Clinical trial NCT02836236
Conditions: HBV Chronic HBV Infection
Keywords: Hepatitis Tenofovir Viread
Sponsor: Gilead Sciences
Start date: 2015-06-19; Completion date: 2023-09-18
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in treatment-naive and treatment-experienced adults with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection in China.

Detailed description:
This study GS-US-320-0108 is an international study planned to enroll participants in global countries, including China. However, due to the review timeline difference in China, full enrollment was reached in the main study (NCT01940341) before China was able to participate. Therefore, this registration only includes the China cohorts as they were not part of the main study analysis. Data for China cohorts were analyzed separately after the main study analysis was completed.

Arms: arm 1: Tenofovir alafenamide (Vemlidy®; TAF) 25 mg tablet + tenofovir disoproxil fumarate (Viread®; TDF) placebo tablet once daily for up to 144 weeks (per amendment 3.1). arm 2: TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks (per amendment 3.1). arm 3: All participants who complete the double-blind period will be eligible to receive open-label TAF until Week 384 of the study.
Interventions: intervention 1: TAF intervention 2: TDF intervention 3: TAF Placebo intervention 4: TDF Placebo
Intervention descriptions: intervention 1: TAF 25 mg tablet administered orally once daily intervention 2: TDF 300 mg tablet administered orally once daily intervention 3: TAF placebo tablet administered orally once daily intervention 4: TDF placebo tablet administered orally once daily

Protocol documents:
SAP_002.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg Negative, Chronic Hepatitis B 
 
 
Name of Test Drug: 
Tenofovir Alafenamide (TAF) 
 
 
Study Number: 
GS-US-320-0108 
 
 
Protocol Version: 
Amendment 3.1 
 
 
Protocol Date: 
23 February 2016 
 
 
Analysis Type: 
Week 48 China 
 
 
Analysis Plan Version: 
Version 1.0 
 
 
Analysis Plan Date: 
24 February 2017 
 
 
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 ................................................................................................................................................ 8 
1.1. 
Study Objectives ...................................................................................................................................... 8 
1.2. 
Study Design .......................................................................................................................................... 10 
1.3. 
Sample Size and Power .......................................................................................................................... 13 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 14 
2.1. 
Data Monitoring Committee (DMC) Analysis ....................................................................................... 14 
2.2. 
Week 48 Analysis (Primary Analysis) ................................................................................................... 14 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 15 
3.1. 
Analysis Sets .......................................................................................................................................... 15 
3.1.1. 
Randomized Analysis Set ..................................................................................................... 15 
3.1.2. 
Safety Analysis Set ............................................................................................................... 15 
3.1.3. 
Full Analysis Set (FAS) ....................................................................................................... 15 
3.1.4. 
Per-protocol Analysis Set ..................................................................................................... 15 
3.1.5. 
Serologically Evaluable Full Analysis Set for HBsAg 
Loss/Seroconversion ............................................................................................................ 16 
3.1.6. 
DXA Analysis Set ................................................................................................................ 16 
3.2. 
Subject Grouping ................................................................................................................................... 17 
3.3. 
Strata and Covariates .............................................................................................................................. 17 
3.4. 
Examination of Subject Subgroups ........................................................................................................ 17 
3.5. 
Missing Data and Outliers ...................................................................................................................... 17 
3.5.1. 
Missing Data ........................................................................................................................ 17 
3.5.2. 
Outliers ................................................................................................................................. 18 
3.6. 
Data Handling Conventions and Transformations ................................................................................. 18 
3.7. 
Analysis Windows ................................................................................................................................. 19 
3.7.1. 
Definition of Study Day 1 and Other Definitions ................................................................. 19 
3.7.2. 
Analysis Windows ................................................................................................................ 20 
3.7.3. 
Selection of Data in the Event of Multiple Records in a Window ....................................... 27 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 28 
4.1. 
Subject Enrollment ................................................................................................................................. 28 
4.2. 
Disposition of Subjects .......................................................................................................................... 28 
4.3. 
Extent of Exposure ................................................................................................................................. 29 
4.3.1. 
Duration of Exposure to Blinded Study Drug ...................................................................... 29 
4.3.2. 
Adherence with Blinded Study Drug Regimen .................................................................... 29 
4.4. 
Protocol Deviations ................................................................................................................................ 30 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 31 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 31 
5.2. 
Medical History ...................................................................................................................................... 32 
6. 
EFFICACY ANALYSES ................................................................................................................................... 33 
6.1. 
Primary Efficacy Endpoints ................................................................................................................... 33 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 33 
6.1.2. 
Analysis of the Primary Efficacy Endpoint .......................................................................... 33 


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6.1.3. 
Secondary Analysis for the Primary Efficacy Endpoint ....................................................... 33 
6.1.4. 
Subgroup Analysis for the Primary Efficacy Endpoint ........................................................ 33 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 34 
6.2.1. 
Definition of Secondary Efficacy Endpoints ........................................................................ 34 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints .......................................................... 35 
6.3. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 35 
7. 
SAFETY ANALYSES ........................................................................................................................................ 36 
7.1. 
Adverse Events....................................................................................................................................... 36 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 36 
7.1.2. 
Adverse Event Severity ........................................................................................................ 36 
7.1.3. 
Relationship of AEs to Study Drug ...................................................................................... 36 
7.1.4. 
Relationship of AEs to Study Procedure .............................................................................. 36 
7.1.5. 
Serious AEs .......................................................................................................................... 36 
7.1.6. 
Treatment-Emergent AEs ..................................................................................................... 37 
7.1.7. 
Summaries of AEs and Deaths ............................................................................................. 38 
7.1.8. 
Potential Uveitis Events ....................................................................................................... 40 
7.1.9. 
Potential Cardiovascular Events ........................................................................................... 40 
7.2. 
Laboratory Evaluations .......................................................................................................................... 40 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 40 
7.2.2. 
Graded Laboratory Values ................................................................................................... 42 
7.2.3. 
ALT Elevation ...................................................................................................................... 43 
7.3. 
Bone Safety Analyses ............................................................................................................................ 43 
7.3.1. 
Bone Mineral Density (BMD) .............................................................................................. 43 
7.3.2. 
Bone Biomakers ................................................................................................................... 44 
7.3.3. 
Fracture Events ..................................................................................................................... 45 
7.3.4. 
Assessment of Fracture Probability ...................................................................................... 45 
7.3.5. 
Bone Events ......................................................................................................................... 45 
7.4. 
Renal Safety Analyses ............................................................................................................................ 46 
7.4.1. 
Confirmed Renal Abnormalities........................................................................................... 46 
7.4.2. 
Serum Creatinine .................................................................................................................. 46 
7.4.3. 
Estimated Glomerular Filtration Rate .................................................................................. 46 
7.4.4. 
Treatment-Emergent Proteinuria (Dipstick) ......................................................................... 47 
7.4.5. 
Urine Creatinine, Urine RBP to Creatinine Ratio and 
Beta-2-microglobulin to Creatinine Ratio ............................................................................ 47 
7.4.6. 
Proteinuria by Quantitative Assessment ............................................................................... 48 
7.4.7. 
Other Renal Biomarkers ....................................................................................................... 48 
7.5. 
Ophthalmologic Assessment .................................................................................................................. 49 
7.6. 
Body Weight .......................................................................................................................................... 49 
7.7. 
Prior Hepatitis B Medications ................................................................................................................ 49 
7.8. 
Concomitant Medications ...................................................................................................................... 49 
7.9. 
Electrocardiogram (ECG) Results .......................................................................................................... 50 
7.10. 
Other Safety Measures ........................................................................................................................... 50 
7.11. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 50 
8. 
REFERENCES ................................................................................................................................................... 51 
9. 
SOFTWARE ....................................................................................................................................................... 52 
10. SAP REVISION .................................................................................................................................................. 53 
11. APPENDICES .................................................................................................................................................... 54 
 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings .............................................. 55 
Appendix 2. 
Fracture Events ....................................................................................................................... 66 


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Appendix 3. 
Bone Events ............................................................................................................................ 68 
Appendix 4. 
Potential Uveitis ..................................................................................................................... 82 
Appendix 5. 
Potential Cardiovascular or Cerebrovascular Events .............................................................. 85 
 
 
LIST OF IN-TEXT TABLES 
 
Table 3-1. 
Subjects Excluded from Week 48 PP Analysis Set Due to Premature 
Discontinuation and/or Missing HBV DNA Assessment in Week 48 Analysis 
Window .................................................................................................................................. 16 
Table 3-2. 
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and Liver 
Function Tests, Urinalysis, Urine Pregnancy Test, eGFR (by CG and CKD-EPI), 
PTH, UACR, UPCR, TmP/GFR, FEPO4, FEUA, Weight, and Vital Sign 
Assessments............................................................................................................................ 21 
Table 3-3. 
Analysis Windows for Safety ECG and Fibrotest .................................................................. 22 
Table 3-4. 
Analysis Windows for BMD Results from DXAand Fasting Lipid Panel ............................. 22 
Table 3-5. 
Analysis Windows for Serum HBsAg (Quantitative) and HBV Serology ............................. 23 
Table 3-6. 
Analysis Windows for Fasting Glucose, Fasting Total Cholesterol, Fasting 
Triglycerides, Renal, and Bone Biomarkers ......................................................................... 24 
Table 3-7. 
Analysis Windows for PTH .................................................................................................... 25 
Table 3-8. 
Analysis Windows for Hepatic Ultrasound ............................................................................ 26 
Table 3-9. 
Analysis Windows for Post-Treatment Assessments except HBV Serology ......................... 26 
Table 3-10. 
Analysis Windows for Post-Treatment HBV Serology .......................................................... 26 
Table 7-1. 
Normal, Osteopenia, and Osteoporosis as Defined by T-score .............................................. 44 


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LIST OF ABBREVIATIONS 
 
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
Anti-HBe 
antibody to HBeAg 
Anti-HBs 
antibody to HBsAg 
AST 
aspartate aminotransferase (SGOT) 
BLQ 
below the limit of quantitation 
BMD 
bone mineral density 
BMI 
body mass index 
bsAP 
bone specific alkaline phosphatase 
CDER 
Center for Drug Evaluation and Research 
CG 
Cockcroft-Gault 
CHB 
chronic hepatitis B 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration formula for calculating 
glomerular filtration rate 
CLCr 
creatinine clearance 
CMH 
Cochran-Mantel-Haenszel  
CRF 
case report form 
CTX 
c-type collagen sequence 
CV 
coefficient of variation 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate 
ESDD 
early study drug discontinuation 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEPO4 
fractional excretion of filtered phosphate 
FEUA 
fractional excretion of uric acid 
GFR 
glomerular filtration rate 
Gilead 
Gilead Sciences, Inc. 
HBeAb 
hepatitis B e antibody 


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HBeAg 
hepatitis B e antigen 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDL 
high density lipoprotein 
HDV 
hepatitis D virus 
HIV 
human immunodeficiency virus 
HLGT 
high-level group term 
HLT 
high-level term 
IVRS 
interactive voice response system   
IWRS 
interactive web response system 
LDL 
low density lipoprotein 
LLN 
lower limit of the normal range 
LLT 
lower-level term 
LOCF 
last observation carried forward 
M = E 
Missing = Excluded 
M = F 
Missing = Failure 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mantel-Haenszel  
OC 
osteocalcin 
P1NP 
procollagen type 1 N-terminal propeptide 
PBMC 
peripheral blood mononuclear cell 
PP 
per protocol 
PT 
preferred term 
Q 
quartile 
Q1 
first quartile 
Q3 
third quartile 
QD 
once daily  
RBP 
retinol binding protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TAF 
tenofovir alafenamide (Vemlidy®) 
TDF 
tenofovir disoproxil fumarate (Viread®) 
TFLs 
tables, figures, and listings 
TFV 
tenofovir 


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TFV-DP 
tenofovir-diphosphate 
TmP 
tubular maximum reabsorption rate of phosphate 
UACR 
urine albumin to creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
GS-US-320-0108 is a randomized, double-blind, noninferiority study to compare the antiviral 
activity of tenofovir alafenamide (TAF) 25 mg once daily versus tenofovir disoproxil fumarate 
(TDF) 300 mg once daily for the treatment of HBeAg-negative, chronic hepatitis B (CHB) in 
treatment-naive and treatment-experienced subjects. For non-China part, 426 subjects were 
randomized in a 2:1 ratio to the treatment groups, and were stratified by plasma hepatitis B virus 
(HBV) DNA level (< 7 log10 IU/mL, ≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL) and 
oral antiviral treatment status (treatment-naive vs treatment-experienced).  
Treatment-naive subjects are defined as subjects with < 12 weeks of previous oral antiviral 
treatment with any nucleoside or nucleotide analogue. Treatment-experienced subjects are 
defined as subjects with ≥ 12 weeks of previous treatment with any nucleoside or nucleotide 
analogue. 
For China, approximately 150 additional subjects (100 in TAF group and 50 in TDF group) will 
be enrolled for local registration purposes. 
The duration of double-blind treatment is 144 weeks (96 weeks under Amendment 1 and 2.1). 
All subjects who complete the double-blind period of treatment are eligible for participation in 
the open label TAF 25 mg extension period for an additional 240 weeks (through Week 384/ED). 
Subjects who already entered open label phase at Week 96 per Amendment 2.1 will continue on 
open label TAF 25 mg QD through Week 384/ED. For the entire duration of the study, subjects 
and investigators will remain blinded to the initial treatment regimen to which they were 
randomized.  
This statistical analysis plan (SAP) describes the analysis plan for the Week 48 analysis of 
subjects enrolled in China only.  
1.1. 
Study Objectives 
The primary objectives of this study are as follows: 
• To compare the efficacy of TAF 25 mg versus TDF 300 mg once daily for the treatment of 
hepatitis B e antigen (HBeAg)-negative, CHB at Week 48 in treatment-naive and 
treatment-experienced subjects. The primary efficacy parameter is the proportion of subjects 
with plasma HBV DNA levels below 29 IU/mL 
• To compare the safety and tolerability of TAF 25 mg once daily versus TDF 300 mg once 
daily for the treatment of HBeAg-negative, CHB at Week 48 in treatment-naive and 
treatment-experienced subjects 


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The key secondary safety objectives of this study are as follows: 
• To compare the safety of TAF 25 mg once daily versus TDF 300 mg once daily as 
determined by the percent change from baseline in hip and spine bone mineral density (BMD) 
at Week 48  
• To compare the safety of TAF 25 mg once daily versus TDF 300 mg once daily as 
determined by the change from baseline in serum creatinine at Week 48 
• To compare the safety of TAF 25 mg once daily versus TDF 300 mg once daily as 
determined by treatment-emergent proteinuria through Week 48 
Other secondary objectives of this study are as follows: 
• To compare the efficacy of TAF 25 mg once daily versus TDF 300 mg once daily for the 
treatment of HBeAg-negative, CHB in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Week 96, and 144 
• To compare the efficacy of TAF 25 mg once daily versus TDF 300 mg once daily for the 
treatment of HBeAg-negative, CHB in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144 
• To compare the biochemical (alanine aminotransferase [ALT] normalization) response of 
TAF 25 mg once daily versus TDF 300 mg once daily for the treatment of HBeAg-negative, 
CHB at Weeks 48, 96, and 144 
• To compare the serological response (loss of hepatitis B surface antigen [HBsAg] with 
seroconversion to antibody to HBsAg [anti-HBs]) of TAF 25 mg once daily versus 
TDF 300 mg once daily for the treatment of HBeAg-negative, CHB at Weeks 48, 96, and 
144 
• To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg once daily versus 
TDF 300 mg once daily for the treatment of HBeAg-negative, CHB at Weeks 48, 96, and 
144 
• To compare the incidence of drug resistant mutations of TAF 25 mg once daily versus 
TDF 300 mg once daily at Weeks 48, 96, and 144 
• To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg once daily versus TDF 300 mg once daily at Weeks 24, 48, 72, 
96, and 144 (or ED visit if prior to Week 144 and more than 24 weeks since prior exam) in a 
subset of subjects 
• To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMCs) in subjects receiving TAF or TDF 


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• To evaluate the comparative open-label efficacy, safety, and drug resistance mutations of 
TAF 25 mg QD from Week 96 (Amendments 1 and 2.1) or Week 144 (Amendment 3.1) 
through Week 384 in subjects initially randomized to TAF 25 mg QD and in subjects 
sequentially treated with TDF 300 mg QD for 96 weeks (Amendments 1 and 2.1) or for 
144 weeks (Amendment 3.1) and then switched to open-label TAF 25 mg QD 
• To compare the safety and tolerability of TAF 25 mg once daily versus TDF 300 mg once 
daily for the treatment of HBeAg-negative, CHB beyond Week 48 during the double-blind 
phase in treatment-naive and treatment-experienced subjects 
1.2. 
Study Design 
Design Configuration and Subject Population 
GS-US-320-0108 is a randomized, double-blind, noninferiority study to compare the antiviral 
activity of TAF 25 mg versus TDF 300 mg for the treatment of HBeAg-negative, CHB in 
treatment-naive and treatment-experienced subjects. 
Treatment Groups 
For non-China part, subjects were randomized in a 2:1 ratio to the following 2 treatment groups: 
• TAF group: TAF 25 mg once daily + matched placebo of TDF 300 mg once daily (n = 285)  
• TDF group: TDF 300 mg once daily + matched placebo of TAF 25 mg once daily (n = 141)  
For China, approximately 150 subjects (100 in TAF group and 50 in TDF group) will be enrolled 
for local registration purposes. 
Key Eligibility Criteria 
Subjects were to have met the following key eligibility criteria: 
• Documented evidence of chronic HBV infection (eg, HBsAg positive for more than 
6 months) 
• HBeAg-negative, CHB with the following: HBeAg-negative and HBeAb-positive at 
screening; screening HBV DNA ≥ 2 × 104 IU/mL; screening serum ALT level > 60 U/L 
(males) or > 38 U/L (females) and ≤ 10 × ULN (by central laboratory range) 
• Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault [CG] 
method) based on serum creatinine and actual body weight as measured at screening 


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Study Periods/Phases 
The duration of randomized, double-blind treatment is 144 weeks (96 weeks under 
Amendment 1 and 2.1). At Week 144, all subjects remaining on blinded treatment will be 
switched to the open-label TAF 25 mg QD extension period for an additional 240 weeks 
(Week 144 through Week 384/ED). Subjects who already assigned to open-label phase at 
Week 96 per Amendment 2.1 and consented to Amendment 3.1 later will continue on open-label 
TAF 25 mg QD through Week 384/ED. All subjects who complete the double-blind period of 
treatment are eligible for participation in the open-label TAF 25 mg QD extension period. 
Subjects who permanently discontinue study drug (either prematurely [early discontinuation, 
ED] or at the end of study [Week 384]) for reasons other than HBsAg loss with confirmed 
seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks off treatment or until 
initiation of alternative, commercially available HBV therapy, whichever occurs first. 
Schedule of Assessments 
Laboratory analyses (serum chemistry, liver tests, hematology, urinalysis, plasma HBV DNA 
levels, pregnancy testing [for females of childbearing potential]), vital signs, adverse events 
(AEs), and concomitant medications will be performed at screening, baseline, and every 4 weeks 
thereafter through Week 48, every 8 weeks through Week 96, every 12 weeks through 
Week 144, and every 24 weeks through Week 384/ED visit.  
HBV serology (HBeAg, hepatitis B e antibody [HBeAb], HBsAg, and reflex hepatitis B surface 
antibody [HBsAb]) will be performed at screening and baseline, and HBsAg and reflex HBsAb 
will be performed every 12 to 16 weeks through Week 144, and every 24 weeks through 
Week 384 /ED, and at Follow up Weeks 12 and 24. Quantitative serum HBsAg will be assessed 
at screening, baseline, every 12-16 weeks until Week 144, every 24 weeks until Week 384/ED, 
and at all Follow Up visits. Bone and renal biomarker testing will be performed at baseline and 
then at defined intervals throughout the study. IL28B polymorphism genotype, HBV genotyping 
and vitamin D assessments will be performed at baseline only. FibroTest® will be performed at 
baseline, and every 48 weeks thereafter through Week 384/ED. Fasting metabolic assessments 
(fasting glucose and lipid panel) will be conducted at baseline, every 24 weeks until Week 144, 
and every 48 weeks until Week 384/ED visit.  
Complete physical examinations will be performed at screening, baseline, and Weeks 24, 48, 
72, 96, 120,144, 240, and 384/ED. Symptom directed physical examinations including body 
weight assessment will be conducted at all other visits. Electrocardiogram (ECG) will be 
performed at screening and every 48 weeks thereafter. At sites in China with the capability only, 
dual energy x-ray absorptiometry (DXA) scans of the hip and spine will be conducted anytime 
during the screening period, and should be conducted at least 14 days prior to the first dose of 
study drug, and will be conducted every 24 weeks through Week 144, and every 48 weeks 
thereafter until Week 384/ED visit if not done within the last 24 weeks of ED visit. Hepatic 
ultrasound for surveillance of hepatocellular carcinoma will be performed starting at Week 96 
and then every 24 weeks thereafter until Week 384/ED. Plasma, serum, and urine will be 
collected at baseline and at every visit thereafter for storage. 


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Follow-up assessments will occur every 4 weeks for 24 weeks and include the following: 
vital signs, hematology, serum chemistry, liver function tests, and plasma HBV DNA. Plasma, 
serum and urine will be collected for storage. HBsAg and reflex HBsAb will be evaluated at 
follow-up Weeks 12 and 24. 
Ophthalmologic Substudy 
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to 
assess ophthalmologic findings, including a fundoscopic examination with slit lamp and retinal 
photographs (both eyes) prior to the first dose of study drug and at Weeks 24, 48, 72, 96, and 
144/ED visits at select sites. An exam should be performed at the ED visit if it is prior to 
Week 144 and not done within the last 24 weeks of this visit. 
Randomization 
Subjects will be randomized in a 2:1 ratio to the 2 treatment groups (TAF vs TDF, respectively). 
Randomization will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naive vs treatment-experienced). 
Site and/or Stratum Enrollment Limits 
Twenty-nine centers participated in China. There is no enrollment limit for individual sites. 
Study Duration 
The duration of the double-blind treatment is 144 weeks (96 weeks under Amendment 1 and 2.1). 
All subjects who complete the double-blind period of treatment are eligible for participation in the 
open label TAF 25 mg extension period for an additional 240 weeks (through Week 384/ED). 
Subjects already assigned to open label TAF 25 mg QD at Week 96 per Amendment 2.1 will 
continue on open label TAF 25 mg QD through Week 384/ED. Subjects who permanently 
discontinue study drug (either prematurely [ED] or at the end of study [Week 384]) for reasons 
other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 
4 weeks for 24 weeks off treatment or until initiation of alternative, commercially available HBV 
therapy, whichever occurs first. All subjects in China are currently enrolled under Amendment 3.1 
and will complete 3 years of double-blind treatment before rolling over to open-label TAF 25 mg 
once daily. 
Subjects with HBsAg loss with confirmed seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion to anti-HBs prior to Week 48 are not permitted to 
discontinue study drug prior to the Week 48 visit. Subjects who discontinue study drug for 
confirmed seroconversion to anti-HBs will be followed off treatment every 4 weeks for 12 weeks 
and then per the study visit schedule through Week 384/ED. Discontinuation of study drug for 
subjects experiencing HBsAg loss with confirmed seroconversion, who have known bridging 
fibrosis or cirrhosis, should be considered on a case by case basis. 


