
visit and laboratory visit dates, including the 30-day follow-up visit date for subjects who 
prematurely discontinued study or who completed study according to study completion 
eCRF. Please note, if study drug start date or end date is partially missing, the imputed date 
(day imputed as 15) will be used.


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11) Toxicity Grades: 
Final 
Version 1.0 
a) With regards to metabolic assessment of lipids tests (triglycerides, total cholesterol, and 
LDL cholesterol), if the fasting status is 'N' or blank, the lab test values will not be 
graded as non-fasting values are not interpretable. 
b) For the summaiy of the toxicity graded tests, all post-baseline graded results (not just 
those at summarized visits) up to 30 days after the last dose of study diug will be 
included. 
c) For hematuria grading, the laborato1y repo1is both dipstick results (urine blood test with 
values of 1 +, 2+, etc) and quantitative results (urine RBC test with a unit of /HPF), only 
summarize toxicity grades of the quantitative (urine RBC) results, but list the grades from 
both tests. 
12) In the listing for viologic outcomes using snapshot algorithm, flag all HIV-RNA records that 
are used in detennining snapshot outcomes including the following: 
• 
Virologic Success - HIV-1 RNA < 50 copies/mL for snapshot virologic outcome 
(ie, the last available HIV-1 RNA record for a ce1iain analysis timepoint) 
• 
Virologic Failure - HIV-1 RNA 
50 copies/mL for snapshot virologic outcome 
• 
Virologic Failure - the last available HIV-1 RNA value of~ 50 copies/mL if subjects 
discontinued study di11g due to other reasons 
• 
No Virologic Data - the last available HIV-1 RNA value of < 50 copies/mL if subjects 
discontinued study di11g due to other reasons 
13) "On-treatment" data in the SAP refer to the data on or prior to the date of pennanent 
discontinuation of study diug (eg, last dose date). For subjects who ai·e ongoing on study 
diug, "on-treatment" data refer to all data up to the data cut for the analysis. 
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15) For HIV-1 RNA Missing = Failure or Missing = Excluded analysis:
Missing = Failure when

The subject has a visit after the missing.

The subject is missing HIV-1 RNA because he has already discontinued the study drug.

The subject came for a lab visit for that visit but the HIV-1 RNA value is missing 
(e.g. sample issue).
Missing is excluded from the denominator when

For ongoing subjects, HIV-1 RNA is missing and upcoming visit has not happened yet 
(excluding ongoing subjects who haven't reached the upper limit of the analysis window 
for corresponding visit).

This subject has neither baseline nor postbaseline lab data.
16) TEAE
Events with Missing Onset Day and/or Month
The event is treatment emergent if the following 3 criteria are met:

The month and year (or year) of onset date is the same as or after the month and year 
(or year) of the first dose of study drug, and

The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of 30th day after the date of the last dose of study drug, and

End date is as follows: 
The (complete) end date is on or after the first dose date, or
The month and year (or year) of end date is the same or after the month and year 
(or year) of the first dose of study drug, or
End date is completely missing
Events with Completely Missing Onset Date
An AE with a completely missing onset date is defined as TEAE if end date is as follows:

The (complete) end date is on or after the first dose date, or

The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of study drug, or

End date is completely missing