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1.3. 
Sample Size and Power 
For China, approximately 150 subjects (100 in TAF group and 50 in TDF group) will be enrolled 
for local registration purposes. 
The sample size and power calculation described below was for non-China subjects. With respect 
to the primary efficacy endpoint of proportion of subjects with plasma HBV DNA levels below 
29 IU/mL at Week 48, a sample size of 130 for the TDF group and 260 for the TAF group will 
have 90% power to rule out the noninferiority margin of 10% at a 1-sided significance level of 
0.025. This assumes the expected difference (TAF − TDF) in proportion of subjects with HBV 
DNA < 29 IU/mL is 0 and the proportion of subjects with HBV DNA < 29 IU/mL in the TDF 
group is 91%. A similar response rate in the TDF group was observed in Study GS-US-174-0102. 
This sample size (n = 260 for the TAF 25 mg group, n = 130 for the TDF 300 mg group) also 
provides the following: 
• At least 90% power to detect a 1% difference in the percentage change from baseline in 
hip BMD at Week 48 (assuming a –1.17% change from baseline in TDF 300 mg group and 
−0.17% change from baseline in the TAF 25 mg group, with a common standard deviation 
(SD) of 2.20% and a 2-sided α = 0.025) 
• At least 77% power to detect a 1% difference in the percent change from baseline in spine 
BMD at Week 48 (assuming a –1.69% change from baseline in the TDF 300 mg group 
and -0.69% change in the TAF 25 mg group, with a common SD of 3.08% and a 2-sided 
α = 0.025) 
• At least 52% power to detect a 0.03 mg/dL difference in the change from baseline in serum 
creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in the TDF 300 mg 
group and 0.01 mg/dL change from baseline in the TAF 25 mg group, with a common 
SD of 0.12) 
These assumptions above were derived from Studies GS-98-437, GS-98-438, GS-US-174-0102, 
GS-US-174-0103, and GS-US-174-0121. 


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2. 
TYPE OF PLANNED ANALYSIS 
The Week 48 analysis for Non-China subjects was already conducted after the last subject 
completed the Week 48 visit or prematurely discontinued study drug. This statistical analysis 
plan (SAP) describes the analysis plan for the Week 48 analysis of subjects enrolled in China 
only.  
2.1. 
Data Monitoring Committee (DMC) Analysis 
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study treatment warrant 
early termination of the study in the best interests of the participants and whether the study 
should continue as planned or with modifications. The DMC may also provide recommendations 
as needed regarding study design. 
The DMC will convene approximately every 24 weeks during the blinded portion of the study 
and approximately every 48 weeks during the open-label phase. More details are documented in 
the independent DMC charter. 
2.2. 
Week 48 Analysis (Primary Analysis) 
The Week 48 analysis will be conducted after the last subject completes the Week 48 visit or 
prematurely discontinues study drug. 
Further analyses after Week 48 will be conducted if warranted. 


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
3.1. 
Analysis Sets 
Analysis sets define which subjects are included in an analysis. The assignment of subjects to 
analysis sets will be done before the study blind is broken for analysis. A summary of the 
number and percentage of subjects in each analysis set will be provided by treatment group and 
in total. 
3.1.1. 
Randomized Analysis Set 
The Randomized Analysis Set includes all subjects who were randomized into the study. This is 
the primary analysis set for by-subject listings. 
3.1.2. 
Safety Analysis Set 
The Safety Analysis Set includes all randomized subjects who have received at least 1 dose of 
study drug. Subjects will be analyzed according to the treatment they actually received during 
the double-blinded phase. This is the primary analysis set for safety analyses.  
3.1.3. 
Full Analysis Set (FAS) 
The FAS includes all randomized subjects who have received at least 1 dose of study drug. 
Subjects will be analyzed according to the treatment to which they were randomized during the 
double-blinded phase. This is the primary analysis set for efficacy analyses.  
3.1.4. 
Per-protocol Analysis Set 
The Week 48 Per-Protocol (PP) Analysis Set includes all subjects who (1) were randomized into 
the study, (2) had received at least 1 dose of study drug, and (3) had not been excluded based on 
criteria below. Subjects will be analyzed according to the treatment they actually received during 
the double-blinded phase. The PP analysis set is the secondary analysis set for efficacy analysis. 
Subjects meeting any of the following criteria will be excluded from the Week 48 PP analysis set: 
• Subjects who do not have on-treatment HBV DNA in the Week 48 analysis window, except for 
subjects who discontinue study drug due to lack of efficacy. (Note: lack of efficacy is defined 
as having the check-box for “Lack of Efficacy” marked as the reason for premature study drug 
discontinuation on the study drug completion electronic case report form [eCRF] page). The 
details are summarized in Table 3-1.  


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Table 3-1. 
Subjects Excluded from Week 48 PP Analysis Set Due to Premature 
Discontinuation and/or Missing HBV DNA Assessment in Week 48 
Analysis Window 
Discontinuation from Study Drug Prior to or on the 
Upper Bound of Week 48 Analysis Window 
HBV DNA Data on Randomized Treatment 
Available in Week 48 Analysis Window 
Yes 
No 
Yes 
Due to Lack of Efficacy 
+ 
+ 
Due to Other Reasons 
+ 
- 
No 
+ 
- 
+ = Inclusion of Subjects in Week 48 PP analysis set; - = Exclusion of Subjects in Week 48 PP analysis set 
• Subjects who meet the exclusion criterion for receiving ongoing therapy with any of the 
prohibited medications listed in the clinical study protocol (Section 4.3, Table 5.1). 
• Subjects with adherence rate for active study drug up to the Week 48 visit below the 
2.5th percentile. 
3.1.5. 
Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion 
The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion includes all 
subjects who were randomized and had received at least 1 dose of study drug, and with HBsAg 
positive and HBsAb negative or missing at baseline. Subjects will be analyzed according to the 
treatment they were randomized to during the double-blinded phase. 
3.1.6. 
DXA Analysis Set 
DXA scans will be performed only at sites in China with capability. 
3.1.6.1. 
Hip DXA Analysis Set 
The Hip DXA Analysis Set includes all subjects who were randomized and had received at least 
1 dose of study drug, and had nonmissing baseline hip BMD values. Subjects will be analyzed 
according to the treatment they actually received during the double-blinded phase. 
3.1.6.2. 
Spine DXA Analysis Set 
The Spine DXA Analysis Set will include all subjects who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline spine BMD values. Subjects will be 
analyzed according to the treatment they actually received during the double-blinded phase. 


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3.2. 
Subject Grouping 
For efficacy analysis using FAS and Serologically Evaluable Full Analysis Set, subjects will be 
analyzed by randomized treatment during the double-blinded phase. For efficacy analysis based 
on the PP analysis set and safety analysis, subjects will be analyzed by actual treatment received 
during the double-blinded phase. The actual treatment received will differ from the randomized 
treatment only when their actual treatment differs from randomized treatment for the entire 
double-blinded treatment duration. 
3.3. 
Strata and Covariates 
Randomization was stratified by plasma HBV DNA level (< 7 log10 IU/mL, ≥ 7 log10 IU/mL - 
< 8 log10 IU/mL, ≥ 8 log10 IU/mL) and oral antiviral treatment status (treatment-naive vs 
treatment-experienced) at screening. HBV DNA strata will be reclassified using baseline HBV 
DNA level for stratified statistical analysis. 
3.4. 
Examination of Subject Subgroups 
The primary endpoint will be analyzed for the following subject subgroups: 
• Age: (a) < 50 years and (b) ≥ 50 years 
• Sex: (a) male and (b) female 
• Baseline HBV DNA: (a) < 7 log10 IU/mL and (b) ≥ 7 log10 IU/mL 
• Oral antiviral treatment status: (a) treatment-naive and (b) treatment-experienced 
• Study drug adherence: (a) < 95% and (b) ≥ 95% (based on adherence up to Week 48 Visit) 
• Genotype: (a) B, (b) C, and (c) Other 
• Baseline ALT by central laboratory normal range: (a) ≤ ULN and (b) > ULN 
• Baseline fibrotest score: (a) < 0.75 and (b) ≥ 0.75 
3.5. 
Missing Data and Outliers 
3.5.1. 
Missing Data 
A missing datum for a given study analysis window may be due to any of the following reasons: 
• A visit occurring in the window but data were not collected or were unusable  
• A visit not occurring in the window 
• A subject permanently discontinuing from the study before reaching the window 


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For the primary endpoint and the secondary efficacy endpoints involving proportions, missing 
data will be handled using M = F approach. Sensitivity analyses will also be performed including 
an analysis excluding all missing data. 
For the 3 key secondary safety endpoints (percentage change from baseline in hip BMD at 
Week 48, percentage change from baseline in spine BMD at Week 48, change from baseline in 
serum creatinine at Week 48), an analysis will be performed using the last observation carried 
forward (LOCF) method to impute missing data. 
For the remaining endpoints, values for missing data will not be imputed, unless specified 
otherwise.  
3.5.2. 
Outliers 
Outliers may be identified during data management and data analysis process, but no sensitivity 
analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes, unless 
specified otherwise. All data will be included in the analysis.  
3.6. 
Data Handling Conventions and Transformations 
Logarithm (base 10) will be used to transform HBV DNA and quantitative HBsAg data.  
Data that are continuous in nature but are below the lower limit of quantitation or above the 
upper limit of quantitation will be imputed as follows except for direct bilirubin, urine creatinine, 
and serum cystatin C:  
• 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” (x is considered as the 
limit of quantitation). 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 stated 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 its summary and the calculation of related ratios. For serum 
cystatin C, a value of “< 0.10” is handled as a missing value in the calculation of estimated 
glomerular filtration rate (eGFR). 
For HBV DNA, if the value in IU/mL (TaqMan) is above the upper limit of quantification, the 
corresponding diluted value (TaqDil), if available, will be used. 


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3.7. 
Analysis Windows 
3.7.1. 
Definition of Study Day 1 and Other Definitions 
Study Day 1 is defined as the day when the first dose of the blinded study drug was taken, as 
recorded on the Study Drug Administration eCRF form. 
Open-Label Study Day 1 is defined as the day when the first dose of the open-label study drug 
was taken, as recorded on the Study Drug Administration eCRF form. 
Study days are calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1 date, study days are calculated as (visit date − Study Day 1 + 1). For events that 
occurred prior to Study Day 1, study days are calculated as (visit date − Study Day 1). 
Open-Label Study days are calculated relative to Open-Label Study Day 1. For events that 
occurred on or after Open-Label Study Day 1 date, study days are calculated as 
(visit date − Open-Label Study Day 1 + 1).  
Follow-up days are for visits occurred during 24-week treatment-free follow-up period and 
calculated as (visit date – last dose date). 
Last Dose Date of Blinded Study Drug is the latest non-missing end date of blinded study drug, 
recorded on the Study Drug Administration eCRF form with “Study Drug Permanently 
Discontinued” box checked for subjects who prematurely discontinued blinded study drug or 
who completed blinded study drug according to Blinded Study Drug Completion eCRF. If the 
last dose date of blinded study drug is missing (eg, due to lost to follow up) for subjects who 
prematurely discontinued blinded study drug, or for subjects who are still on blinded study drug, 
the latest of nonmissing blinded study drug start dates and end dates, the clinical visit dates and 
the laboratory visit dates excluding the dates of open-label and 24-week treatment-free follow-up 
visits will be used to impute the last dose date of blinded study drug.  
For subjects who prematurely discontinued blinded study drug or who completed blinded study 
drug but did not enter open-label phase, the Last Dose Date is the same as Last Dose Date of 
Blinded Study Drug.  
For subjects who completed blinded study drug and entered open-label phase, the Last Dose 
Date is the latest non-missing end date of open-label study drug, recorded on the Study Drug 
Administration eCRF form with “Study Drug Permanently Discontinued” box checked for 
subjects who prematurely discontinued open-label study drug or who completed open-label study 
drug according to Open-Label Study Drug Completion eCRF. If the last dose date is missing 
(eg, due to lost to follow up) for subjects who prematurely discontinued open-label study drug, 
or for subjects who are still on open-label study drug, the latest of nonmissing open-label study 
drug start dates and end dates, the clinical visit dates and the laboratory visit dates excluding the 
dates of 24-week treatment-free follow-up visits will be used to impute the last dose date. 


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Last Study Date is the latest of nonmissing study drug (blinded or open-label) start dates and 
end dates, the clinic visit and the laboratory visit dates including the 24-week treatment-free 
follow-up visit date for subjects who prematurely discontinued study or who completed study 
according to Study Completion eCRF. 
Baseline value is defined as the last nonmissing value obtained on or prior to Study Day 1. For 
DXA BMD, it is defined as the last value on or prior to Study Day 14.  
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.  
The following windows (Table 3-2 to Table 3-8) apply to baseline and on-treatment assessments 
only, ie, data collected up to the last dose date for those who discontinued study drug 
prematurely (except efficacy data [HBV DNA, quantitative HBsAg, HBV serology, ALT, 
fibrotest score] for subjects who discontinue study drug after Week 48 due to HBsAg loss with 
confirmed seroconversion to anti-HBs), or data collected up to database finalization date for 
those who have not discontinued study drug permanently.  
For subjects who discontinue study drug early due to HBsAg loss with confirmed 
seroconversion, all efficacy data including data collected after the last dose date of the study drug 
will be reassigned analysis visits using the on-treatment assessment windows (Table 3-2, 
Table 3-3, and Table 3-5).  
The analysis windows for HBV DNA, hematology, serum chemistry and liver function tests, 
urinalysis, urine pregnancy test, eGFR (by CG and Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI]), renal biomarkers urine albumin to creatinine ratio (UACR), urine 
protein to creatinine ratio (UPCR), renal tubular maximum reabsorption rate of phosphate to the 
glomerular filtration rate (TmP/GFR), urine fractional excretion of filtered phosphate (FEPO4), 
fractional excretion of uric acid (FEUA), weight, and vital sign assessments are presented in 
Table 3-2.  


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Table 3-2. 
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and 
Liver Function Tests, Urinalysis, Urine Pregnancy Test, eGFR (by CG 
and CKD-EPI), PTH, UACR, UPCR, TmP/GFR, FEPO4, FEUA, 
Weight, and Vital Sign Assessments 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 4 
28 
2 
41 
Week 8 
56 
42 
69 
Week 12 
84 
70 
97 
Week 16 
112 
98 
125 
Week 20 
140 
126 
153 
Week 24 
168 
154 
181 
Week 28 
196 
182 
209 
Week 32 
224 
210 
237 
Week 36 
252 
238 
265 
Week 40 
280 
266 
293 
Week 44 
308 
294 
321 
Week 48 
336 
322 
363 
Week 56 
392 
364 
419 
Week 64 
448 
420 
475 
Week 72 
504 
476 
531 
Week 80 
560 
532 
587 
Week 88 
616 
588 
643 
Week 96 
672 
644 
713 
Week 108 
756 
714 
797 
Week 120 
840 
798 
881 
Week 132 
924 
882 
965 
Week 144 
1008 
966 
1091 
Week 168 
1176 
1092 
1259 
Week 192 
1344 
1260 
1427 
Week 216 
1512 
1428 
1595 
Week 240 
1680 
1596 
1763 
Week 264 
1848 
1764 
1931 
Week 288 
2016 
1932 
2099 
Week 312 
2184 
2100 
2267 
Week 336 
2352 
2268 
2435 
Week 360 
2520 
2436 
2603 
Week 384 
2688 
2604 
2771 
 


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The analysis windows for safety ECG and fibrotest are presented in Table 3-3. 
Table 3-3. 
Analysis Windows for Safety ECG and Fibrotest 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 48 
336 
2 
503 
Week 96 
672 
504 
839 
Week 144 
1008 
840 
1175 
Week 192 
1344 
1176 
1511 
Week 240 
1680 
1512 
1847 
Week 288 
2016 
1848 
2183 
Week 336 
2352 
2184 
2519 
Week 384 
2688 
2520 
2855 
 
The analysis windows for BMD results from DXA, and fasting lipid panel including direct low 
density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol to HDL ratio, are 
presented in Table 3-4. 
Table 3-4. 
Analysis Windows for BMD Results from DXAand Fasting Lipid 
Panel 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1(14a) 
Week 24 
168 
2(15a) 
251 
Week 48 
336 
252 
419 
Week 72 
504 
420 
587 
Week 96 
672 
588 
839 (755b) 
Week 120b 
840 
756b 
923b 
Week 144 
1008 
840 (924b) 
1175 
Week 192 
1344 
1176 
1511 
Week 240 
1680 
1512 
1847 
Week 288 
2016 
1848 
2183 
Week 336 
2352 
2184 
2519 
Week 384 
2688 
2520 
2855 
a 
This applies to DXA only. Upper limit for baseline DXA BMD is Day 14 and lower limit for Week 24 DXA BMD is 
Day 15. 
b 
This applies to the subjects who consented to Amendment 3.1. 


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The analysis windows for serum HBsAg (quantitative) and HBV serology are presented in 
Table 3-5. 
Table 3-5. 
Analysis Windows for Serum HBsAg (Quantitative) and HBV 
Serology 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 12 
84 
2 
125 
Week 24 
168 
126 
209 
Week 36 
252 
210 
293 
Week 48 
336 
294 
391 
Week 64 
448 
392 
503 
Week 80 
560 
504 
615 
Week 96 
672 
616 
713 
Week 108 
756 
714 
797 
Week 120 
840 
798 
881 
Week 132 
924 
882 
965 
Week 144 
1008 
966 
1091 
Week 168 
1176 
1092 
1259 
Week 192 
1344 
1260 
1427 
Week 216 
1512 
1428 
1595 
Week 240 
1680 
1596 
1763 
Week 264 
1848 
1764 
1931 
Week 288 
2016 
1932 
2099 
Week 312 
2184 
2100 
2267 
Week 336 
2352 
2268 
2435 
Week 360 
2520 
2436 
2603 
Week 384 
2688 
2604 
2771 
 
The analysis windows for fasting glucose, fasting total cholesterol, fasting triglycerides, renal 
biomarkers including urine retinol binding protein (RBP) to creatinine ratio, urine 
beta-2-microglobulin to creatinine ratio, and bone biomarkers including C-type collagen 
sequence (CTX), procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (OC), and bone 
specific alkaline phosphatase (bsAP) are presented in Table 3-6. 


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Table 3-6. 
Analysis Windows for Fasting Glucose, Fasting Total Cholesterol, 
Fasting Triglycerides, Renal, and Bone Biomarkers 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 4 
28 
2 
55 
Week 12 
84 
56 
125 
Week 24 
168 
126 
251 
Week 48 
336 
252 
419 
Week 72 
504 
420 
587 
Week 96 
672 
588 
839 (755a) 
Week 120a 
840 
756a 
923a 
Week 144 
1008 
840 (924a) 
1175 
Week 192 
1344 
1176 
1511 
Week 240 
1680 
1512 
1847 
Week 288 
2016 
1848 
2183 
Week 336 
2352 
2184 
2519 
Week 384 
2688 
2520 
2855 
a 
This applies to the subjects who consented to Amendment 3.1  
The analysis window for serum parathyroid hormone (PTH) is presented in Table 3-7. 


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Table 3-7. 
Analysis Windows for PTH 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 4 
28 
2 
41 
Week 8 
56 
42 
69 
Week 12 
84 
70 
97 
Week 16 
112 
98 
125 
Week 20 
140 
126 
153 
Week 24 
168 
154 
181 
Week 28 
196 
182 
209 
Week 32 
224 
210 
237 
Week 36 
252 
238 
265 
Week 40 
280 
266 
293 
Week 44 
308 
294 
321 
Week 48 
336 
322 
363 
Week 56 
392 
364 
419 
Week 64 
448 
420 
475 
Week 72 
504 
476 
531 
Week 80 
560 
532 
587 
Week 88 
616 
588 
643 
Week 96 
672 
644 
713 
Week 108 
756 
714 
797 
Week 120 
840 
798 
881 
Week 132 
924 
882 
965 
Week 144 
1008 
966 
1175 
Week 192 
1344 
1176 
1511 
Week 240 
1680 
1512 
1847 
Week 288 
2016 
1848 
2183 
Week 336 
2352 
2184 
2519 
Week 384 
2688 
2520 
2855 
 
The analysis window for hepatic ultrasound for hepatocellular carcinoma (HCC) surveillance is 
presented in Table 3-8. 


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Table 3-8. 
Analysis Windows for Hepatic Ultrasound 
Visit ID 
Nominal Day 
Lower Limit 
Upper Limit 
Baseline 
 
 
1 
Week 96 
672 
588 
755 
Week 120 
840 
756 
923 
Week 144 
1008 
924 
1091 
Week 168 
1176 
1092 
1259 
Week 192 
1344 
1260 
1427 
Week 216 
1512 
1428 
1595 
Week 240 
1680 
1596 
1763 
Week 264 
1848 
1764 
1931 
Week 288 
2016 
1932 
2099 
Week 312 
2184 
2100 
2267 
Week 336 
2352 
2268 
2435 
Week 360 
2520 
2436 
2603 
Week 384 
2688 
2604 
2855 
This applies to the subjects who consented to Amendment 3.1. 
Data collected after the last dose date will be considered as post-treatment visits. The analysis 
windows for post-treatment assessments are presented in Table 3-9 and Table 3-10. 
Table 3-9. 
Analysis Windows for Post-Treatment Assessments except HBV 
Serology 
Visit ID 
Nominal Follow-Up Day 
Lower Limit 
Upper Limit 
Follow-Up Week 4 
28 
1 
41 
Follow-Up Week 8 
56 
42 
69 
Follow-Up Week 12 
84 
70 
97 
Follow-Up Week 16 
112 
98 
125 
Follow-Up Week 20 
140 
126 
153 
Follow-Up Week 24 
168 
154 
181 
 
Table 3-10. 
Analysis Windows for Post-Treatment HBV Serology 
Visit ID 
Nominal Follow-Up Day 
Lower Limit 
Upper Limit 
Follow-Up Week 12 
84 
1 
125 
Follow-Up Week 24 
168 
126 
209 
 


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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 are required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rule(s) will be used.  
For baseline, the last available record on or prior to the first dose of study drug will be selected. 
For DXA BMD, it is defined as the last value on or prior to Study Day 14. If there are multiple 
records with the same time or no time recorded on the same day for numeric observations, 
average will be computed for that day, except that for HBV DNA and Quantitative HBsAg, 
geometric mean will be taken. If there are multiple records with the same time or no time 
recorded on the same day for categorical observations, the most conservative value will be taken, 
eg, negative will be selected over positive for HBeAg and HBsAg, and positive will be selected 
over negative for HBeAb and HBsAb. 
The following specified rules will be used for postbaseline visits: 
• ALT: The largest value will be included in the analysis when 2 or more ALT values occur 
within the same visit window. 
• BMD: The latest record in the window will be selected. 
• HBV DNA (IU/mL) and Quantitative HBsAg (IU/mL): The record closest to the nominal 
day for that visit will be selected. If there are 2 records equidistant from the nominal day, the 
latest will be selected. If there is more than 1 record on the selected day, the geometric mean 
will be taken. 
• Serology: For HBeAg, HBeAb, HBsAg, and HBsAb, the record closest to the nominal day 
for that visit will be selected. If there are 2 records equidistant from the nominal day, the 
latest will be selected. If there is more than 1 record on the selected day, the most 
conservative value will be taken, ie, positive will be selected over negative for HBeAg and 
HBsAg, and negative will be selected over positive for HBeAb and HBsAb. 
For all other laboratory parameters:  
• If multiple valid non-missing numeric observations exist in a window, then records will be 
chosen as follows: 
 The record closest to the nominal day for that visit will be selected. If there are 2 records 
equidistant from the nominal day, the latest will be selected. If there is more than 1 record 
on the selected day, the average will be taken. 
• If multiple valid non-missing categorical observations (eg, safety ECG results) exist in a 
window, then records will be chosen as follows: 
 The most conservative value (eg, abnormal will be selected over normal for safety ECG) 
within the window will be selected. In the event that 2 values within a window are of 
equal abnormality, the value collected nearest to the nominal date will be used. 


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment 
The number and percentage of subjects randomized each investigator will be summarized by 
treatment group and overall using the Safety Analysis Set. Similarly, the number and percentage 
of subjects enrolled in each randomization stratum will be summarized based on interactive 
voice response system/web response system (IVRS/IWRS) data.  
If there are discrepancies between IVRS/IWRS and laboratory data with regard to stratum 
assignment, a listing of the discrepancies will be provided. If there are differences between 
randomization stratum for HBV DNA using screening and baseline HBV DNA value, a listing of 
the differences will be provided. 
4.2. 
Disposition of Subjects 
The summary of subject disposition will be provided by treatment group and overall. This 
summary will include the number of subjects screened, screen failure subjects who were not 
randomized, subjects who met all eligibility criteria and were not randomized, subjects in the 
Randomized Analysis Set, subjects randomized but not treated, subjects in the Safety Analysis 
Set, and subjects in FAS. 
In addition, the number and percentage of the subjects in the following categories will be 
summarized using the Safety Analysis Set: 
Study Drug Completion 
• Remaining on double-blind study treatment up to the data-cut date 
• Prematurely discontinued double-blind study treatment prior to the data-cut date 
(with summary of reasons for discontinuing treatment) 
• Completed double-blind study treatment up to the data-cut date 
• Entered open-label phase up to the data-cut date 
Study Completion 
• Entered 24-week treatment-free follow-up period up to the data-cut date 
• Remaining on study up to the data-cut date 
• Prematurely discontinued study prior to the data-cut date (with summary of reasons for 
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• Started another HBV therapy up to the data-cut date 
• Completed protocol-planned duration of the study up to the data-cut date 
A data listing of reasons for premature study drug/study discontinuation will be provided. 
4.3. 
Extent of Exposure 
Exposure data described below will be summarized for the double-blind phase only. 
4.3.1. 
Duration of Exposure to Blinded Study Drug 
Duration of exposure to blinded study drug will be defined as (last dose date of blinded study 
drug – first dose date of blinded study drug + 1), regardless of temporary interruptions in study 
drug administration, and will be expressed in weeks (recorded to 1 decimal place, eg, 4.5 weeks). 
If subjects are still on blinded study drug, the latest of blinded study drug start and end dates, and 
the clinic and laboratory visit dates (excluding the open-label and 24-week treatment-free 
follow-up visit dates) will be used to impute the last dose date of blinded study drug for 
calculating the duration of blinded study drug exposure. 
Duration of exposure to blinded study drug will be summarized using descriptive statistics 
(sample size, mean, standard deviation [SD], median, Q1, Q3, minimum, and maximum) and as 
the number and percentage of subjects exposed for specified periods, eg, ≥ 4 weeks (28 days), 
≥ 8 weeks (56 days), etc.  
Summaries will be provided by treatment group for subjects in the Safety Analysis Set.  
Time to premature discontinuation of blinded study drug will be analyzed by the Kaplan-Meier 
method using the Safety Analysis Set. Subjects who completed the blinded study drug will be 
censored on the last dose date of blinded study drug. Subjects who remain on blinded study drug 
will be censored on the imputed last dose date of blinded study drug as defined in this section. 
4.3.2. 
Adherence with Blinded Study Drug Regimen 
Study drug regimen adherence will be computed based on tablet counts for the active drug only 
(eg, adherence in TAF group only includes TAF and not placebo for TDF). The numbers of 
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Adherence (%) of study drug regimen will be calculated as follows: 
prescribed
 
 tablets
of
Number 
 taken
 tablets
of
Number 
100
 
 
(%)
 
Adherence
×
=
 
 
[2]
 
period
 
dispensing
 
each
at 
 
prescribed
 
 tablets
of
 
No.
[1]
  
period
 
dispensing
 
each
at 
 
 taken
 tablets
of
 
No.
100
 
 
∑
∑
×
=
 
[1] Number of tablets taken at a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number 
of tablets prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same 
dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number of 
tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable 
dispensing periods. 
[2] Number of tablets prescribed at a distinct dispensing period for a study drug is calculated as the daily number of tablets 
prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. 
Total number of tablets prescribed is determined by summing the number of tablets prescribed from all evaluable dispensing 
periods. 
The duration of treatment at a dispensing period for a study drug is calculated as the 
minimum of (a) the last returned date of the same dispensing period for the study drug, 
(b) date of premature discontinuation of the study drug, and (c) next dispensing date of the 
study drug, minus dispensing date of the study drug. 
The next dispensing date is the following dispensing date of the study drug regardless of the 
bottle return date.  
For a record where the number of tablets returned was missing (with “Yes” answered for 
“Was bottle returned?” question), it is assumed the number of tablets returned was 0. If the 
number of tablets dispensed was missing or any study drug bottle was not returned or the bottle 
return status was unknown for the same dispensing date, then all records for the same dispensing 
date for that study drug will be excluded from both denominator and numerator calculation. 
Adherence up to Week 48 visit will be calculated for each subject. 
The number and percentage of subjects who return at least 1 bottle and have calculable adherence 
during the study, descriptive statistics for adherence up to Week 48 visit for a study drug regimen 
(sample size, mean, SD, median, Q1, Q3, minimum, and maximum) along with the number and 
percentage of subjects belonging to adherence categories (eg, < 80%, ≥ 80% to < 90%, 
≥ 90% to < 95%, ≥ 95%) will be provided by treatment group for the Safety Analysis Set.  
4.4. 
Protocol Deviations 
A listing will be provided for subjects in the Randomized Analysis Set who violated at least 
1 inclusion or exclusion criterion. The listing will include the unmet criteria. A listing of subjects 
who received the wrong study treatment will also be provided. 


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic data (eg, age, sex) and baseline characteristics (eg, body weight, height, 
body mass index [BMI], and Vitamin D) will be summarized by treatment group and overall 
using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) 
for continuous data and by the number and percentage of subjects for categorical data. Age is 
calculated as age in years at the first dose of study drug. The summaries of demographic data and 
baseline subject characteristics will be provided for the Safety Analysis Set. 
In addition, the following baseline characteristics and medical history will be summarized: 
• BMI categories (< 18.5 kg/m2 [underweight], ≥ 18.5 - 25.0 kg/m2 [normal], 
≥ 25.0 - 30.0 kg/m2 [overweight], and ≥ 30.0 kg/m2 [obese]) 
• HBV DNA (log10 IU/mL) 
• HBV DNA categories (< 7 log10 IU/mL, ≥ 7 log10 IU/mL - < 8 log10 IU/mL, 
≥ 8 log10 IU/mL) 
• ALT (U/L) 
• ALT level based on central laboratory normal range (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN - 10 × ULN, > 10 ULN) 
• ALT level based on American Association for the Study of Liver Diseases (AASLD) normal 
range with the ULN as 19 U/L for female and 30 U/L for male (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN - 10 × ULN, > 10 ULN) 
• Estimated GFR by CG, CKD-EPI creatinine, and CKD-EPI Cystatin C methods 
• HBeAg status (positive, negative) 
• HBeAb status (positive, negative) 
• Previous oral nucleoside/nucleotide treatment experience (yes, no) 
• Previous interferon experience (yes, no) 
• Years positive for HBV  
• HBV Genotype (A, B, C, D, E, F, etc) 
• Fibrotest score 


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• Fibrosis stage by fibrotest score (0 - 0.48, 0.49 - 0.74, 0.75 - 1) 
• Cirrhosis history (yes, no, indeterminate/unknown) 
• Proteinuria by urinalysis (dipstick) (Grade 0, Grade 1, Grade 2, Grade 3) 
• Medical history: diabetes mellitus (yes, no), hypertension (yes, no), cardiovascular disease 
(yes, no), and hyperlipidemia (yes, no) 
• Clinical BMD status (normal, osteopenia, osteoporosis) 
• Hip fracture and major osteoporotic fracture probabilities estimated using FRAX® 
(see Section 7.3.4) 
• IL28B Genotype  
Diabetes mellitus, hypertension, cardiovascular disease, and hyperlipidemia above are 
determined by medical history and/or concomitant medication data, which will be reviewed by 
the Gilead medical monitor before unblinding. 
5.2. 
Medical History 
A listing of medical history data will be provided for the Randomized Analysis Set. 


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6. 
EFFICACY ANALYSES 
For the Week 48 analyses, efficacy data will be summarized for the double-blind phase up to 
Week 96), with the exception that summaries using M = F approach will be presented up to 
Week 48 only. All efficacy data up to the Week 48 data-cut including data collected during 
open-label phase and 24-week treatment-free follow-up period will be listed. 
6.1. 
Primary Efficacy Endpoints 
6.1.1. 
Definition of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with HBV DNA < 29 IU/mL at 
Week 48. 
6.1.2. 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy analysis will be conducted after the last randomized subject reaches 
Week 48 or discontinues study drug prematurely. An M = F approach will be employed. In this 
approach, all missing data will be treated as not achieving the primary endpoint 
(ie, having HBV DNA ≥ 29 IU/mL).The primary analysis will use the FAS. 
The number and percentage of subjects who achieved and did not achieve HBV DNA < 29 IU/mL, 
and reasons for no HBV DNA data at Week 48 will be summarized. 
6.1.3. 
Secondary Analysis for the Primary Efficacy Endpoint 
A Missing = Excluded (M = E) approach will be used to summarize proportion of subjects with 
HBV DNA < 29 IU/mL by visit. In this approach, all missing data will be excluded in the 
computation (ie, missing data points will be excluded from both the numerator and denominator 
in proportion computation). 
A secondary analysis based on the Week 48 PP analysis set will also be performed to evaluate 
the robustness of the primary analysis of the primary endpoint. 
6.1.4. 
Subgroup Analysis for the Primary Efficacy Endpoint 
The analysis of proportion of subjects who achieved HBV DNA < 29 IU/mL at Week 48 will be 
repeated within each subgroup specified in Section 3.4 using FAS. 
For each level of subgroup factors, the number and percentage of subjects who achieved 
HBV DNA < 29 IU/mL at Week 48 will be summarized.  


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6.2. 
Secondary Efficacy Endpoints 
6.2.1. 
Definition of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• The proportion of subjects with plasma HBV DNA < 29 IU/mL at Weeks 96, 144, 240, and 
384 
• The proportion of subjects with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96, 144, 240, and 384 
• The proportion of subjects with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 48, 96, 144, 240, and 384 
• The proportion of subjects with HBsAg loss at Weeks 48, 96, 144, 240, and 384 
• The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 48, 96, 144, 
240, and 384 
• The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96, 144, 240, 
and 384 
• The incidence of drug resistant mutations at Weeks 48, 96, 144, 240, and 384 
• The change from baseline in log10 (HBV DNA) (IU/mL) at Weeks 48, 96, 144, 240, and 384 
• The change from baseline in log10 (HBsAg) (IU/mL) at Weeks 48, 96, 144, 240, and 384 
• The change from baseline in ALT at Weeks 48, 96, 144, 240, and 384 
The secondary endpoints beyond Week 96 (Weeks 144, 240, and 384) will not be summarized 
for the Week 48 analysis. Incidence of drug resistant mutations will be reported in a separate 
virology report. 
For the Week 48 analysis, the following definitions will be used: 
• HBsAg loss is defined as HBsAg test result changes from HBsAg positive at baseline to 
HBsAg negative at a postbaseline visit with baseline HBsAb negative or missing 
• HBsAg seroconversion is defined as HBsAg loss and HBsAb test result changes from 
HBsAb negative or missing at baseline to HBsAb positive at a postbaseline visit  
• ALT normalization is defined as ALT > ULN (by central laboratory normal range or AASLD 
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Both baseline and postbaseline borderline serology results will be imputed using the following 
rules: 
• HBsAg and HBeAg borderline will be considered as HBsAg positive and HBeAg positive 
• HBsAb and HBeAb borderline will be considered as HBsAb negative and HBeAb negative 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints 
The analyses for the secondary efficacy endpoints will be conducted using the FAS. 
All the secondary efficacy endpoints involving proportions will be analyzed using the same 
statistical method (M = F) applied to the analysis of the primary efficacy endpoint. Sensitivity 
analyses will be performed using the M = E approach as well.  
The change from baseline in log10 (HBV DNA) (IU/mL), log10 (HBsAg) (IU/mL), and ALT will 
be summarized by visit using observed data (ie, missing will be excluded). In addition, the 
proportion of subjects with HBV DNA < 29 IU/mL, mean change from baseline in log10 
(HBV DNA) (IU/mL), log10 (HBsAg) (IU/mL), and ALT (U/L) will be plotted with 95% CI over 
time using observed data for FAS. 
Fibrosis assessed by FibroTest® at each visit and the change from baseline in fibrotest score will 
be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, 
and maximum) by treatment group. A shift table of fibrosis stage based on fibrotest score by visit 
will also be provided. Mean change from baseline in fibrotest score will be plotted with 95% CI 
over time using observed data for FAS. A listing of fibrosis assessment by FibroTest® will also 
be provided. 
6.3. 
Changes From Protocol-Specified Efficacy Analyses 
Change from baseline in log10 (HBV DNA) (IU/mL), log10 (HBsAg) (IU/mL), and ALT were 
added in the SAP as secondary efficacy endpoints to fully explore the treatment effect of TAF 
versus TDF.  
Randomized Analysis Set was not defined in the protocol but is added in the SAP. 


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7. 
SAFETY ANALYSES 
For Week 48 analysis, safety data will be summarized for the double-blind phase only 
up to Week 96. The upper limit of the least frequent schedule analysis window of Week 96 
(Study Day 839) will be used as Week 96 data cut for cumulative summaries of safety events 
(eg, treatment-emergent AEs, treatment-emergent laboratory abnormalities). All safety data up to 
the Week 48 data-cut including data collected during the open-label phase and the 24-week 
treatment-free follow-up period will be included in data listings. 
7.1. 
Adverse Events 
7.1.1. 
Adverse Event Dictionary 
AEs 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. 
7.1.2. 
Adverse Event Severity 
AEs 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 5 of the clinical 
study protocol. The severity grade of events for which the investigator did not record severity 
will be categorized as “missing” for tabular summaries and 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 “Yes” 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 purpose. Data listings will show 
relationship as missing. 
7.1.4. 
Relationship of AEs to Study Procedure 
AEs for which ‘Yes’ is marked for question ‘Related to Study Procedures?’ in the eCRF will be 
identified and included in AE listing. 
7.1.5. 
Serious AEs 
Serious AEs are those identified as serious in the eCRF, where ‘Yes’ was marked for ‘AE 
serious’. The clinical database will be reconciled with the serious AE database (from the 
Drug Safety and Public Health 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 occurring during the double-blind phase are defined as: 
• Any AE with an onset date on or after the blinded study drug start date and no later than the 
study drug stop date for those who discontinued blinded study drug permanently, or 
• Any AE with an onset date on or after the blinded study drug start date for those who remain 
on the blinded study drug, or 
• Any AE leading to blinded study drug discontinuation. 
Treatment-emergent AEs occurring during the open-label phase are defined as: 
• Any AE with an onset date on or after the open-label study drug start date and no later than 
the open-label study drug stop date for those who discontinued open-label study drug 
permanently, or 
• Any AE with an onset date on or after the open-label study drug start date for those who 
remain on the open-label study drug, or 
• Any AE leading to open-label study drug discontinuation.  
7.1.6.2. 
Incomplete Dates 
If an AE onset date is incomplete or completely missing, the following rules will be used to 
define treatment-emergent AE during the double-blind and open-label phases:  
Events with Missing Onset Day and/or Month 
The event is treatment-emergent during the double-blind phase if the following 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 the blinded study drug, and 
• For those who discontinued the blinded study drug permanently only: the month and year (or 
year) of onset date is the same as or before the month and year (or year) of the date of the last 
dose of the blinded study drug, and  
• End date is as follows: 
 The (complete) end date is on or after the first dose date of the blinded study drug, 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 the blinded study drug, or 
 End date is completely missing 


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The event is treatment-emergent during the open-label phase if the following 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 the open-label study drug, and 
• For those who discontinued the open-label study drug permanently only: the month and year 
(or year) of onset date is the same as or before the month and year (or year) of the date of the 
last dose of the open-label study drug, and  
• End date is as follows: 
 The (complete) end date is on or after the first dose date of the open-label study drug, 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 the open-label 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 treatment-emergent AE during the 
double-blind phase if end date is as follows: 
• The (complete) end date is on or after the first dose date of the blinded study drug, 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 the blinded study drug, or 
• End date is completely missing 
An AE with a completely missing onset date is defined as treatment-emergent AE during the 
open-label phase if end date is as follows: 
• The (complete) end date is on or after the first dose date of the open-label study drug, 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 the open-label study drug, or 
• End date is completely missing 
7.1.7. 
Summaries of AEs and Deaths 
A brief summary of AEs (ie, the number and percentage of subjects) will be presented by 
treatment group for the following: (1) any treatment-emergent AE, (2) any Grade 3 or 4 
treatment-emergent AE, (3) any Grade 2, 3 or 4 treatment-emergent AE, (4) any treatment-emergent 
study drug-related AE, (5) any Grade 3 or 4 treatment-emergent study drug-related AE, 
(6) any Grade 2, 3 or 4 treatment-emergent study drug-related AE, (7) any treatment-emergent 
serious adverse event (SAE), (8) any treatment-emergent study drug-related SAE, 


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(9) any treatment-emergent AE leading to premature study drug discontinuation, 
(10) any treatment-emergent AE leading to dose modification or study drug interruption, and 
(11) any treatment-emergent death. 
Treatment-emergent death refers to death that occurs between the first dose date and the last dose 
date (inclusive). 
Summaries (number and percentage of subjects) of AEs (by SOC, HLT [if specified below], 
and PT) will be provided by treatment group and overall using the Safety Analysis Set as 
follows: 
• All treatment-emergent AEs summarized by SOC, HLT, and PT 
• Any Grade 3 or 4 treatment-emergent AEs 
• Any Grade 2, 3, or 4 treatment-emergent AEs 
• All treatment-emergent nonserious AEs occurring in at least 5% of subjects in any 
treatment group (this summary is generated per requirement for reporting in 
ClinicalTrials.gov)  
• All treatment-emergent study drug-related AE summarized by SOC, HLT, and PT 
• 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 leading to premature discontinuation from study drug 
• All treatment-emergent AEs leading to dose modification or study drug interruption 
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC (and HLT) 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 by-treatment summaries, data listings will be provided for the following: 
• All AEs 
• Grade 3 and 4 AEs 
• SAEs 


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• Study drug-related SAEs 
• Deaths 
• AEs leading to premature discontinuation of study drug 
• AEs leading to dose modification or study drug interruption 
7.1.8. 
Potential Uveitis Events 
Analysis will be performed to detect AEs where the symptoms reported may potentially 
represent uveitis. The list of PTs for potential uveitis events were defined by selecting eye 
disorder PTs based on MedDRA 19.1, which will be reviewed and edited by an external 
ophthalmologist for comprehensiveness. 
A summary (number and percentage of subjects) of treatment-emergent potential uveitis events 
by PT will be provided by treatment group based on the Safety Analysis Set. A data listing of 
potential uveitis events will be provided. 
7.1.9. 
Potential Cardiovascular Events 
Potential cardiovascular events are defined as events with predefined list of MedDRA PTs based 
on 3 MedDRA SMQs: Ischemic central nervous system vascular conditions, Other ischemic 
heart disease, and Myocardial infarction, which was provided by Gilead Drug Safety and Public 
Health representative and reviewed by Gilead medical monitors. 
A summary (number and percentage of subjects) of potential treatment-emergent cardiovascular 
events and serious cardiovascular events by PT will be provided by treatment group based on the 
Safety Analysis Set. A data listing of potential cardiovascular events will be provided. 
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 by treatment group for each laboratory test specified in the study protocol as follows: 
• Baseline values 
• Values at each postbaseline analysis window 
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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3. 
Median (Q1, Q3) change from baseline in selected safety endpoints including the fasting lipid 
panel parameters, and fasting glucose over time will be plotted. 
Metabolic Assessments 
For the lipid panel and glucose measurements, only those under fasting status will be 
summarized.  
Fasting lipid data (including total cholesterol, LDL, HDL and triglycerides) will also be analyzed 
using the following National Cholesterol Education Program (NCEP) Adult Treatment Panel 
(ATP) III categories {National Cholesterol Education Program (NCEP) 2001}: 
• For total cholesterol (mg/dL): < 200 (desirable), 200-239 (borderline high), and ≥ 240 (high) 
• For LDL (mg/dL): < 100 (optimal), 100-129 (near optimal/above optimal), 
130-159 (borderline high), 160-189 (high), and ≥ 190 (very high) 
• For HDL (mg/dL): < 40 (low), 40-59 (normal), and ≥ 60 (high) 
• For triglycerides (mg/dL): < 150 (normal), 150-199 (borderline high), 200-499 (high), and 
≥ 500 (very high) 
The number and proportion of subjects for the above categories of each lipid parameter will be 
summarized by its baseline category for each treatment group at each visit. 
In addition, the number and proportion of subjects who took lipid modifying medications at the 
study entry and initiated the medications will be provided, respectively. 
A lipid modifying medication is defined as a medication with drug class = “LIPID MODIFYING 
AGENTS” and CMDECOD containing the wording of “STATIN”. 
A sensitivity analysis of fasting lipid tests (including total cholesterol, LDL, HDL, triglycerides, 
and total cholesterol to HDL ratio) will be performed by excluding subjects who took lipid 
modifying medications at study entry or initiated the medications: baseline, postbaseline, and 
changes from baseline at Weeks 48 and 96 will be summarized. Only subjects with both baseline 
and postbaseline values (at Weeks 48 and 96 respectively) will be included in the analysis. 
Calcium Corrected for Albumin 
Calcium corrected for albumin will be calculated and summarized. 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)). 
When albumin value is ≥ 4.0 g/dL, the actual calcium results will be used. Toxicity grading for 
calcium will be applied based on the corrected values. 


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7.2.2. 
Graded Laboratory Values 
The criteria specified in the protocol will be used to grade laboratory results as Grade 0, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life-threatening). 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; analysis for each direction 
(ie, increased, decreased) will be presented separately.  
For triglycerides, LDL, and total cholesterol, the protocol-specified toxicity grade scale is for 
fasting test values; non-fasting lipid results (or lipid results without known fasting status) will not 
be graded or summarized by toxicity grades.  
If any laboratory toxicity grading scale overlaps with normal reference ranges (eg, Grade 1 scale 
overlaps with normal reference ranges), laboratory values within normal range will not be graded 
except for lipid tests.  
7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities occuring in the double-blind phase are defined as 
values that increase by at least 1 toxicity grade from baseline at any postbaseline visit up to and 
including the last does date of the blinded study drug (or ‘last dose date of the blinded study drug 
+ 1’ for those who enter the open-label phase) for those who discontinued blinded study drug 
prematurely, or values that increase by at least 1 toxicity grade from baseline at any postbaseline 
visit for those who are still on the blinded study drug. If the relevant baseline laboratory data are 
missing, any laboratory abnormality of at least Grade 1 will be considered treatment-emergent. 
Treatment-emergent laboratory abnormalities occurring in the open-label phase are defined as 
values that increase by at least 1 toxicity grade from the open-label baseline at any open-label 
postbaseline visit up to and including the last dose date of open-label study drug for those who 
discontinued open-label study drug prematurely, or values that increase by at least 
1 toxicity grade from the open-label baseline at any open-label postbaseline visit for those who 
are still on the open-label study drug. For the analyses of abnormalities occurring during 
open-label treatment, baseline will be considered to be the last available record on or prior to 
Open-Label Study Day 1. 
Fasting glucose and nonfasting glucose are graded based on different grading scales. 
Treatment-emergent laboratory abnormalities will be summarized for fasting glucose. Since 
nonfasting glucose was not assessed at baseline, the maximum postbaseline grade will be 
summarized. 
7.2.2.2. 
Treatment-Emergent Marked Laboratory Abnormalities 
Treatment-emergent marked laboratory abnormalities occurring in the double-blind phase are 
defined as values that worsen by at least 3 grades from baseline at any postbaseline visit up to 
and including the last dose date of the blinded study drug (or ‘last dose date of the blinded study 
drug + 1’ for those who enter the open-label phase) for those who discontinued study drug 


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prematurely, or values that worsen by at least 3 grades from baseline at any postbaseline visit for 
those who are still on blinded study drug. If relevant baseline laboratory data are missing, any 
laboratory abnormalities of at least Grade 3 or 4 will be considered as treatment-emergent 
marked laboratory abnormalities. 
Treatment-emergent marked laboratory abnormalities occurring in the open-label phase are 
defined as values that worsen by at least 3 grades from the open-label baseline at any open-label 
postbaseline visit up to and including the last dose date of open-label study drug for those who 
discontinued open-label study drug prematurely, or values that worsen by at least 3 grades from 
the open-label baseline at any open-label postbaseline visit for those who are still on open-label 
study drug. 
7.2.2.3. 
Summaries of Laboratory Abnormalities 
The following summaries (number and percentage of subjects) of laboratory abnormalities will 
be provided by treatment group (subjects categorized according to most severe abnormality 
grade): 
• Treatment-emergent laboratory abnormalities 
• Treatment-emergent Grade 3 and 4 laboratory abnormalities 
• Treatment-emergent marked laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
any nonmissing postbaseline value in the given study period. A listing of treatment-emergent 
Grade 3 or 4 laboratory abnormalities will be provided. 
7.2.3. 
ALT Elevation 
An ALT elevation is defined as serum ALT > 2 × baseline value and > 10 × ULN, with or 
without associated symptoms. Confirmed ALT elevation (ALT flare) is defined as ALT 
elevations at 2 consecutive postbaseline visits. All treatment-emergent ALT elevations including 
confirmed ALT elevations will be summarized for the double-blind phase. All 
treatment-emergent and nontreatment-emergent ALT elevations will be included in a listing. 
7.3. 
Bone Safety Analyses 
7.3.1. 
Bone Mineral Density (BMD) 
For BMD analysis during the double-blind phase, any available on-treatment record on or prior 
to Open-label Study Day 14 will be included into the double-blind phase summary for those who 
enter the open-label phase after completion of the double-blind phase. 
Percentage change from baseline in hip BMD and spine BMD a will be summarized by treatment 
group and visit using descriptive statistics for subjects in the Hip and Spine DXA Analysis Sets, 
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Missing values for hip and spine BMD will be imputed using LOCF up to Week 96 for the 
analyses of percentage change from baseline. The last on-treatment postbaseline observation will 
be carried forward to impute the missing value. Baseline observation will not be carried forward. 
Percentage change from baseline in observed hip and spine BMD will be analyzed similarly 
provided up to Week 96. 
Observed BMD values will be used for all the analyses described below: 
For each subject and each visit, the clinical BMD status will be defined for hip and spine BMD 
based on the corrected t-score in Table 7-1. 
Table 7-1. 
Normal, Osteopenia, and Osteoporosis as Defined by T-score 
Clinical Status 
BMD T-score 
Normal 
t-score ≥ -1.0 
Osteopenia 
-2.5 ≤ t-score < -1.0 
Osteoporosis 
t-score < -2.5 
 
The number and percentage of subjects in each clinical BMD status (normal, osteopenia, 
and osteoporosis) will be summarized by visit and by baseline clinical status for both hip and 
spine.  
For each subject and each visit, percentage change from baseline in hip BMD and spine BMD will 
be classified into 10 categories: > 7% decrease, > 5% to ≤ 7% decrease, > 3% to ≤ 5% 
decrease, >1% to ≤ 3% decrease, > 0 to ≤ 1% decrease, 0 to ≤ 1% increase, > 1% to ≤ 3% 
increase, > 3% to ≤ 5% increase, > 5% to ≤ 7% increase, and > 7% increase. The number and 
percentage of subjects in each category will be summarized by visit.  
Median (Q1, Q3) and mean (95% CI) of percentage change from baseline in observed hip and 
spine BMD over time will be plotted by treatment group. Listings of hip and spine DXA results 
will be provided.  
7.3.2. 
Bone Biomakers 
Bone biomarkers include serum CTX, P1NP, PTH, OC, and bsAP. 
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone 
biomarkers will be summarized by treatment group and visit using descriptive statistics.  
Median (Q1, Q3) percentage change from baseline in bone biomarkers over time will be plotted 
by treatment group. A listing of bone biomarker data will be provided. 


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7.3.3. 
Fracture Events 
The PTs for fracture events were defined based on both Standardised MedDRA Query (SMQ) of 
Osteoporosis/Osteopenia and HLGT of Fractures from MedDRA 19.1. These PTs were reviewed 
by the Gilead medical monitor before unblinding to identify appropriate fracture event PTs from 
the SMQ of Osteoporosis/Osteopenia and HLGT of Fractures. Treatment-emergent fracture 
events will be summarized based on the identified PTs from SMQ alone and both SMQ and 
HLGT combined. The number and percentage of subjects who experienced fracture events will 
be summarized by treatment group. A data listing of fracture events will be provided. 
7.3.4. 
Assessment of Fracture Probability 
Fracture probabilities will be assessed using FRAX®, a computer based algorithm developed by 
the World Health Organization (WHO; http://www.shef.ac.uk/FRAX). 
The FRAX algorithm is based on individual patient models that integrate the risks associated 
with clinical risk factors as well as BMD at the femoral neck. The algorithm provides both the 
10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture 
(clinical spine, forearm, hip, or shoulder fracture). 
The FRAX model is constructed from real data in population-based cohorts around the world 
that have a limited age range. For an age below 40 or above 90 years, the tool will calculate the 
probability of fracture at the age of 40 or 90 years, respectively. Due to the age limitation, 
2 sets of analyses of fracture probabilities will be performed. 
In the first set of analysis, summaries of baseline and change from baseline in the 10-year 
probabilities of hip fracture, as well as major osteoporotic fracture will be presented by treatment 
group and visit for subjects aged between 40 and 90 years.  
In the second set of analysis, the above-specified analysis will be performed to include all 
subjects, where subjects with an age below 40 or above 90 years will be treated as having an age 
of 40 or 90 years, respectively, in computing their fracture probabilities. 
Data listings of fracture risk assessment questionnaire and FRAX fracture probabilities will be 
provided. 
7.3.5. 
Bone Events 
The PTs for bone events were defined by selecting relevant bone PTs based on MedDRA 19.1. 
The predefined list of PTs, included Osteoporosis/Osteopenia and Osteonecrosis SMQ, HLGT of 
Fractures, and HLTs relevant to bone disorders, bone metabolism, and bone procedures. These 
PTs were reviewed by the Gilead medical monitor before unblinding to identify appropriate bone 
event PTs. The number and percentage of subjects who experienced treatment-emergent bone 
events will be summarized by treatment group. A data listing of bone events will be provided. 


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7.4. 
Renal Safety Analyses 
7.4.1. 
Confirmed Renal Abnormalities 
Confirmed renal abnormalities are defined as follows: 
• Confirmed increase from baseline in creatinine of at least 0.5 mg/dL or 
• Confirmed CLCr by CG below 50 mL/min or 
• Confirmed phosphorous < 2 mg/dL 
Treatment-emergent confirmed renal abnormalities will be summarized for double-blind phase. 
All confirmed renal abnormalities including those occurred during open-label phase and 24-week 
treatment-free follow-up period will be listed.  
7.4.2. 
Serum Creatinine 
The baseline and change from baseline in serum creatinine at Week 48 will be summarized 
using descriptive statistics.  
Missing values for serum creatinine will be imputed using LOCF up to Week 96 for the analyses 
of change from baseline in serum creatinine. The last on-treatment postbaseline observation will 
be carried forward to impute the missing value. Baseline observation will not be carried forward. 
Change from baseline in observed serum creatinine will be analyzed similarly. 
For all of the other renal safety analyses, observed creatinine values will be used. 
Median (Q1, Q3) and mean (95% CI) of change from baseline in observed serum creatinine 
overtime will be plotted by treatment group. 
7.4.3. 
Estimated Glomerular Filtration Rate 
The following formulae will be used to calculate eGFR:  
• CG: 
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (SCr (mg/dL) × 72), 
where weight is actual total body mass in kilograms, and SCr is serum creatinine. 
• CKD-EPI Creatinine Based: 
eGFRCKD-EPI, creatinine (mL/min/1.73 m2) = 141 × min(SCr/κ,1)α × max(SCr/κ,1)-1.209 × 0.993Age × 
1.018 (if female) × 1.159 (if black), 
where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, 
min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1 
{Levey 2009}. 


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• CKD-EPI Cystatin C based: 
eGFRCKD-EPI, cysC (mL/min/1.73 m2) = 133 × min(SCys/0.8, 1)-0.499 × max(SCys/0.8, 1)-1.328 × 
0.996age [× 0.932 if female], 
where SCys is serum cystatin C. 
Change from baseline in eGFRCG and eGFRCKD-EPI, creatinine at each postbaseline visit will also be 
provided.  
The number and proportion of subjects with decrease from baseline of ≥ 25% and ≥ 50% in 
eGFRCG and eGFRCKD-EPI, creatinine will be summarized by treatment groups.  
The number and proportion of subjects in each stage of CKD will be summarized by baseline 
stages of CKD for the double-blind phase up to Week 96.  
The stages of CKD are defined as follows: 
• Stage 1: eGFRCG ≥ 90 mL/min 
• Stage 2: eGFRCG ≥ 60 and < 90 mL/min 
• Stage 3: eGFRCG ≥ 30 and < 60 mL/min 
• Stage 4: eGFRCG < 30 mL/min 
Cystatin C will be collected for each subject at baseline visit (protocol amendment 2.1 and after) 
and whenever their postbaseline eGFR by CG < 50 mL/min. Therefore, eGFRCKD-EPI, cysC will be 
summarized as the baseline disease characteristics only. All postbaseline eGFRCKD-EPI, cysC with 
percentage change from baseline will be listed. 
Median (Q1, Q3) change from baseline in eGFRCG and eGFRCKD-EPI, creatinine over time will be 
plotted. 
7.4.4. 
Treatment-Emergent Proteinuria (Dipstick) 
Treatment-emergent proteinuria by urinalysis (dipstick) through Week 48 will be summarized by 
treatment group. A listing of subjects with treatment-emergent proteinuria will be provided. 
7.4.5. 
Urine Creatinine, Urine RBP to Creatinine Ratio and Beta-2-microglobulin 
to Creatinine Ratio 
Baseline, postbaseline, change from baseline and percentage change from baseline in urine 
creatinine, urine RBP to creatinine ratio and beta-2-microglobulin to creatinine ratio will be 
summarized by treatment group and visit using descriptive statistics. Median (Q1, Q3) 
percentage change from baseline over time will be plotted by treatment group. 


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7.4.6. 
Proteinuria by Quantitative Assessment 
Baseline, postbaseline, changes from baseline, and percentage change from baseline in UPCR 
and UACR will be summarized by treatment group and visit using descriptive statistics.  
The number and proportion of subjects with UPCR ≤ 200 mg/g versus > 200 mg/g will be 
summarized by baseline category for each postbaseline visit {KDIGO Guideline Development 
Staff 2013}. 
Median (Q1, Q3) percentage change from baseline over time will be plotted by treatment group. 
7.4.7. 
Other Renal Biomarkers 
Other renal biomarkers include TmP/GFR, FEPO4, and FEUA. 
TmP/GFR based on serum creatinine {Barth 2000} will be calculated as follows: 
[
]
86
.0
)
8.0
(
1
/
3.0
/
86
.0
/
4
4
>
×
×
−
×
=
≤
×
=
TRP
if
SPO
TRP
TRP
GFR
TmP
TRP
if
SPO
TRP
GFR
TmP
 
where TRP (tubular reabsoprtion of phosphate) is calculated by: 
UCr
SCr
SPO
UPO
TRP
×
−
=
4
4
1
 
where SCr is serum creatinine concentration (mg/dL), UPO4 is urine phosphate concentration 
(mg/dL), SPO4 is serum phosphate concentration, and UCr is urine creatinine concentration 
(mg/dL). 
Urine FEPO4 will be calculated as follows: 
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%) 
Urine FEUA will be calculated as follows: 
FEUA (%) = (SCr × UUa) / (SUa × UCr) × 100 (%) 
where UUa and SUa are urine and serum uric acid (mg/dL), respectively.  
The baseline, postbaseline, and change from baseline in TmP/GFR, FEPO4, and FEUA will be 
summarized by treatment group and visit using descriptive statistics.  
Median (Q1, Q3) change from baseline in TmP/GFR, FEPO4, and FEUA over time will be 
plotted by treatment group. A listing of renal biomarker data will be provided. 


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7.5. 
Ophthalmologic Assessment 
As no Ophthalmologic assessment was performed in China, no analysis will be conducted. 
7.6. 
Body Weight 
Body weight at each visit and change from baseline in body weight will be summarized using 
descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group for each postbaseline analysis window. In the case of multiple values in an 
analysis window, data will be selected for analysis as described in Section 3.7.3. 
7.7. 
Prior Hepatitis B Medications 
Prior HBV medications will be summarized by treatment group. A listing of prior HBV 
medications will also be provided. 
7.8. 
Concomitant Medications 
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 blinded study drug will be summarized (number and percentage of 
subjects) for the double-blind phase by treatment group and WHO drug class and preferred 
name. Multiple drug use (by preferred name) will be counted only once 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 concomitant medications is incomplete, the month and year 
(or year alone if month is not recorded) of start or stop date will be used to determine if the 
medications are concomitant as follows. The medication is concomitant for the double-blind 
phase 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 blinded 
study drug 
• The month and year of stop of the medication is before the date of the first dose of blinded 
study drug 
If the start and stop date of the medications are not missing, and the start date is not after the last 
dose date of double-blind phase and the stop date is not before the first dose date of double-blind 
phase, or the medications are marked as ongoing and start date is on or before the last dose date 
of double-blind phase, the medications are considered concomitant of double-blind phase. 
Summaries of concomitant medications will be provided for the Safety Analysis Set. Subjects 
with any concomitant medication use will also be listed. 


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7.9. 
Electrocardiogram (ECG) Results 
The number and percentage of subjects in the Safety Analysis Set with an investigator’s ECG 
assessment of normal, abnormal but not clinically significant, or abnormal and clinically 
significant will be summarized by treatment group and by baseline result for each visit.  
A by-subject listing of safety ECG results will be provided including treatment, assessment date 
and time, and ECG results. 
7.10. 
Other Safety Measures 
A data listing will be provided for subjects experiencing pregnancy during the study.  
Listings of cirrhosis and hepatocellular carcinoma assessment results will be provided. 
Alcohol use data will also be listed. 
7.11. 
Changes From Protocol-Specified Safety Analyses 
Treatment-emergent proteinuria was not included as a key secondary safety endpoint in protocol 
amendment 3.1 and is added in the SAP.  
As no Ophthalmologic assessment was performed in China, no analysis will be conducted. 
Comparison of the safety and tolerability of TAF versus TDF for the treatment of 
HBeAg-negative, CHB beyond Week 48 during the double-blind phase in treatment-naive and 
treatment-experienced subjects was not included as a secondary objective of this study and is 
added in the SAP. 


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8. 
REFERENCES 
Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the 
algorithm performs better than the nomogram. Ann Clin Biochem 2000;37 ( Pt 
1):79-81. 
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the 
Evaluation and Management of Chronic Kidney Disease. Kidney international. 
Supplement 2013;3 (1):v-150. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150 (9):604-
12. 
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. 
National Institute of Health  May, 2001. 
 
 


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9. 
SOFTWARE 
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, 
listings, and figures. 
nQuery Advisor® (Statistical Solutions Ltd., Version 6.0, Cork, Ireland) was used for the sample 
size and power calculation. 
FRAX® (WHO Collaborating Center for Metabolic Bone Disease, University of Sheffield, UK) 
is to be used for the 10-year probabilities of hip fracture or a major osteoporotic fracture. 


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10. 
SAP REVISION 
Revision Date 
(dd month yyyy) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 


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11. 
APPENDICES 
Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
Appendix 2. 
Fracture Events 
Appendix 3. 
Bone Events 
Appendix 4. 
Potential Uveitis 
Appendix 5. 
Potential Cardiovascular or Cerebrovascular Events 
 


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Appendix 1. 
Table of Contents for Statistical Tables, Figures, and Listings 
Table of contents of TFLs for Week 48 analysis is as follows:  
Table Number 
Title 
Analysis Set 
1 
Enrollment by Region, Country, and Investigator 
Safety Analysis Set 
2 
Enrollment by Randomization Stratum 
Safety Analysis Set 
3 
Subject Disposition 
All Screened Subjects 
4 
Analysis Set 
Randomized Analysis Set 
5 
Demographics and Baseline Characteristics 
Safety Analysis Set 
6 
Baseline Disease Characteristics 
Safety Analysis Set 
7 
Risk Factors for HBV Infections 
Safety Analysis Set 
8 
Prior HBV Medications 
Safety Analysis Set 
9 
Duration of Exposure to Blinded Study Drug 
Safety Analysis Set 
10.1 
Time to Premature Discontinuation of Blinded Study Drug 
(Kaplan-Meier Estimate) 
Safety Analysis Set 
10.2 
Supporting Table for Table 11.1: Percentiles of Time to 
Premature Discontinuation of Blinded Study Drug 
Safety Analysis Set 
10.3 
Supporting Table for Table 11.1: Listing of Time and Censoring 
Status of Premature Discontinuation of Blinded Study Drug 
Safety Analysis Set 
11 
Adherence to Blinded Study Drug 
Safety Analysis Set 
12 
HBV DNA Outcome at Week 48 (HBV DNA Cutoff at 
29 IU/mL, Missing = Failure) 
Full Analysis Set 
13 
HBV DNA Outcome at Week 48 (HBV DNA Cutoff at 
29 IU/mL, Missing = Failure) 
Week 48 PP Analysis Set 
14.1 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit 
(Missing = Failure) 
Full Analysis Set 
14.2 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit 
(Missing = Excluded) 
Full Analysis Set 
15 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit 
(Missing = Failure) 
Week 48 PP Analysis Set 
16 
Proportion of Subjects with HBV DNA < 29 IU/mL at Week 48 
by Subgroup (Missing = Failure) 
Full Analysis Set 
17 
HBV DNA (log10 IU /mL) and Change from Baseline in 
HBV DNA (log10 IU /mL) by Visit  
Full Analysis Set 
18.1 
Proportion of Subjects with HBeAg Loss/Seroconversion by 
Visit (Missing = Failure) 
Serologically Evaluable 
Full Analysis Set 
18.2 
Proportion of Subjects with HBeAg Loss/Seroconversion by 
Visit (Missing = Excluded) 
Serologically Evaluable 
Full Analysis Set 
19.1 
Proportion of Subjects with HBsAg Loss/Seroconversion by 
Visit (Missing = Failure) 
Serologically Evaluable 
Full Analysis Set 
19.2 
Proportion of Subjects with HBsAg Loss/Seroconversion by 
Visit (Missing = Excluded) 
Serologically Evaluable 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
20 
HBsAg (log10 IU /mL) and Change from Baseline in HBsAg 
(log10 IU /mL) by Visit 
Full Analysis Set 
21.1.1 
Proportion of Subjects with Normal ALT by Visit by Central Lab 
Normal Range (Missing = Failure) 
Full Analysis Set 
21.1.2 
Proportion of Subjects with Normal ALT by Visit by Central Lab 
Normal Range (Missing = Excluded) 
Full Analysis Set 
21.2.1 
Proportion of Subjects with Normal ALT by Visit by AASLD 
Normal Range (Missing = Failure) 
Full Analysis Set 
21.2.2 
Proportion of Subjects with Normal ALT by Visit by AASLD 
Normal Range (Missing = Excluded) 
Full Analysis Set 
22.1.1 
Proportion of Subjects with ALT Normalization by Visit by 
Central Lab Normal Range (Missing = Failure) 
Full Analysis Set with 
Baseline ALT > ULN 
22.1.2 
Proportion of Subjects with ALT Normalization by Visit by 
Central LabNormal Range (Missing = Excluded) 
Full Analysis Set with 
Baseline ALT > ULN 
22.2.1 
Proportion of Subjects with ALT Normalization by Visit by 
AASLD Normal Range (Missing = Failure) 
Full Analysis Set with 
Baseline ALT > ULN 
22.2.2 
Proportion of Subjects with ALT Normalization by Visit by 
AASLD Normal Range (Missing = Excluded) 
Full Analysis Set with 
Baseline ALT > ULN 
23 
ALT (U/L) and Change from Baseline in ALT (U/L) by Visit 
Full Analysis Set 
24 
Fibrotest Score and Change from Baseline in Fibrotest Score 
by Visit 
Full Analysis Set 
25 
Shift Table of Fibrosis Stage by FibroTest® by Visit 
Full Analysis Set 
26 
Treatment-Emergent Adverse Events: Overall Summary 
Safety Analysis Set 
27 
Treatment-Emergent Adverse Events 
Safety Analysis Set 
28 
Treatment-Emergent Nonserious Adverse Events Occurring in 
>= 5% of Subjects in Any Treatment Group 
Safety Analysis Set 
29 
Grade 2, 3, or 4 Treatment-Emergent Adverse Events  
Safety Analysis Set 
30 
Grade 3 or 4 Treatment-Emergent Adverse Events  
Safety Analysis Set 
31 
Treatment-Emergent Study Drug-Related Adverse Events 
Safety Analysis Set 
32 
Grade 2, 3, or 4 Treatment-Emergent Study Drug-Related 
Adverse Events 
Safety Analysis Set 
33 
Grade 3 or 4 Treatment-Emergent Study Drug-Related 
Adverse Events  
Safety Analysis Set 
34 
Treatment-Emergent Serious Adverse Events 
Safety Analysis Set 
35 
Treatment-Emergent Study Drug-Related Serious Adverse 
Events 
Safety Analysis Set 
36 
Treatment-Emergent Adverse Events Leading to Premature 
Study Drug Discontinuation 
Safety Analysis Set 
37 
Treatment-Emergent Adverse Events Leading to Dose 
Modification or Study Drug Interruption 
Safety Analysis Set 
38 
Treatment-Emergent Potential Uveitis Events 
Safety Analysis Set 
39 
Treatment-Emergent Potential Cardiovascular Events 
Safety Analysis Set 


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Table Number 
Title 
Analysis Set 
40 
Treatment-Emergent Potential Serious Cardiovascular Events 
Safety Analysis Set 
41 
Treatment-Emergent Laboratory Abnormalities 
Safety Analysis Set 
42 
Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities 
Safety Analysis Set 
43 
Treatment-Emergent Marked Laboratory Abnormalities 
Safety Analysis Set 
44 
Treatment-Emergent ALT Elevation 
Safety Analysis Set 
45.1 
Hematology: Summary of Hemoglobin (g/dL) by Visit 
Safety Analysis Set 
45.2 
Hematology: Summary of Hematocrit (%) by Visit 
Safety Analysis Set 
45.3 
Hematology: Summary of MCH (pg) by Visit 
Safety Analysis Set 
45.4 
Hematology: Summary of MCHC (g/dL) by Visit 
Safety Analysis Set 
45.5 
Hematology: Summary of MCV (fL) by Visit 
Safety Analysis Set 
45.6 
Hematology: Summary of RBC (10^6/uL) by Visit 
Safety Analysis Set 
45.7 
Hematology: Summary of Absolute Basophils (10^3/uL) by Visit 
Safety Analysis Set 
45.8 
Hematology: Summary of Absolute Eosinophils (10^3/uL) 
by Visit 
Safety Analysis Set 
45.9 
Hematology: Summary of Absolute Lymphocytes (10^3/uL) 
by Visit 
Safety Analysis Set 
45.10 
Hematology: Summary of Absolute Monocytes (10^3/uL) 
by Visit 
Safety Analysis Set 
45.11 
Hematology: Summary of Absolute Neutrophils (10^3/uL) 
by Visit 
Safety Analysis Set 
45.12 
Hematology: Summary of Platelet Count (10^3/uL) by Visit 
Safety Analysis Set 
45.13 
Hematology: Summary of WBC (10^3/uL) by Visit 
Safety Analysis Set 
46.1 
Chemistry: Summary of Bicarbonate (mEq/L) by Visit 
Safety Analysis Set 
46.2 
Chemistry: Summary of Calcium (Albumin Corrected, mg/dL) 
by Visit 
Safety Analysis Set 
46.3 
Chemistry: Summary of Chloride (mEq/L) by Visit 
Safety Analysis Set 
46.4 
Chemistry: Summary of Magnesium (mg/dL) by Visit 
Safety Analysis Set 
46.5 
Chemistry: Summary of Phosphorus (mg/dL) by Visit 
Safety Analysis Set 
46.6 
Chemistry: Summary of Potassium (mEq/L) by Visit 
Safety Analysis Set 
46.7 
Chemistry: Summary of Sodium (mEq/L) by Visit 
Safety Analysis Set 
46.8 
Chemistry: Summary of Alkaline Phosphatase (U/L) by Visit 
Safety Analysis Set 
46.9 
Chemistry: Summary of AST (U/L) by Visit 
Safety Analysis Set 
46.10 
Chemistry: Summary of Amylase (U/L) by Visit 
Safety Analysis Set 
46.11 
Chemistry: Summary of Lipase (U/L) by Visit 
Safety Analysis Set 
46.12 
Chemistry: Summary of Total Bilirubin (mg/dL) by Visit 
Safety Analysis Set 
46.13 
Chemistry: Summary of Direct Bilirubin (mg/dL) by Visit 
Safety Analysis Set 
46.14 
Chemistry: Summary of Indirect Bilirubin (mg/dL) by Visit 
Safety Analysis Set 
46.15 
Chemistry: Summary of GGT (U/L) by Visit 
Safety Analysis Set 


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Table Number 
Title 
Analysis Set 
46.16 
Chemistry: Summary of LDH (U/L) by Visit 
Safety Analysis Set 
46.17 
Chemistry: Summary of Blood Urea Nitrogen (BUN, mg/dL) 
by Visit 
Safety Analysis Set 
46.18 
Chemistry: Summary of Uric Acid (mg/dL) by Visit 
Safety Analysis Set 
46.19 
Chemistry: Summary of Albumin (g/dL) by Visit 
Safety Analysis Set 
46.20 
Chemistry: Summary of Creatine Kinase (U/L) by Visit 
Safety Analysis Set 
46.21 
Chemistry: Summary of Total Protein (g/dL) by Visit 
Safety Analysis Set 
47.1.1 
Metabolic Assessments: Summary of Fasting Total Cholesterol 
(mg/dL) by Visit 
Safety Analysis Set 
47.1.2 
Metabolic Assessments: Shift Table of Fasting Total Cholesterol 
(mg/dL) by Visit 
Safety Analysis Set 
47.2.1 
Metabolic Assessments: Summary of Fasting Direct LDL 
(mg/dL) by Visit 
Safety Analysis Set 
47.2.2 
Metabolic Assessments: Shift Table of Fasting Direct LDL 
(mg/dL) by Visit 
Safety Analysis Set 
47.3.1 
Metabolic Assessments: Summary of Fasting HDL (mg/dL) 
by Visit 
Safety Analysis Set 
47.3.2 
Metabolic Assessments: Shift Table of Fasting HDL (mg/dL) 
by Visit 
Safety Analysis Set 
47.4 
Metabolic Assessments: Summary of Fasting Total Cholesterol 
to HDL Ratio by Visit 
Safety Analysis Set 
47.5.1 
Metabolic Assessments: Summary of Fasting Triglycerides 
(mg/dL) by Visit 
Safety Analysis Set 
47.5.2 
Metabolic Assessments: Shift Table of Fasting Triglycerides 
(mg/dL) by Visit 
Safety Analysis Set 
47.6 
Metabolic Assessments: Summary of Fasting Glucose (mg/dL) 
by Visit 
Safety Analysis Set 
47.7.1 
Summary of Subjects Taking Lipid Modifying Medications at 
Study Entry 
Safety Analysis Set 
47.7.2 
Summary of Subjects Initiating Lipid Modifying Medications 
during Double-Blind Phase 
Safety Analysis Set 
47.8.1 
Summary of Fasting Total Cholesterol (mg/dL) at Baseline and 
Week 48 (Excluding Subjects Taking any Lipid Modifying 
Medication) 
Safety Analysis Set 
47.8.2 
Summary of Fasting Direct LDL (mg/dL) at Baseline and 
Week 48 (Excluding Subjects Taking any Lipid Modifying 
Medication) 
Safety Analysis Set 
47.8.3 
Summary of Fasting HDL (mg/dL) at Baseline and Week 48 
(Excluding Subjects Taking any Lipid Modifying Medication) 
Safety Analysis Set 
47.8.4 
Summary of Fasting Triglycerides (mg/dL) at Baseline and 
Week 48 (Excluding Subjects Taking any Lipid Modifying 
Medication) 
Safety Analysis Set 


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Table Number 
Title 
Analysis Set 
47.8.5 
Summary of Fasting Total Cholesterol to HDL Ratio at Baseline 
and Week 48 (Excluding Subjects Taking any Lipid Modifying 
Medication) 
Safety Analysis Set 
48.1.1 
Percentage Change from Baseline in Hip Bone Mineral Density 
by Visit (LOCF Imputation) 
Hip DXA Analysis Set 
48.1.2 
Percentage Change from Baseline in Hip Bone Mineral Density 
by Visit (Observed Data) 
Hip DXA Analysis Set 
48.2.1 
Percentage Change from Baseline in Spine Bone Mineral Density 
by Visit (LOCF Imputation) 
Spine DXA Analysis Set 
48.2.2 
Percentage Change from Baseline in Spine Bone Mineral Density 
by Visit (Observed Data) 
Spine DXA Analysis Set 
49.1 
Clinical Hip Bone Mineral Density Status by Baseline Status and 
Visit 
Hip DXA Analysis Set 
49.2 
Clinical Spine Bone Mineral Density Status by Baseline Status 
and Visit 
Spine DXA Analysis Set 
50.1 
Gradation of the Percentage Change in Hip Bone Mineral 
Density by Visit 
Hip DXA Analysis Set 
50.2 
Gradation of the Percentage Change in Spine Bone Mineral 
Density by Visit 
Spine DXA Analysis Set 
51.1 
Bone Biomarkers: Summary of Serum C-type Collagen 
Sequence (CTX, ng/mL) by Visit 
Safety Analysis Set 
51.2 
Bone Biomarkers: Summary of Serum Bone Procollagen Type 1 
N-terminal Propeptide (P1NP, ng/mL) by Visit 
Safety Analysis Set 
51.3 
Bone Biomarkers: Summary of Serum Parathyroid Hormone 
(PTH, pg/mL) by Visit 
Safety Analysis Set 
51.4 
Bone Biomarkers: Summary of Osteocalcin (OC, ng/mL) by Visit 
Safety Analysis Set 
51.5 
Bone Biomarkers: Summary of Bone Specific Alkaline 
Phosphatase (bsAP, ug/L) by Visit 
Safety Analysis Set 
52 
Treatment-Emergent Fracture Events 
Safety Analysis Set 
53.1.1 
Summary of 10 Year Probability of Hip Fracture (%) by Visit 
(Age ≥ 40 Years) 
Hip DXA Analysis Set 
53.1.2 
Summary of 10 Year Probability of Hip Fracture (%) by Visit 
(All Subjects) 
Hip DXA Analysis Set 
53.2.1 
Summary of 10 Year Probability of Major Osteoporotic Fracture 
(%) by Visit (Age ≥ 40 Years) 
Hip DXA Analysis Set 
53.2.2 
Summary of 10 Year Probability of Major Osteoporotic Fracture 
(%) by Visit (All Subjects) 
Hip DXA Analysis Set 
54 
Treatment-Emergent Bone Events 
Safety Analysis Set 
55 
Treatment-Emergent Confirmed Renal Laboratory Abnormality  
Safety Analysis Set 
56.1 
Summary of Serum Creatinine (mg/dL) by Visit 
(LOCF Imputation) 
Safety Analysis Set 
56.2 
Summary of Serum Creatinine (mg/dL) by Visit (Observed Data) 
Safety Analysis Set 


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Table Number 
Title 
Analysis Set 
57.1 
Summary of Estimated Glomerular Filtration Rate (eGFR) by 
Cockcroft-Gault (mL/min) by Visit 
Safety Analysis Set 
57.2 
Summary of Estimated Glomerular Filtration Rate (eGFR) by 
CKD-EPI Creatinine (mL/min/1.73 m^2) by Visit 
Safety Analysis Set 
57.3 
Summary of Subjects with Percentage Decrease from Baseline 
>= 25% and >= 50% in eGFR 
Safety Analysis Set 
57.4 
Shift Table of Chronic Kidney Disease (CKD) Stage by Baseline 
CKD Stage 
Safety Analysis Set 
58 
Treatment-Emergent Proteinuria by Urinalysis (Dipstick) 
Safety Analysis Set 
59.1 
Renal Biomarkers: Summary of Urine Creatinine (mg/dL) by 
Visit 
Safety Analysis Set 
59.2 
Renal Biomarkers: Summary of Urine RBP to Creatinine Ratio 
(ug/g) by Visit 
Safety Analysis Set 
59.3 
Renal Biomarkers: Summary of Urine Beta-2-Microglobulin to 
Creatinine Ratio (ug/g) by Visit 
Safety Analysis Set 
59.4 
Renal Biomarkers: Summary of Urine Protein to Creatinine Ratio 
(UPCR, mg/g) by Visit 
Safety Analysis Set 
59.5 
Renal Biomarkers: Summary of Urine Albumin to Creatinine 
Ratio (UACR, mg/g) by Visit 
Safety Analysis Set 
60.1 
Shift Table of Urine Protein to Creatinine Ratio (UPCR) 
Category (≤ 200 vs > 200 mg/g) by Baseline Category 
Safety Analysis Set 
60.2 
Shift Table of Urine Albumin to Creatinine Ratio (UACR) 
Category (< 30 vs ≥ 30 mg/g) by Baseline Category 
Safety Analysis Set 
61 
Summary of TmP/GFR Ratio (mg/dL) by Visit 
Safety Analysis Set 
62 
Summary of Urine Fractional Excretion of Phosphate 
(FEPO4, %) by Visit 
Safety Analysis Set 
63 
Summary of Urine Fractional Excretion of Uric Acid (FEUA, %) 
by Visit 
Safety Analysis Set 
64 
Summary of Body Weight (kg) by Visit 
Safety Analysis Set 
65 
Concomitant Medications During Study by Drug Class and 
Generic Name 
Safety Analysis Set 
66 
Safety ECG Results by Baseline ECG Category and Visit 
Safety Analysis Set 
 


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Figure Number 
Title 
Analysis Set 
1 
Subject Disposition 
All Screened Subjects 
2 
Time to Premature Discontinuation of Blinded Study Drug 
(Kaplan-Meier Estimate) 
Safety Analysis Set 
3.1 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit: 
Missing = Failure 
Full Analysis Set 
3.2 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit: 
Missing = Excluded 
Full Analysis Set 
4 
Proportion of Subjects with HBV DNA < 29 IU/mL by Visit: 
Missing = Failure 
Week 48 PP Analysis Set 
5 
Mean and 95% CIs of Change from Baseline in HBV DNA 
(log10 IU/mL) by Visit (Observed Data) 
Full Analysis Set 
6 
Mean and 95% CIs of Change from Baseline in HBsAg 
(log10 IU/mL) by Visit (Observed Data) 
Full Analysis Set 
7.1 
Proportion of Subjects with ALT Normalization by Visit by 
Central Laboratory Normal Range: Missing = Failure 
Full Analysis Set 
7.2 
Proportion of Subjects with ALT Normalization by Visit by 
AASLD Normal Range: Missing = Failure 
Full Analysis Set 
8 
Mean and 95% CIs of Change from Baseline in ALT (U/L) 
(Observed Data) 
Full Analysis Set 
9 
Mean and 95% CIs of Change from Baseline in Fibrotest Score 
(Observed Data) 
Full Analysis Set 
10.1 
Median (Q1, Q3) of Change from Baseline in Fasting Total 
Cholesterol (mg/dL) by Visit 
Safety Analysis Set 
10.2 
Median (Q1, Q3) of Change from Baseline in Fasting Direct 
LDL (mg/dL) by Visit 
Safety Analysis Set 
10.3 
Median (Q1, Q3) of Change from Baseline in Fasting HDL 
(mg/dL) by Visit 
Safety Analysis Set 
10.4 
Median (Q1, Q3) of Change from Baseline in Fasting Total 
Cholesterol to HDL Ratio by Visit 
Safety Analysis Set 
10.5 
Median (Q1, Q3) of Change from Baseline in Fasting 
Triglycerides (mg/dL) by Visit 
Safety Analysis Set 
10.6 
Median (Q1, Q3) of Change from Baseline in Fasting Glucose 
(mg/dL) by Visit 
Safety Analysis Set 
11.1.1 
Median (Q1, Q3) of Percentage Change from Baseline in Hip 
Bone Mineral Density by Visit (Observed Data) 
Hip DXA Analysis Set 
11.1.2 
Median (Q1, Q3) of Percentage Change from Baseline in Spine 
Bone Mineral Density by Visit (Observed Data) 
Spine DXA Analysis Set 
11.2.1 
Mean and 95% CIs of Percentage Change from Baseline in Hip 
Bone Mineral Density by Visit (Observed Data) 
Hip DXA Analysis Set 


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Figure Number 
Title 
Analysis Set 
11.2.2 
Mean and 95% CIs of Percentage Change from Baseline in Spine 
Bone Mineral Density by Visit (Observed Data) 
Spine DXA Analysis Set 
12.1 
Median (Q1, Q3) of Percentage Change from Baseline in Serum 
C-type Collagen Sequence (CTX) by Visit 
Safety Analysis Set 
12.2 
Median (Q1, Q3) of Percentage Change from Baseline in Serum 
Bone Procollagen Type 1 N-terminal Propeptide (P1NP) by Visit 
Safety Analysis Set 
12.3 
Median (Q1, Q3) of Percentage Change from Baseline in Serum 
Parathyroid Hormone (PTH) by Visit 
Safety Analysis Set 
12.4 
Median (Q1, Q3) of Percentage Change from Baseline in 
Osteocalcin (OC) by Visit 
Safety Analysis Set 
12.5 
Median (Q1, Q3) of Percentage Change from Baseline in Bone 
Specific Alkaline Phosphatase (bsAP) by Visit 
Safety Analysis Set 
13.1 
Median (Q1, Q3) of Change from Baseline in Serum Creatinine 
(mg/dL) by Visit (Observed Data) 
Safety Analysis Set 
13.2 
Mean and 95% CIs of Change from Baseline in Serum Creatinine 
(mg/dL) by Visit (Observed Data) 
Safety Analysis Set 
14.1 
Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
Cockcroft-Gault (mL/min) by Visit 
Safety Analysis Set 
14.2 
Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
CKD-EPI Creatinine (mL/min/1.73 m^2) by Visit 
Safety Analysis Set 
15.1 
Median (Q1, Q3) of Percentage Change from Baseline in Urine 
RBP to Creatinine Ratio by Visit 
Safety Analysis Set 
15.2 
Median (Q1, Q3) of Percentage Change from Baseline in Urine 
Beta-2-Microglobulin to Creatinine Ratio by Visit 
Safety Analysis Set 
16.1 
Median (Q1, Q3) of Percentage Change from Baseline in Urine 
Protein to Creatinine Ratio (UPCR) by Visit 
Safety Analysis Set 
16.2 
Median (Q1, Q3) of Percentage Change from Baseline in Urine 
Albumin to Creatinine Ratio (UACR) by Visit 
Safety Analysis Set 
17 
Median (Q1, Q3) of Change from Baseline in TmP/GFR Ratio 
(mg/dL) by Visit 
Safety Analysis Set 
18 
Median (Q1, Q3) of Change from Baseline in Urine Fractional 
Excretion of Phosphate (FEPO4, %) by Visit 
Safety Analysis Set 
19 
Median (Q1, Q3) of Change from Baseline in Urine Fractional 
Excretion of Uric Acid (FEUA, %) by Visit 
Safety Analysis Set 
 


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Listing Number 
Title 
Analysis Set 
1 
Subject Profiles 
Randomized Analysis Set 
2 
Subject Disposition 
Randomized Analysis Set 
3.1 
Subjects Who Were Excluded from Analysis Sets 
Randomized Analysis Set 
3.2 
Subjects Who Were in the Full Analysis Set but Not in the 
PP Analysis Set  
Full Analysis Set 
4.1 
Enrollment  
Randomized Analysis Set 
4.2 
Eligibility Criteria Not Met 
Randomized Analysis Set 
4.3 
Enrollment Summary 
Subjects Not Enrolled 
5.1 
HBV DNA Stratification Discrepancies Between HBV DNA 
Stratum Entered into IWRS and Actual Screening HBV DNA 
Stratum 
Randomized Analysis Set 
5.2 
HBV DNA Level Classification Difference Between 
Randomization Stratum by Screening and Baseline HBV DNA 
Level 
Randomized Analysis Set 
6 
Subjects Who Received the Wrong Study Drug Treatment 
(Other Than That They Were Randomized to) 
Randomized Analysis Set 
7 
Demographics and Baseline Characteristics 
Randomized Analysis Set 
8.1 
Baseline Disease Characteristics (Part I) 
Randomized Analysis Set 
8.2 
Baseline Disease Characteristics (Part II) 
Randomized Analysis Set 
9 
Medical History 
Randomized Analysis Set 
10 
Risk Factors for HBV Infection 
Randomized Analysis Set 
11 
Prior HBV Medications 
Randomized Analysis Set 
12 
Study Drug Administration 
Randomized Analysis Set 
13 
Study Drug Accountability and Adherence 
Randomized Analysis Set 
14 
HBV DNA 
Randomized Analysis Set 
15 
Subjects with HBV DNA value above or at 29 IU/mL at 
Week 48 (or Last Visit if Prior to Week 48) 
Randomized Analysis Set 
16 
HBV Serology 
Randomized Analysis Set 
17 
Subjects with HBeAg Loss and/or HBeAg Seroconversion 
Randomized Analysis Set: 
Subjects with Serologically 
Evaluable Data 
18 
Subjects with HBsAg Loss and/or HBsAg Seroconversion 
Randomized Analysis Set: 
Subjects with Serologically 
Evaluable Data 
19 
Fibrosis Assessment by FibroTest® 
Randomized Analysis Set 
20 
All Adverse Events 
Randomized Analysis Set 
21 
Grade 3 and 4 Adverse Events 
Randomized Analysis Set 


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Listing Number 
Title 
Analysis Set 
22 
Serious Adverse Events 
Randomized Analysis Set 
23 
Study Drug-Related Serious Adverse Events 
Randomized Analysis Set 
24 
Adverse Events Leading to Premature Study Drug Discontinuation 
Randomized Analysis Set 
25 
Adverse Events Leading to Dose Modification or Study Drug 
Interruption 
Randomized Analysis Set 
26 
Death Report 
Randomized Analysis Set 
27 
Potential Uveitis Events 
Randomized Analysis Set 
28 
Potential Cardiovascular Events 
Randomized Analysis Set 
29 
Graded Laboratory Abnormalities 
Randomized Analysis Set 
30 
Grade 3 or 4 Laboratory Abnormalities 
Randomized Analysis Set 
31 
Laboratory Tests Related to Hepatic Function 
Randomized Analysis Set 
32 
Hepatic Ultrasound for Hepatocellular Carcinoma (HCC) 
Surveillance 
Randomized Analysis Set 
33 
ALT Elevation 
Randomized Analysis Set 
34.1 
Clinical Laboratory Data: Hematology (Part I) 
Randomized Analysis Set 
34.2 
Clinical Laboratory Data: Hematology (Part II) 
Randomized Analysis Set 
34.3 
Clinical Laboratory Data: Hematology (Part III) 
Randomized Analysis Set 
34.4 
Clinical Laboratory Data: Hematology (Part IV) 
Randomized Analysis Set 
35.1 
Clinical Laboratory Data: Chemistry (Part I) 
Randomized Analysis Set 
35.2 
Clinical Laboratory Data: Chemistry (Part II) 
Randomized Analysis Set 
35.3 
Clinical Laboratory Data: Chemistry (Part III) 
Randomized Analysis Set 
35.4 
Clinical Laboratory Data: Chemistry (Part IV) 
Randomized Analysis Set 
36 
Metabolic Assessment: Glucose and Lipid Panel 
Randomized Analysis Set 
37.1 
Clinical Laboratory Data: Urinalysis (Part I) 
Randomized Analysis Set 
37.2 
Clinical Laboratory Data: Urinalysis (Part II) 
Randomized Analysis Set 
37.3 
Clinical Laboratory Data: Urinalysis (Part III) 
Randomized Analysis Set 
38.1 
Clinical Laboratory Data: Urine Chemistry (Part I) 
Randomized Analysis Set 
38.2 
Clinical Laboratory Data: Urine Chemistry (Part II) 
Randomized Analysis Set 
39 
Clinical Laboratory Data: HAV/HCV/HDV/HEV/HIV Serology  
Randomized Analysis Set 
40 
Clinical Laboratory Data: Pregnancy Test 
Randomized Analysis Set 
41 
Reference Ranges for Laboratory Tests 
 
42.1 
Hip Bone Mineral Density Results 
Randomized Analysis Set: 
Subjects with Any 
Hip DXA Data 


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Listing Number 
Title 
Analysis Set 
42.2 
Spine Bone Mineral Density Results 
Randomized Analysis Set: 
Subjects with Any Spine 
DXA Data 
43.1 
Subjects with > 5% Decline in Hip Bone Mineral Density 
Randomized Analysis Set: 
Subjects with Any Hip 
DXA Data 
43.2 
Subjects with > 5% Decline in Spine Bone Mineral Density 
Randomized Analysis Set: 
Subjects with Any Spine 
DXA Data 
44.1 
Bone Biomarkers Results (Part I) 
Randomized Analysis Set 
44.2 
Bone Biomarkers Results (Part II) 
Randomized Analysis Set 
45 
Fracture Events 
Randomized Analysis Set 
46.1 
FRAX 10 Year Fracture Probabilities 
Randomized Analysis Set: 
Subjects with Any 
Hip DXA Data 
46.2 
FRAX Risk Assessment Questionnaire 
Randomized Analysis Set 
47 
Bone Events 
Randomized Analysis Set 
48 
Confirmed Renal Abnormalities 
Randomized Analysis Set 
49 
Serum Creatinine and Estimated Glomerular Filtration Rate 
(eGFR) 
Randomized Analysis Set 
50 
Subjects with eGFR < 50 (by CG, CKD-EPI Creatinine, or 
CKD-EPI Cystatin C) 
Randomized Analysis Set 
51 
Treatment-Emergent Proteinuria 
Randomized Analysis Set 
52.1 
Renal Biomarkers Results (Part I) 
Randomized Analysis Set 
52.2 
Renal Biomarkers Results (Part II) 
Randomized Analysis Set 
53.1 
Subjects with UPCR > 200 mg/g 
Randomized Analysis Set 
53.2 
Subjects with UACR ≥ 30 mg/g 
Randomized Analysis Set 
54 
Vital Signs  
Randomized Analysis Set 
55 
Concomitant Medications 
Randomized Analysis Set 
56 
12-Lead Electrocardiogram Results 
Randomized Analysis Set 
57 
Pregnancy Report 
Randomized Analysis Set 
58 
Cirrhosis Assessment 
Randomized Analysis Set 
59 
Hepatocellular Carcinoma Assessment 
Randomized Analysis Set 
60 
Alcohol Use 
Randomized Analysis Set 
 


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Appendix 2. 
Fracture Events 
The selected PTs of fracture events from SMQ of Osteoporosis/Osteopenia and HLGT of 
Fractures are listed as follows: 
 
Selected Preferred Terms 
Selection Type 
1 
Acetabulum fracture 
cSMQ+cHLGT  
2 
Ankle fracture 
cHLGT 
3 
Atypical femur fracture 
cSMQ+cHLGT  
4 
Atypical fracture 
cHLGT 
5 
Avulsion fracture 
cHLGT 
6 
Bone fissure 
cHLGT 
7 
Bone fragmentation 
cHLGT 
8 
Cervical vertebral fracture 
cSMQ+cHLGT  
9 
Chance fracture 
cHLGT 
10 
Clavicle fracture 
cHLGT 
11 
Closed fracture manipulation 
cSMQ 
12 
Comminuted fracture 
cHLGT 
13 
Complicated fracture 
cHLGT 
14 
Compression fracture 
cHLGT 
15 
Craniofacial fracture 
cHLGT 
16 
Epiphyseal fracture 
cHLGT 
17 
External fixation of fracture 
cSMQ 
18 
Facial bones fracture 
cHLGT 
19 
Femoral neck fracture 
cSMQ+cHLGT  
20 
Femur fracture 
cSMQ+cHLGT  
21 
Fibula fracture 
cHLGT 
22 
Flail chest 
cHLGT 
23 
Foot fracture 
cHLGT 
24 
Forearm fracture 
cSMQ+cHLGT  
25 
Fracture 
cSMQ+cHLGT  
26 
Fracture displacement 
cHLGT 
27 
Fracture of clavicle due to birth trauma 
cHLGT 
28 
Fracture treatment 
cSMQ 
29 
Fractured coccyx 
cHLGT 
30 
Fractured ischium 
cSMQ+cHLGT  
31 
Fractured sacrum 
cSMQ+cHLGT  
32 
Fractured skull depressed 
cHLGT 
33 
Greenstick fracture 
cHLGT 
34 
Hand fracture 
cHLGT 
35 
Hip fracture 
cSMQ+cHLGT  
36 
Humerus fracture 
cHLGT 


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Selected Preferred Terms 
Selection Type 
37 
Ilium fracture 
cSMQ+cHLGT  
38 
Impacted fracture 
cHLGT 
39 
Internal fixation of fracture 
cSMQ 
40 
Jaw fracture 
cHLGT 
41 
Limb fracture 
cHLGT 
42 
Lower limb fracture 
cHLGT 
43 
Lumbar vertebral fracture 
cSMQ+cHLGT  
44 
Multiple fractures 
cSMQ+cHLGT  
45 
Open fracture 
cHLGT 
46 
Open reduction of fracture 
cSMQ 
47 
Open reduction of spinal fracture 
cSMQ 
48 
Osteochondral fracture 
cHLGT 
49 
Osteoporotic fracture 
cSMQ+cHLGT  
50 
Patella fracture 
cHLGT 
51 
Pathological fracture 
cSMQ+cHLGT  
52 
Pelvic fracture 
cSMQ+cHLGT  
53 
Periprosthetic fracture 
cHLGT 
54 
Pubis fracture 
cSMQ+cHLGT  
55 
Radius fracture 
cSMQ+cHLGT  
56 
Rib fracture 
cSMQ+cHLGT  
57 
Sacroiliac fracture 
cSMQ+cHLGT  
58 
Scapula fracture 
cHLGT 
59 
Scapulothoracic dissociation 
cHLGT 
60 
Skull fracture 
cHLGT 
61 
Skull fractured base 
cHLGT 
62 
Spinal compression fracture 
cSMQ+cHLGT  
63 
Spinal fracture 
cSMQ+cHLGT  
64 
Sternal fracture 
cHLGT 
65 
Stress fracture 
cHLGT 
66 
Tartrate-resistant acid phosphatase decreased 
cSMQ 
67 
Thoracic vertebral fracture 
cSMQ+cHLGT  
68 
Tibia fracture 
cHLGT 
69 
Torus fracture 
cHLGT 
70 
Traumatic fracture 
cHLGT 
71 
Ulna fracture 
cHLGT 
72 
Upper limb fracture 
cHLGT 
73 
Vertebroplasty 
cSMQ 
74 
Wrist fracture 
cSMQ+cHLGT  
75 
Vertebral body replacement 
cSMQ 
 


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Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
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Appendix 3. 
Bone Events 
The selected PTs of bone events based on MedDRA 19.1 are listed as follows: 
 
Selected Preferred Terms 
1 
Costal cartilage fracture 
2 
Chronic kidney disease-mineral and bone disorder 
3 
Astragalectomy 
4 
Gluteoplasty 
5 
Rotationplasty 
6 
Orthoroentgenogram 
7 
Atypical femur fracture 
8 
Carpal collapse 
9 
Osteonecrosis 
10 
Osteonecrosis of external auditory canal 
11 
Osteonecrosis of jaw 
12 
Osteoradionecrosis 
13 
Abscess jaw 
14 
Abscess oral 
15 
Alveolar osteitis 
16 
Arthrodesis 
17 
Biopsy bone abnormal 
18 
Bone abscess 
19 
Bone debridement 
20 
Bone graft 
21 
Bone infarction 
22 
Bone loss 
23 
Bone pain 
24 
Bone scan abnormal 
25 
Candida osteomyelitis 
26 
Chronic recurrent multifocal osteomyelitis 
27 
Dental necrosis 
28 
Exposed bone in jaw 
29 
Face and mouth X-ray abnormal 
30 
Groin pain 


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CONFIDENTIAL 
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Selected Preferred Terms 
31 
Hip arthroplasty 
32 
Hip surgery 
33 
Jaw lesion excision 
34 
Jaw operation 
35 
Joint arthroplasty 
36 
Joint prosthesis user 
37 
Joint resurfacing surgery 
38 
Maxillofacial operation 
39 
Oral surgery 
40 
Osteitis 
41 
Osteoarthropathy 
42 
Osteomyelitis 
43 
Osteomyelitis acute 
44 
Osteomyelitis bacterial 
45 
Osteomyelitis blastomyces 
46 
Osteomyelitis chronic 
47 
Osteomyelitis drainage 
48 
Osteomyelitis fungal 
49 
Osteomyelitis salmonella 
50 
Osteomyelitis viral 
51 
Osteotomy 
52 
Pain in jaw 
53 
Periodontal destruction 
54 
Primary sequestrum 
55 
Resorption bone increased 
56 
Secondary sequestrum 
57 
Sequestrectomy 
58 
Staphylococcal osteomyelitis 
59 
Subperiosteal abscess 
60 
Tertiary sequestrum 
61 
Tooth abscess 
62 
Tooth infection 
63 
X-ray limb abnormal 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 70 
 
24 February 2017 
 
Selected Preferred Terms 
64 
X-ray of pelvis and hip abnormal 
65 
Bone density decreased 
66 
Bone formation decreased 
67 
Bone marrow oedema syndrome 
68 
Osteopenia 
69 
Osteoporosis 
70 
Osteoporosis postmenopausal 
71 
Osteoporotic fracture 
72 
Senile osteoporosis 
73 
Acetabulum fracture 
74 
Body height abnormal 
75 
Body height below normal 
76 
Body height decreased 
77 
Bone density abnormal 
78 
Bone formation test abnormal 
79 
Bone metabolism disorder 
80 
Bone resorption test abnormal 
81 
Cervical vertebral fracture 
82 
Closed fracture manipulation 
83 
C-telopeptide increased 
84 
Deoxypyridinoline urine increased 
85 
External fixation of fracture 
86 
Femoral neck fracture 
87 
Femur fracture 
88 
Forearm fracture 
89 
Fracture 
90 
Fracture treatment 
91 
Fractured ischium 
92 
Fractured sacrum 
93 
Hip fracture 
94 
Ilium fracture 
95 
Internal fixation of fracture 
96 
Kyphoscoliosis 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 71 
 
24 February 2017 
 
Selected Preferred Terms 
97 
Kyphosis 
98 
Lumbar vertebral fracture 
99 
Multiple fractures 
100 
N-telopeptide urine increased 
101 
Open reduction of fracture 
102 
Open reduction of spinal fracture 
103 
Osteocalcin increased 
104 
Osteoporosis prophylaxis 
105 
Pathological fracture 
106 
Pelvic fracture 
107 
Post-traumatic osteoporosis 
108 
Pubis fracture 
109 
Pyridinoline urine increased 
110 
Radius fracture 
111 
Rib fracture 
112 
Sacroiliac fracture 
113 
Spinal compression fracture 
114 
Spinal deformity 
115 
Spinal fracture 
116 
Tartrate-resistant acid phosphatase decreased 
117 
Thoracic vertebral fracture 
118 
Vertebral body replacement 
119 
Vertebroplasty 
120 
Wrist fracture 
121 
Wrist surgery 
122 
Ankle fracture 
123 
Atypical fracture 
124 
Avulsion fracture 
125 
Bone fissure 
126 
Bone fragmentation 
127 
Chance fracture 
128 
Clavicle fracture 
129 
Comminuted fracture 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 72 
 
24 February 2017 
 
Selected Preferred Terms 
130 
Complicated fracture 
131 
Compression fracture 
132 
Craniofacial fracture 
133 
Epiphyseal fracture 
134 
Facial bones fracture 
135 
Fibula fracture 
136 
Flail chest 
137 
Foot fracture 
138 
Fracture delayed union 
139 
Fracture displacement 
140 
Fracture malunion 
141 
Fracture nonunion 
142 
Fracture of clavicle due to birth trauma 
143 
Fractured coccyx 
144 
Fractured skull depressed 
145 
Greenstick fracture 
146 
Hand fracture 
147 
Humerus fracture 
148 
Impacted fracture 
149 
Jaw fracture 
150 
Limb fracture 
151 
Lower limb fracture 
152 
Open fracture 
153 
Osteochondral fracture 
154 
Patella fracture 
155 
Periprosthetic fracture 
156 
Pseudarthrosis 
157 
Scapula fracture 
158 
Scapulothoracic dissociation 
159 
Skull fracture 
160 
Skull fractured base 
161 
Spinal fusion fracture 
162 
Sternal fracture 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 73 
 
24 February 2017 
 
Selected Preferred Terms 
163 
Stress fracture 
164 
Tibia fracture 
165 
Torus fracture 
166 
Traumatic fracture 
167 
Ulna fracture 
168 
Upper limb fracture 
169 
Bone formation test 
170 
Bone resorption test 
171 
C-telopeptide 
172 
Deoxypyridinoline urine 
173 
N-telopeptide 
174 
N-telopeptide urine 
175 
N-telopeptide urine abnormal 
176 
N-telopeptide urine decreased 
177 
N-telopeptide urine normal 
178 
Osteocalcin 
179 
Osteocalcin decreased 
180 
Osteoprotegerin 
181 
Osteoprotegerin decreased 
182 
Osteoprotegerin increased 
183 
Osteoprotegerin ligand 
184 
Osteoprotegerin ligand decreased 
185 
Pyridinoline urine 
186 
Pyridinoline urine decreased 
187 
Tartrate-resistant acid phosphatase 
188 
Aneurysmal bone cyst 
189 
Bone callus excessive 
190 
Bone contusion 
191 
Bone cyst 
192 
Bone development abnormal 
193 
Bone disorder 
194 
Bone erosion 
195 
Bone fistula 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 74 
 
24 February 2017 
 
Selected Preferred Terms 
196 
Bone formation increased 
197 
Bone hyperpigmentation 
198 
Bone lesion 
199 
Callus formation delayed 
200 
Cemento osseous dysplasia 
201 
Dental alveolar anomaly 
202 
Dental cyst 
203 
Enostosis 
204 
Erdheim-Chester disease 
205 
Exostosis 
206 
Exostosis of external ear canal 
207 
Exostosis of jaw 
208 
Extraskeletal ossification 
209 
Hyperphosphatasaemia 
210 
Hypertrophic osteoarthropathy 
211 
Inadequate osteointegration 
212 
Jaw cyst 
213 
Jaw disorder 
214 
Medial tibial stress syndrome 
215 
Melorheostosis 
216 
Osteitis condensans 
217 
Osteitis deformans 
218 
Osteorrhagia 
219 
Osteosclerosis 
220 
Osteosis 
221 
Periosteal haematoma 
222 
Periostitis 
223 
Periostitis hypertrophic 
224 
Periostosis 
225 
Periprosthetic osteolysis 
226 
Post transplant distal limb syndrome 
227 
Radiation osteitis 
228 
Skeletal injury 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 75 
 
24 February 2017 
 
Selected Preferred Terms 
229 
Spinal column injury 
230 
Spinal disorder 
231 
Sternal injury 
232 
Vertebral column mass 
233 
Vertebral lesion 
234 
Vertebral wedging 
235 
Bone atrophy 
236 
Bone decalcification 
237 
Brown tumour 
238 
Craniotabes 
239 
Gorham's disease 
240 
Hereditary hypophosphataemic rickets 
241 
High turnover osteopathy 
242 
Hungry bone syndrome 
243 
Hypochondroplasia 
244 
Hypophosphataemic rickets 
245 
Low turnover osteopathy 
246 
Oncogenic osteomalacia 
247 
Osteolysis 
248 
Osteomalacia 
249 
Osteoporosis circumscripta cranii 
250 
Rachitic rosary 
251 
Resorption bone decreased 
252 
Rickets 
253 
Bone marrow oedema 
254 
Bone swelling 
255 
Coccydynia 
256 
Eagle's syndrome 
257 
Metatarsalgia 
258 
Os trigonum syndrome 
259 
Pubic pain 
260 
Spinal pain 
261 
Bone cyst excision 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 76 
 
24 February 2017 
 
Selected Preferred Terms 
262 
Bone electrostimulation therapy 
263 
Bone graft removal 
264 
Bone lesion excision 
265 
Bone operation 
266 
Bone prosthesis insertion 
267 
Bone trimming 
268 
Cementoplasty 
269 
Epiphyseal surgery 
270 
Epiphysiodesis 
271 
Orthopaedic procedure 
272 
Ostectomy 
273 
Osteopathic treatment 
274 
Osteosynthesis 
275 
Removal of epiphyseal fixation 
276 
Removal of internal fixation 
277 
Calcification metastatic 
278 
Calciphylaxis 
279 
Calcium deficiency 
280 
Calcium intoxication 
281 
Calcium metabolism disorder 
282 
Chondrocalcinosis pyrophosphate 
283 
Chvostek's sign 
284 
Dent's disease 
285 
Familial hypocalciuric hypercalcaemia 
286 
Hypercalcaemia 
287 
Hypercalcaemia of malignancy 
288 
Hypercalcaemic nephropathy 
289 
Hypercalcitoninaemia 
290 
Hypercalciuria 
291 
Hypocalcaemia 
292 
Hypocalcaemic seizure 
293 
Hypocalciuria 
294 
Hypoparathyroidism 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 77 
 
24 February 2017 
 
Selected Preferred Terms 
295 
Hypoparathyroidism secondary 
296 
Latent tetany 
297 
Periarthritis calcarea 
298 
Primary hypoparathyroidism 
299 
Pseudohypercalcaemia 
300 
Pseudohypoparathyroidism 
301 
Tetany 
302 
Tooth demineralisation 
303 
Trousseau's sign 
304 
Williams syndrome 
305 
Congenital syphilitic osteochondritis 
306 
Epiphyseal disorder 
307 
Epiphyseal injury 
308 
Epiphyses delayed fusion 
309 
Epiphyses premature fusion 
310 
Epiphysiolysis 
311 
Epiphysitis 
312 
Fracture debridement 
313 
Fracture reduction 
314 
Fractured maxilla elevation 
315 
Fractured zygomatic arch elevation 
316 
Intramedullary rod insertion 
317 
Skeletal traction 
318 
Surgical fixation of rib fracture 
319 
Radial head dislocation 
320 
Amputation 
321 
Arm amputation 
322 
Calcanectomy 
323 
Finger amputation 
324 
Finger repair operation 
325 
Foot amputation 
326 
Foot operation 
327 
Hand amputation 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 78 
 
24 February 2017 
 
Selected Preferred Terms 
328 
Hand repair operation 
329 
Hip disarticulation 
330 
Interscapulothoracic amputation 
331 
Leg amputation 
332 
Limb amputation 
333 
Limb immobilisation 
334 
Limb operation 
335 
Limb reattachment surgery 
336 
Limb reconstructive surgery 
337 
Metacarpal excision 
338 
Metatarsal excision 
339 
Microsurgery to hand 
340 
Talipes correction 
341 
Toe amputation 
342 
Toe operation 
343 
Trapezectomy 
344 
Alveolar bone resorption 
345 
Dwarfism 
346 
Osteodystrophy 
347 
Renal rickets 
348 
Aspiration bursa 
349 
Aspiration bursa abnormal 
350 
Aspiration bursa normal 
351 
Aspiration joint 
352 
Aspiration joint abnormal 
353 
Aspiration joint normal 
354 
Biopsy abdominal wall 
355 
Biopsy abdominal wall abnormal 
356 
Biopsy abdominal wall normal 
357 
Biopsy bone 
358 
Biopsy bone normal 
359 
Biopsy cartilage 
360 
Biopsy cartilage abnormal 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 79 
 
24 February 2017 
 
Selected Preferred Terms 
361 
Biopsy cartilage normal 
362 
Biopsy chest wall 
363 
Biopsy chest wall abnormal 
364 
Biopsy chest wall normal 
365 
Biopsy ligament 
366 
Biopsy ligament abnormal 
367 
Biopsy ligament normal 
368 
Biopsy muscle 
369 
Biopsy muscle abnormal 
370 
Biopsy muscle normal 
371 
Biopsy soft tissue 
372 
Biopsy tendon 
373 
Biopsy tendon abnormal 
374 
Biopsy tendon normal 
375 
Intervertebral disc biopsy 
376 
Synovial biopsy 
377 
Synovial biopsy abnormal 
378 
Synovial fluid cell count 
379 
Synovial fluid crystal 
380 
Synovial fluid crystal present 
381 
Synovial fluid red blood cells 
382 
Synovial fluid red blood cells positive 
383 
Synovial fluid white blood cells 
384 
Synovial fluid white blood cells positive 
385 
Arthrogram 
386 
Arthrogram abnormal 
387 
Arthrogram normal 
388 
Arthroscopy 
389 
Arthroscopy abnormal 
390 
Arthroscopy normal 
391 
Bone densitometry 
392 
Bone density increased 
393 
Bone scan 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 80 
 
24 February 2017 
 
Selected Preferred Terms 
394 
Bone scan normal 
395 
Discogram 
396 
Discogram abnormal 
397 
Discogram normal 
398 
Face and mouth X-ray 
399 
Face and mouth X-ray normal 
400 
Skeletal survey 
401 
Skeletal survey abnormal 
402 
Skeletal survey normal 
403 
Skull X-ray 
404 
Skull X-ray abnormal 
405 
Skull X-ray normal 
406 
Spinal X-ray 
407 
Spinal X-ray abnormal 
408 
Spinal X-ray normal 
409 
Ultrasound joint 
410 
X-ray limb 
411 
X-ray limb normal 
412 
X-ray of pelvis and hip 
413 
X-ray of pelvis and hip normal 
414 
Acute phosphate nephropathy 
415 
Hyperphosphataemia 
416 
Hyperphosphaturia 
417 
Hypophosphataemia 
418 
Phosphorus metabolism disorder 
419 
Pseudohyperphosphataemia 
420 
Dislocation of vertebra 
421 
Intervertebral disc injury 
422 
Ankle arthroplasty 
423 
Ankle operation 
424 
Arthrectomy 
425 
Arthrolysis 
426 
Arthroscopic surgery 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 81 
 
24 February 2017 
 
Selected Preferred Terms 
427 
Arthrotomy 
428 
Baker's cyst excision 
429 
Bone groove deepening 
430 
Bunion operation 
431 
Capsulorrhaphy 
432 
Delayed spinal fusion 
433 
Elbow operation 
434 
Incomplete spinal fusion 
435 
Knee arthroplasty 
436 
Knee operation 
437 
Ligament operation 
438 
Maxillonasal dysplasia 
439 
Meniscus operation 
440 
Meniscus removal 
441 
Patella replacement 
442 
Patellectomy 
443 
Radiolucency around implant 
444 
Radiotherapy to joint 
445 
Removal of foreign body from joint 
446 
Rheumatoid nodule removal 
447 
Rotator cuff repair 
448 
Shoulder arthroplasty 
449 
Shoulder operation 
450 
Synovectomy 
451 
Synoviorthesis 
452 
Temporomandibular joint surgery 
453 
Tophus removal operation 
 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 82 
 
24 February 2017 
Appendix 4. 
Potential Uveitis 
The selected PTs of potential uveitis from SOC of Eye Disorders are listed as follows: 
 
Selected Preferred Terms 
1 
Homonymous diplopia 
2 
Keratic precipitates 
3 
Retinal thickening 
4 
Vitreous haze 
5 
Acute zonal occult outer retinopathy 
6 
Anterior chamber cell 
7 
Anterior chamber fibrin 
8 
Anterior chamber flare 
9 
Anterior chamber inflammation 
10 
Aqueous fibrin 
11 
Autoimmune retinopathy 
12 
Autoimmune uveitis 
13 
Behcet's syndrome 
14 
Birdshot chorioretinopathy 
15 
Blau syndrome 
16 
Blindness 
17 
Blindness transient 
18 
Blindness unilateral 
19 
Chemical iritis 
20 
Chorioretinitis 
21 
Chorioretinopathy 
22 
Choroiditis 
23 
Ciliary hyperaemia 
24 
Cogan's syndrome 
25 
Cyclitic membrane 
26 
Cyclitis 
27 
Cystoid macular oedema 
28 
Cytomegalovirus chorioretinitis 
29 
Eales' disease 
30 
Endophthalmitis 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 83 
 
24 February 2017 
 
Selected Preferred Terms 
31 
Exudative retinopathy 
32 
Eye inflammation 
33 
Fuchs' syndrome 
34 
Glaucomatocyclitic crises 
35 
Hypopyon 
36 
Hypotony of eye 
37 
IRVAN syndrome 
38 
Infectious iridocyclitis 
39 
Iridocyclitis 
40 
Iritis 
41 
Koeppe nodules 
42 
Macular oedema 
43 
Necrotising retinitis 
44 
Non-infectious endophthalmitis 
45 
Noninfective chorioretinitis 
46 
Noninfective retinitis 
47 
Ocular lymphoma 
48 
Ocular sarcoidosis 
49 
Ocular toxicity 
50 
Ocular vasculitis 
51 
Optic discs blurred 
52 
Panophthalmitis 
53 
Photophobia 
54 
Photopsia 
55 
Retinal exudates 
56 
Retinal oedema 
57 
Retinal perivascular sheathing 
58 
Retinal pigment epitheliopathy 
59 
Retinal toxicity 
60 
Retinal vasculitis 
61 
Retinitis 
62 
Subretinal fluid 
63 
Sudden visual loss 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 84 
 
24 February 2017 
 
Selected Preferred Terms 
64 
Susac's syndrome 
65 
Sympathetic ophthalmia 
66 
Traumatic iritis 
67 
Tubulointerstitial nephritis and uveitis syndrome 
68 
Uveitic glaucoma 
69 
Uveitis 
70 
Uveitis-glaucoma-hyphaema syndrome 
71 
Vision blurred 
72 
Visual acuity reduced 
73 
Visual acuity reduced transiently 
74 
Visual field defect 
75 
Visual impairment 
76 
Vitreal cells 
77 
Vitreous fibrin 
78 
Vitreous floaters 
79 
Vitreous opacities 
80 
Vitritis 
81 
Vogt-Koyanagi-Harada syndrome 
 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 85 
 
24 February 2017 
Appendix 5. 
Potential Cardiovascular or Cerebrovascular Events 
 
Selected Preferred Terms 
1 
Amaurosis fugax 
2 
Basal ganglia infarction 
3 
Basal ganglia stroke 
4 
Basilar artery occlusion 
5 
Basilar artery stenosis 
6 
Basilar artery thrombosis 
7 
Brachiocephalic arteriosclerosis 
8 
Brachiocephalic artery occlusion 
9 
Brachiocephalic artery stenosis 
10 
Brain hypoxia 
11 
Brain stem embolism 
12 
Brain stem infarction 
13 
Brain stem ischaemia 
14 
Brain stem stroke 
15 
Brain stem thrombosis 
16 
Capsular warning syndrome 
17 
Carotid angioplasty 
18 
Carotid arterial embolus 
19 
Carotid arteriosclerosis 
20 
Carotid artery bypass 
21 
Carotid artery calcification 
22 
Carotid artery disease 
23 
Carotid artery insufficiency 
24 
Carotid artery occlusion 
25 
Carotid artery restenosis 
26 
Carotid artery stenosis 
27 
Carotid artery stent insertion 
28 
Carotid artery stent removal 
29 
Carotid artery thrombosis 
30 
Carotid endarterectomy 
31 
Carotid revascularisation 
32 
Cerebellar artery occlusion 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 86 
 
24 February 2017 
 
Selected Preferred Terms 
33 
Cerebellar artery thrombosis 
34 
Cerebellar embolism 
35 
Cerebellar infarction 
36 
Cerebellar ischaemia 
37 
Cerebral arteriosclerosis 
38 
Cerebral artery embolism 
39 
Cerebral artery occlusion 
40 
Cerebral artery restenosis 
41 
Cerebral artery stenosis 
42 
Cerebral artery thrombosis 
43 
Cerebral gas embolism 
44 
Cerebral infarction 
45 
Cerebral infarction foetal 
46 
Cerebral ischaemia 
47 
Cerebral microembolism 
48 
Cerebral revascularisation 
49 
Cerebral septic infarct 
50 
Cerebral small vessel ischaemic disease 
51 
Cerebral thrombosis 
52 
Cerebral vascular occlusion 
53 
Cerebral vasoconstriction 
54 
Cerebral venous thrombosis 
55 
Cerebrovascular accident 
56 
Cerebrovascular disorder 
57 
Cerebrovascular insufficiency 
58 
Cerebrovascular stenosis 
59 
Delayed ischaemic neurological deficit 
60 
Embolic cerebral infarction 
61 
Embolic stroke 
62 
Hypoxic-ischaemic encephalopathy 
63 
Inner ear infarction 
64 
Ischaemic cerebral infarction 
65 
Ischaemic stroke 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 87 
 
24 February 2017 
 
Selected Preferred Terms 
66 
Lacunar infarction 
67 
Lacunar stroke 
68 
Lateral medullary syndrome 
69 
Migrainous infarction 
70 
Millard-Gubler syndrome 
71 
Moyamoya disease 
72 
Perinatal stroke 
73 
Post cardiac arrest syndrome 
74 
Post procedural stroke 
75 
Precerebral arteriosclerosis 
76 
Precerebral artery occlusion 
77 
Reversible cerebral vasoconstriction syndrome 
78 
Reversible ischaemic neurological deficit 
79 
Spinal artery embolism 
80 
Spinal artery thrombosis 
81 
Stroke in evolution 
82 
Subclavian steal syndrome 
83 
Thalamic infarction 
84 
Thrombotic cerebral infarction 
85 
Thrombotic stroke 
86 
Transient ischaemic attack 
87 
Vascular encephalopathy 
88 
Vascular stent occlusion 
89 
Vascular stent restenosis 
90 
Vascular stent stenosis 
91 
Vertebral artery occlusion 
92 
Vertebral artery stenosis 
93 
Vertebral artery thrombosis 
94 
Vertebrobasilar insufficiency 
95 
Angina pectoris 
96 
Angina unstable 
97 
Anginal equivalent 
98 
Arteriosclerosis coronary artery 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 88 
 
24 February 2017 
 
Selected Preferred Terms 
99 
Arteriospasm coronary 
100 
Coronary angioplasty 
101 
Coronary arterial stent insertion 
102 
Coronary artery bypass 
103 
Coronary artery disease 
104 
Coronary artery dissection 
105 
Coronary artery insufficiency 
106 
Coronary artery restenosis 
107 
Coronary artery stenosis 
108 
Coronary brachytherapy 
109 
Coronary bypass stenosis 
110 
Coronary endarterectomy 
111 
Coronary no-reflow phenomenon 
112 
Coronary ostial stenosis 
113 
Coronary revascularisation 
114 
Coronary vascular graft stenosis 
115 
Dissecting coronary artery aneurysm 
116 
ECG signs of myocardial ischaemia 
117 
External counterpulsation 
118 
Haemorrhage coronary artery 
119 
Ischaemic cardiomyopathy 
120 
Ischaemic mitral regurgitation 
121 
Microvascular coronary artery disease 
122 
Myocardial ischaemia 
123 
Percutaneous coronary intervention 
124 
Prinzmetal angina 
125 
Stress cardiomyopathy 
126 
Subclavian coronary steal syndrome 
127 
Subendocardial ischaemia 
128 
Arteriogram coronary abnormal 
129 
Cardiac stress test abnormal 
130 
Cardiopulmonary exercise test abnormal 
131 
Computerised tomogram coronary artery abnormal 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 89 
 
24 February 2017 
 
Selected Preferred Terms 
132 
Electrocardiogram ST segment depression 
133 
Electrocardiogram ST-T segment abnormal 
134 
Electrocardiogram ST-T segment depression 
135 
Electrocardiogram T wave abnormal 
136 
Electrocardiogram T wave inversion 
137 
Exercise electrocardiogram abnormal 
138 
Exercise test abnormal 
139 
Post angioplasty restenosis 
140 
Stress echocardiogram abnormal 
141 
Vascular stent restenosis 
142 
Vascular stent stenosis 
143 
Acute coronary syndrome 
144 
Acute myocardial infarction 
145 
Angina unstable 
146 
Blood creatine phosphokinase MB abnormal 
147 
Blood creatine phosphokinase MB increased 
148 
Coronary artery embolism 
149 
Coronary artery occlusion 
150 
Coronary artery reocclusion 
151 
Coronary artery thrombosis 
152 
Coronary bypass thrombosis 
153 
Coronary vascular graft occlusion 
154 
Kounis syndrome 
155 
Myocardial infarction 
156 
Myocardial necrosis 
157 
Myocardial reperfusion injury 
158 
Myocardial stunning 
159 
Papillary muscle infarction 
160 
Post procedural myocardial infarction 
161 
Postinfarction angina 
162 
Silent myocardial infarction 
163 
Troponin I increased 
164 
Troponin increased 


TAF 
GS-US-320-0108 Week 48 China Analysis 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 90 
 
24 February 2017 
 
Selected Preferred Terms 
165 
Troponin T increased 
166 
Blood creatine phosphokinase abnormal 
167 
Blood creatine phosphokinase increased 
168 
Cardiac ventricular scarring 
169 
ECG electrically inactive area 
170 
ECG signs of myocardial infarction 
171 
Electrocardiogram Q wave abnormal 
172 
Electrocardiogram ST segment abnormal 
173 
Electrocardiogram ST segment elevation 
174 
Electrocardiogram ST-T segment elevation 
175 
Infarction 
176 
Myocardial necrosis marker increased 
177 
Scan myocardial perfusion abnormal 
178 
Vascular graft occlusion 
179 
Vascular stent occlusion 
180 
Vascular stent thrombosis 
 

SAP_004.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg Negative, Chronic Hepatitis B
Name of Test Drug:
Tenofovir Alafenamide (TAF)
Study Number:
GS-US-320-0108
Protocol Version:
Amendment 3.4
Protocol Date:
25 September 2019
Analysis Type:
Final Analysis China
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
20 December 2023
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


TAF
GS-US-320-0108 Final China
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 2
20 December 2023
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF IN-TEXT TABLES .........................................................................................................................................4
LIST OF ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................8
1.1.
Study Objectives........................................................................................................................................9
1.2.
Study Design ...........................................................................................................................................10
1.2.1.
Design Configuration and Participant Population.................................................................10
1.2.2.
Treatment Groups..................................................................................................................10
1.2.3.
Key Eligibility Criteria..........................................................................................................11
1.2.4.
Study Periods/Phases.............................................................................................................11
1.2.5.
Schedule of Assessments.......................................................................................................11
1.2.6.
Randomization.......................................................................................................................12
1.2.7.
Site and/or Stratum Enrollment Limits..................................................................................13
1.2.8.
Study Duration.......................................................................................................................13
1.3.
Sample Size and Power ...........................................................................................................................13
2.
TYPE OF PLANNED ANALYSIS......................................................................................................................15
2.1.
Data Monitoring Committee (DMC) Analysis........................................................................................15
2.2.
Week 48 Analysis (Primary Analysis) ....................................................................................................15
2.3.
Final Analysis (Week 384)......................................................................................................................15
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................16
3.1.
Analysis Sets ...........................................................................................................................................16
3.1.1.
Randomized Analysis Set......................................................................................................16
3.1.2.
Safety Analysis Set................................................................................................................16
3.1.3.
Open-Label Safety Analysis Set............................................................................................16
3.1.4.
Full Analysis Set (FAS).........................................................................................................16
3.1.5.
Serologically Evaluable Full Analysis Set for HBsAg 
Loss/Seroconversion .............................................................................................................16
3.1.6.
DXA Analysis Set .................................................................................................................17
3.2.
Participant Grouping ...............................................................................................................................17
3.3.
Strata and Covariates...............................................................................................................................17
3.4.
Missing Data and Outliers.......................................................................................................................18
3.4.1.
Missing Data..........................................................................................................................18
3.4.2.
Outliers ..................................................................................................................................18
3.5.
Data Handling Conventions and Transformations ..................................................................................18
3.6.
Analysis Windows...................................................................................................................................19
3.6.1.
Definition of Study Day 1 and Other Definitions .................................................................19
3.6.2.
Analysis Windows.................................................................................................................21
3.6.3.
Selection of Data in the Event of Multiple Records in a Window ........................................28
4.
PARTICIPANT DISPOSITION ..........................................................................................................................30
4.1.
Participant Enrollment.............................................................................................................................30
4.2.
Disposition of Participants ......................................................................................................................30
4.3.
Extent of Exposure ..................................................................................................................................31
4.3.1.
Duration of Exposure to Blinded Study Drug .......................................................................31
4.3.2.
Adherence with Blinded Study Drug Regimen.....................................................................32
4.3.3.
Duration of Exposure to Open-Label Study Drug.................................................................33


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4.3.4.
Adherence with Open-Label Study Drug Regimen...............................................................33
4.4.
Protocol Deviations .................................................................................................................................34
4.5.
Assessment of COVID-19 Impact...........................................................................................................34
4.5.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................34
4.5.2.
Protocol Deviations Due to COVID-19 ................................................................................34
4.5.3.
Missed and Virtual Visits due to COVID-19 ........................................................................34
4.5.4.
Adverse Events Due to COVID-19 .......................................................................................35
4.5.5.
Overall Assessment of COVID-19 Pandemic Impact...........................................................35
5.
BASELINE CHARACTERISTICS .....................................................................................................................36
5.1.
Demographics and Baseline Characteristics ...........................................................................................36
5.2.
Medical History.......................................................................................................................................37
6.
EFFICACY ANALYSES.....................................................................................................................................38
6.1.
Primary Efficacy Endpoints ....................................................................................................................38
6.2.
Secondary Efficacy Endpoints ................................................................................................................38
6.2.1.
Definition of Secondary Efficacy Endpoints.........................................................................38
6.2.2.
Analysis Methods for Secondary Efficacy End points..........................................................40
6.3.
Changes From Protocol-Specified Efficacy Analyses ............................................................................40
7.
SAFETY ANALYSES.........................................................................................................................................41
7.1.
Adverse Events........................................................................................................................................41
7.1.1.
Adverse Event Dictionary .....................................................................................................41
7.1.2.
Adverse Event Severity .........................................................................................................41
7.1.3.
Relationship of AEs to Study Drug.......................................................................................41
7.1.4.
Relationship of AEs to Study Procedure...............................................................................41
7.1.5.
Serious AEs ...........................................................................................................................42
7.1.6.
Treatment-Emergent AEs......................................................................................................42
7.1.7.
Summaries of AEs and Deaths..............................................................................................43
7.1.8.
Potential Uveitis Events ........................................................................................................45
7.1.9.
Potential Cardiovascular Events............................................................................................45
7.2.
Laboratory Evaluations ...........................................................................................................................46
7.2.1.
Summaries of Numeric Laboratory Results ..........................................................................46
7.2.2.
Graded Laboratory Values ....................................................................................................47
7.2.3.
ALT Elevation.......................................................................................................................49
7.3.
Bone Safety Analyses..............................................................................................................................49
7.3.1.
Bone Mineral Density (BMD)...............................................................................................49
7.3.2.
Bone Biomarkers...................................................................................................................50
7.3.3.
Fracture Events......................................................................................................................50
7.3.4.
Bone Events...........................................................................................................................51
7.4.
Renal Safety Analyses.............................................................................................................................51
7.4.1.
Confirmed Renal Abnormalities............................................................................................51
7.4.2.
Serum Creatinine...................................................................................................................51
7.4.3.
Estimated Glomerular Filtration Rate ...................................................................................52
7.4.4.
Treatment-Emergent Proteinuria (Dipstick)..........................................................................53
7.4.5.
Urine Creatinine, Urine RBP to Creatinine Ratio and 
Beta-2-Microglobulin to Creatinine Ratio ............................................................................54
7.4.6.
Proteinuria by Quantitative Assessment................................................................................54
7.4.7.
Other Renal Biomarkers........................................................................................................54
7.5.
Ophthalmologic Assessment ...................................................................................................................55
7.6.
Body Weight............................................................................................................................................55
7.7.
Prior Hepatitis B Medications .................................................................................................................55
7.8.
Concomitant Medications........................................................................................................................55
7.9.
Electrocardiogram (ECG) Results...........................................................................................................57


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7.10.
Other Safety Measures ............................................................................................................................57
7.11.
Changes From Protocol-Specified Safety Analyses................................................................................57
8.
REFERENCES.....................................................................................................................................................58
9.
SOFTWARE.........................................................................................................................................................59
10.
SAP REVISION...................................................................................................................................................60
11.
APPENDICES......................................................................................................................................................61
Appendix 1.
Adverse Events of COVID-19.................................................................................................62
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19...................................................63
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and Liver 
Function Tests, Urinalysis, Urine Pregnancy Test, eGFR (by CG and CKD-EPI), 
UACR, UPCR, TmP/GFR, FEPO4, FEUA, Weight, and Vital Sign Assessments ................22
Table 3-2.
Analysis Windows for Safety ECG and Fibrotest...................................................................23
Table 3-3.
Analysis Windows for BMD Results from DXA and Fasting Lipid Panel.............................23
Table 3-4.
Analysis Windows for Serum HBsAg (Quantitative) and HBV Serology..............................24
Table 3-5.
Analysis Windows for Fasting Glucose, Fasting Total Cholesterol, Fasting 
Triglycerides, Renal, and Bone Biomarkers............................................................................25
Table 3-6.
Analysis Windows for PTH.....................................................................................................26
Table 3-7.
Analysis Windows for Hepatic Ultrasound.............................................................................27
Table 3-8.
Analysis Windows for Post-Treatment Assessments Except HBV Serology .........................27
Table 3-9.
Analysis Windows for Post-Treatment HBV Serology...........................................................28
Table 7-1.
Normal, Osteopenia, and Osteoporosis as Defined by T-Score ..............................................50
Table 7-2.
Method of Serum Creatinine Correction .................................................................................52
Table 11-1.
Example Search Terms for “COVID-19” and “Virtual” Used to Identify 
Missed/Virtual Visits...............................................................................................................63


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LIST OF ABBREVIATIONS
AASLD
American Association for the Study of Liver Diseases
AE
adverse event
ALT
alanine aminotransferase (SGPT)
ANCOVA
analysis of covariance
ANOVA
analysis of variance
Anti-HBe
antibody to HBeAg
Anti-HBs
antibody to HBsAg
AST
aspartate aminotransferase (SGOT)
BLQ
below the limit of quantitation
BMD
bone mineral density
BMI
body mass index
bsAP
bone specific alkaline phosphatase
CDER
Center for Drug Evaluation and Research
CG
Cockcroft-Gault
CHB
chronic hepatitis B
CI
confidence interval
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration formula for calculating 
glomerular filtration rate
CLCr
creatinine clearance
CMH
Cochran-Mantel-Haenszel 
CRF
case report form
CTX
c-type collagen sequence
CV
coefficient of variation
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DXA
dual-energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
eGFR
estimated glomerular filtration rate
ESDD
early study drug discontinuation
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEPO4
fractional excretion of filtered phosphate
FEUA
fractional excretion of uric acid
GFR
glomerular filtration rate
Gilead
Gilead Sciences, Inc.
HBeAb
hepatitis B e antibody


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HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high density lipoprotein
HDV
hepatitis D virus
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
IVRS
interactive voice response system
IWRS
interactive web response system
LDL
low density lipoprotein
LLN
lower limit of the normal range
LLT
lower-level term
LOCF
last observation carried forward
M = E 
missing = excluded
M = F 
missing = failure
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mantel-Haenszel 
OC
osteocalcin
P1NP
procollagen type 1 N-terminal propeptide
PBMC
peripheral blood mononuclear cell
PK
pharmacokinetic
pol/RT
polymerase/reverse transcriptase
PT
preferred term
Q
quartile
Q1
first quartile
Q3
third quartile
QD
QD
RBP
retinol binding protein
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TAF
tenofovir alafenamide 
TDF
tenofovir disoproxil fumarate (Viread®)
TFFU
Treatment-free Follow-up


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TFLs
tables, figures, and listings
TFV
Tenofovir
TFV-DP
tenofovir-diphosphate
TmP
tubular maximum reabsorption rate of phosphate
UACR
urine albumin to creatinine ratio
ULN
upper limit of normal
UPCR
urine protein to creatinine ratio
WHO
World Health Organization


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1.
INTRODUCTION
GS-US-320-0108 is a randomized, double-blind, noninferiority study to compare the antiviral 
activity of tenofovir alafenamide (TAF) 25 mg QD versus tenofovir disoproxil fumarate (TDF) 
300 mg QD for the treatment of hepatitis B e antigen (HBeAg)-negative, chronic hepatitis B 
(CHB) in treatment naive and treatment-experienced participants. For the non-China cohort, 
426 participants were planned to be randomized in a 2:1 ratio to receive the blinded treatment 
for 144 weeks (96 weeks for participants who reached Week 96 prior to consenting for 
Amendment 3), and were stratified by plasma hepatitis B virus (HBV) DNA level 
(< 7 log10 IU/mL, ≥ 7 log10 IU/mL < 8 log10 IU/mL, ≥ 8 log10 IU/mL ) and oral antiviral 
treatment status (treatment-naive vs treatment-experienced). All participants who completed the 
double-blind phase were eligible for participation in the open-label TAF 25 mg extension period 
for an additional 240 weeks (through Week 384/ED). Participants who already entered the 
open-label phase at Week 96 per Amendment 1 or 2 and consented to Amendment 3 later were 
to continue open-label TAF 25 mg QD through Week 384/ED.
Treatment-naive participants are defined as participants with < 12 weeks of previous oral 
antiviral treatment with any nucleoside or nucleotide analogue. Treatment-experienced 
participants are defined as participants with ≥ 12 weeks of previous treatment with any 
nucleoside or nucleotide analogue.
For China, approximately 150 additional participants (100 in TAF group and 50 in TDF group) 
were planned to be enrolled as agreed upon for local registration purposes. All China cohort 
participants were to receive the blinded treatment for 144 weeks based on Amendment 3.1, and 
those who completed the double-blind phase were eligible for participation in the open-label 
TAF 25 mg extension period for an additional 240 weeks (through Week 384/ED).
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the final clinical study report 
(CSR) for China (participants enrolled China only). This SAP is based on the study protocol 
amendment 3.4 dated 25 September 2019 and the electronic case report form (eCRF). The SAP 
will be finalized before database finalization. Any changes made after the finalization of the SAP 
will be documented in the CSR for China.


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1.1.
Study Objectives
The primary and secondary objectives and end points on or before Week 48 were presented in 
the Week 48 CSR for China. This SAP will focus on the efficacy and safety analyses of all 
participants after Week 48.
The primary objectives of this study are as follows:
•
To compare the efficacy of TAF 25 mg versus TDF 300 mg QD for the treatment of 
HBeAg-negative, CHB at Week 48 in treatment-naive and treatment experienced 
participants. The primary efficacy parameter is the proportion of participants with plasma 
HBV DNA levels below 29 IU/mL.
•
To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg- negative, CHB at Week 48 in treatment-naive and 
treatment-experienced participants
The key secondary safety objectives of this study are as follows:
•
To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine bone mineral density (BMD) at Week 48 
•
To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
•
To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by 
treatment-emergent proteinuria through Week 48
Other secondary objectives of this study are as follows:
•
To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, CHB in regard to the proportion of participants with plasma HBV DNA 
levels below 29 IU/mL at Weeks 96 and 144
•
To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, CHB in regard to the proportion of participants with plasma HBV DNA 
levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144
•
To compare the biochemical (alanine aminotransferase [ALT] normalization) response of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, CHB at 
Weeks 48, 96, and 144
•
To compare the serological response (loss of hepatitis B surface antigen [HBsAg] with 
seroconversion to anti-HBs) of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
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•
To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, CHB at Weeks 48, 96, and 144
•
To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144
•
To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QDat Weeks 24, 48, 72, 96, and 144 in a 
subset of participants
•
To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMCs) in participants receiving TAF or TDF
•
To evaluate the comparative open-label efficacy, safety and drug resistance mutations of 
TAF 25 mg QD from Week 144 (Amendment 3.1) through Week 384 in participants initially 
randomized to TAF 25mg QD and in participants sequentially treated with TDF 300 mg QD 
for 144 weeks and then switched to open label TAF 25 mg QD
•
To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, CHB beyond Week 48 during the double-blind phase in 
treatment-naive and treatment-experienced participants
1.2.
Study Design
1.2.1.
Design Configuration and Participant Population
GS-US-320-0108 is a randomized, double-blind, noninferiority study to compare the antiviral 
activity of TAF 25 mg versus TDF 300 mg for the treatment of HBeAg-negative, CHB in 
treatment-naive and treatment-experienced participants.
1.2.2.
Treatment Groups
Participants were randomized in a 2:1 ratio to the following 2 treatment groups:
•
TAF group: TAF 25 mg QD + matched placebo of TDF 300 mg QD
•
TDF group: TDF 300 mg QD + matched placebo of TAF 25 mg QD
For China, approximately 150 additional participants were planned to be randomized in a 
2:1 ratio (TAF: TDF) to the treatment groups for local registration purpose.


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1.2.3.
Key Eligibility Criteria
Participants were to have met the following key eligibility criteria:
•
Documented evidence of chronic HBV infection (eg, HBsAg positive for more than 
6 months)
•
HBeAg-negative, CHB with the following: HBeAg-negative and HBeAb-positive at 
screening; screening HBV DNA ≥ 2 × 104 IU/mL; screening serum ALT level > 60 U/L 
(males) or > 38 U/L (females) and ≤ 10 × ULN (by central laboratory range)
•
Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault [CG] 
method) based on serum creatinine and actual body weight as measured at screening
1.2.4.
Study Periods/Phases
The duration of randomized, double-blind treatment is 144 weeks (under Amendments 3.1). All 
participants who complete double-blind phase are eligible for participation in the open-label TAF 
25 mg extension period for an additional 240 weeks (through Week 384/ED). All China cohort 
participants were to receive the blinded treatment for 144 weeks based on Amendment 3.1, and 
no participant in China entered the open-label phase at Week 96. All participants who complete 
double-blind period of treatment are eligible for participation in the open-label TAF 25 mg QD 
extension period. Participants who permanently discontinue study drug (either prematurely [early 
discontinuation, ED] or at the end of open-label phase [Week 384]) for reasons other than 
HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 
weeks off treatment or until initiation of alternative, commercially available HBV therapy, 
whichever occurs first.
Participants with HBsAg loss, with confirmed seroconversion to anti-HBs should discontinue 
study drug within 3-6 months following confirmation of seroconversion to anti-HBs, or after 
Week 48, if seroconversion occurs prior to this visit. Participants with HBsAg loss with 
confirmed seroconversion to anti-HBs prior to Week 48 are not permitted to discontinue study 
drug prior to the Week 48 visit. After Week 48, these participants who discontinue study drug 
will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule 
through Week 384/ED. Discontinuation of study drug for participants experiencing HBsAg loss 
with confirmed seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, 
should be considered on a case by case basis.
1.2.5.
Schedule of Assessments
Laboratory analyses (serum chemistry, liver tests, hematology, urinalysis, plasma HBV DNA 
levels, pregnancy testing [for females of childbearing potential]), vital signs, adverse events 
(AEs), and concomitant medications will be performed at screening, baseline, and every 4 weeks 
thereafter through Week 48, every 8 weeks through Week 96, every 12 weeks through 
Week 144, and every 24 weeks through Week 384/ED visit. 


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HBV serology (HBeAg, reflex hepatitis B e antibody [HBeAb], HBsAg, and reflex hepatitis B 
surface antibody [HbsAb]) will be performed at screening and baseline, and HBsAg and reflex 
HBsAb will be performed every 12 to 16 weeks through Week 144, and every 24 weeks through 
Week 384/ED, and at Follow up Weeks 12 and 24. Quantitative serum HBsAg will be assessed 
at screening, baseline, every 12-16 weeks until Week 144, every 24 weeks until Week 384/ED, 
and at all Follow Up visits. Bone and renal biomarker testing will be performed at baseline and 
then at defined intervals throughout the study. IL28B polymorphism genotype, HBV genotyping 
and vitamin D assessments will be performed at baseline only. FibroTest® will be performed at 
baseline, and every 48 weeks thereafter through Week 384/ED. Fasting metabolic assessments 
(fasting glucose and lipid panel) will be conducted at baseline, every 24 weeks until Week 144, 
and every 48 weeks until Week 384/ED visit. 
Complete physical examinations will be performed at screening, baseline, and Weeks 24, 48, 
72, 96, 120, 144, 240, and 384/ED. Symptom directed physical examinations including body 
weight assessment will be conducted at all other visits. Electrocardiogram (ECG) will be 
performed at screening and every 48 weeks thereafter.
Only at sites in China with DXA capability, DXA scans of the hip and spine will be conducted 
during the screening period, and should be conducted at least 14 days prior to the first dose of 
study drug, and will be subsequently conducted every 24 weeks through Week 144, and every 
48 weeks thereafter until Week 384/ ED visit, if not done within the last 24 weeks of ED visit.
Fracture risk assessment will be evaluated at Baseline. In China, this fracture risk assessment 
will be evaluated at sites with DXA capability only.
Hepatic ultrasound for surveillance of hepatocellular carcinoma will be performed starting at 
Week 96 and then every 24 weeks thereafter until Week 384/ED. Participants who have 
completed the Week 96 visit (under Amendment 2.1) should begin ultrasound assessments at the 
next visit at which an ultrasound assessment is included. Plasma, serum, and urine will be 
collected at baseline and at every visit thereafter for storage.
Treatment-free Follow-up (TFFU) assessments after premature study drug discontinuation will 
occur every 4 weeks for 24 weeks and include the following: vital signs, hematology, serum 
chemistry, liver function tests, and plasma HBV DNA. Plasma, serum and urine will be collected 
for storage. HBeAg, reflex HBeAb, HBsAg and reflex HBsAb will be evaluated at Follow Up 
Weeks 12 and 24.
1.2.6.
Randomization
Participants will be randomized in a 2:1 ratio to the 2 treatment groups (TAF vs TDF, 
respectively). Randomization will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naive vs treatment-experienced).


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1.2.7.
Site and/or Stratum Enrollment Limits
Twenty-nine centers participated in China. There was no enrollment limit for individual sites.
1.2.8.
Study Duration
The duration of the double-blind treatment is 144 weeks (under Amendment 3.1). After 
completing the double-blind period of treatment, all participants will be eligible to receive open-
label TAF 25 mg once daily, for up to an additional 240 weeks (through Week 384/ED). 
Participants who permanently discontinue study drug (either prematurely [ED] or at the end of 
study [Week 384]) will be followed every 4 weeks for 24 weeks off treatment or until initiation 
of alternative, commercially available HBV therapy, whichever occurs first.
Participants with HBsAg loss, with confirmed seroconversion to anti-HBs should discontinue 
study drug within 3 to 6 months following confirmation of seroconversion to anti-HBs or after 
Week 48, if seroconversion occurs prior to this visit. These participants will be followed off 
treatment every 4 weeks for 12 weeks and then per the study visit schedule through 
Week 384/ED.
1.3.
Sample Size and Power
For China, approximately 150 additional participants (100 in TAF group and 50 in TDF group) 
were to be enrolled for local registration purposes.
The sample size and power calculation described below was for non-China participants. With 
respect to the primary efficacy end point of proportion of participants with plasma HBV DNA 
levels below 29 IU/mL at Week 48, a sample size of 130 for the TDF group and 260 for the TAF 
group will have 90% power to rule out the noninferiority margin of 10% at a 1-sided significance 
level of 0.025. This assumes the expected difference (TAF − TDF) in proportion of participants 
with HBV DNA < 29 IU/mL is 0 and the proportion of participants with HBV DNA < 29 IU/mL 
in the TDF group is 91%. A similar response rate in the TDF group was observed in 
Study GS-US-174-0102.
This sample size (n = 260 for the TAF 25 mg group, n = 130 for the TDF 300 mg group) also 
provides the following: 
•
At least 90% power to detect a 1% difference in the percentage change from baseline in hip 
BMD at Week 48 (assuming a –1.17% change from baseline in TDF 300 mg group and 
−0.17% change from baseline in the TAF 25 mg group, with a common standard deviation 
(SD) of 2.20% and a 2-sided α = 0.025)
•
At least 77% power to detect a 1% difference in the percent change from baseline in spine 
BMD at Week 48 (assuming a –1.69% change from baseline in the TDF 300 mg group and 
0.69% change in the TAF 25 mg group, with a common SD of 3.08% and a 2 sided 
α = 0.025)
•
At least 52% power to detect a 0.03 mg/dL difference in the change from baseline in serum 
creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in the TDF 300 mg 


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group and 0.01 mg/dL change from baseline in the TAF 25 mg group, with a common 
SD of 0.12)
The preceding assumptions were derived from Studies GS-98-437, GS-98-438, 
GS-US-174-0102, GS-US-174-0103, and GS-US-174-0121.


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2.
TYPE OF PLANNED ANALYSIS
The final analysis for non-China participants has already been conducted which occurred after 
the last participant completed the study or prematurely discontinued study. This statistical 
analysis plan (SAP) describes the analysis plan for the final analysis of participants enrolled in 
China only.
2.1.
Data Monitoring Committee (DMC) Analysis
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study treatment warrant 
early termination of the study in the best interests of the participants and whether the study 
should continue as planned or with modifications. The DMC may also provide recommendations 
as needed regarding study design.
The DMC was convened approximately every 24 weeks during the blinded portion of the study 
and approximately every 48 weeks during the open-label phase. More details are documented in 
the independent DMC charter. The last DMC meeting was conducted on 24 October 2019 where 
the DMC members concluded that they would transfer the primary responsibilities for 
monitoring study conduct and patient safety to Gilead and stand ready to re-engage should 
concerns arise regarding any aspects of the study.
2.2.
Week 48 Analysis (Primary Analysis)
The Week 48 analysis was conducted after the last participant completed the Week 48 visit or 
prematurely discontinued study drug in China.
2.3.
Final Analysis (Week 384)
The final analysis will be conducted after the last participant completes the Week 384 visit or 
prematurely discontinues study drug in China.
Since no participants entered the TFFU phase after completing the Week 384 visit, this statistical 
analysis plan (SAP) describes the analysis plan for the Week 384 analysis only and is considered 
as Final analysis. 


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
Analysis sets define which participants are included in an analysis. The assignment of 
participants to analysis sets was done before the study blind was broken for analysis. A summary 
of the number and percentage of participants in each analysis set will be provided by treatment 
group and in total.
3.1.1.
Randomized Analysis Set
The Randomized Analysis Set includes all participants who were randomized into the study. This 
is the primary analysis set for by-participant listings.
3.1.2.
Safety Analysis Set
The Safety Analysis Set includes all randomized participants who have received at least 1 dose 
of study drug. Participants will be analyzed according to the treatment they actually received. 
The actual treatment received will differ from the randomized treatment only when their actual 
treatment differs from randomized treatment for the entire double-blinded treatment duration. 
3.1.3.
Open-Label Safety Analysis Set
The Open-Label Safety Analysis Set includes all randomized participants who have received at 
least 1 dose of open-label study drug. Participants will be analyzed according to the treatment 
they actually received during the double-blind phase. 
3.1.4.
Full Analysis Set (FAS)
The FAS includes all randomized participants who have received at least 1 dose of study drug. 
Participants will be analyzed according to the treatment to which they were randomized. 
3.1.5.
Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion
The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion includes all 
participants who were randomized and had received at least 1 dose of study drug, and with 
HBsAg positive and HBsAb negative or missing at baseline. Participants will be analyzed 
according to the treatment they were randomized to.


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3.1.6.
DXA Analysis Set
DXA scans will be performed only at sites in China with DXA capability.
3.1.6.1.
Hip DXA Analysis Set
The Hip DXA Analysis Set includes all participants who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline hip BMD values. Participants will be 
analyzed according to the treatment they actually received.
3.1.6.2.
Spine DXA Analysis Set
The Spine DXA Analysis Set includes all participants who were randomized and had received at 
least 1 dose of study drug, and had nonmissing baseline spine BMD values. Participants will be 
analyzed according to the treatment they actually received.
3.2.
Participant Grouping
Participants will be grouped into the following treatment groups:
Entire study treatment period and double-blind phase summaries:
•
Double-blind TAF 25 mg
•
Double-blind TDF 300 mg
Open-label phase summaries:
•
Double-blind TAF 25 mg participants who switched to open-label TAF 25 mg (TAF-TAF)
•
Double-blind TDF 300 mg participants who switched to open-label TAF 25 mg (TDF-TAF)
3.3.
Strata and Covariates
Randomization was stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naive vs treatment-experienced) at screening. HBV DNA strata will be reclassified 
using baseline HBV DNA level for stratified statistical analysis.


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3.4.
Missing Data and Outliers
3.4.1.
Missing Data
A missing datum for a given study analysis window may be due to any of the following reasons:
•
A visit occurring in the window but data were not collected or were unusable 
•
A visit not occurring in the window
•
A participant permanently discontinuing from the study before reaching the window
For the primary endpoint and the secondary efficacy endpoints involving proportions, missing 
data will be handled using M = F approach. Sensitivity analyses will also be performed including 
M = E approach.
For the remaining endpoints, values for missing data will not be imputed, unless specified 
otherwise. 
3.4.2.
Outliers
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be done to evaluate the impact of outliers on efficacy or safety outcomes, unless 
specified otherwise. All data will be included in the analysis. 
3.5.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:
•
If only month and year of birth is collected, then “15” will be imputed as the day of birth
•
If only year of birth is collected, then “01 July” will be imputed as the day and month of birth
•
If year of birth is missing, then date of birth will not be imputed.


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Laboratory Data that are continuous in nature but are below the lower limit of quantitation 
(LOQ) or above the upper LOQ will be imputed as follows except for the scenarios described 
below for direct bilirubin, urine creatinine, and serum cystatin C: 
•
A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics 
if the datum is reported in the form of “< x” (x is considered as the LOQ). 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 LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (x is considered as the LOQ). Values with decimal 
points will follow the same logic as stated 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 LOQ).
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 its summary and the calculation of related ratios. For serum 
cystatin C, a value of “< 0.10” is handled as a missing value in the calculation of estimated 
glomerular filtration rate (eGFR).
Logarithm (base 10) will be used to transform HBV DNA and quantitative HBsAg data. 
For HBV DNA, if the value in IU/mL (TaqMan) is above the upper limit of quantification, the 
corresponding diluted value (TaqDil), if available, will be used.
3.6.
Analysis Windows
3.6.1.
Definition of Study Day 1 and Other Definitions
Study Day 1 is defined as the day when the first dose of blinded study drug was taken, as 
recorded on the Study Drug Administration eCRF form.
Open-Label Study Day 1 is defined as the day when the first dose of the open-label study drug 
was taken, as recorded on the Study Drug Administration eCRF form.
Study days are calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1 date, study days are calculated as (visit date − Study Day 1 + 1). For events that 
occurred prior to Study Day 1, study days are calculated as (visit date − Study Day 1).
Open-Label study days are calculated relative to Open-Label Study Day 1. For events that 
occurred on or after Open-Label Study Day 1 date, study days are calculated as 
(visit date − Open-Label Study Day 1 + 1). 
Follow-up days are for visits that occur during the 24-week TFFU period and calculated as 
(visit date – last dose date).


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Last Dose Date of Blinded Study Drug is the latest non-missing end date of blinded study drug, 
recorded on the Study Drug Administration eCRF form with “Study Drug Permanently 
Discontinued” box checked for participants who prematurely discontinued blinded study drug or 
who completed blinded study drug according to Blinded Study Drug Completion eCRF. If the 
last dose date of blinded study drug is missing (eg, due to lost to follow up) for participants who 
prematurely discontinued blinded study drug, or for participants who are still on blinded study 
drug, the latest of nonmissing blinded study drug start dates and end dates, the clinical visit dates 
and the laboratory visit dates excluding the dates of open-label and 24-week TFFU visits will be 
used to impute the last dose date of blinded study drug. 
For participants who prematurely discontinued blinded study drug or who completed blinded 
study drug but did not enter open-label phase, the Last Dose Date is the same as Last Dose Date 
of Blinded Study Drug. 
For participants who completed blinded study drug and entered open-label phase, the 
Last Dose Date is the latest non-missing end date of open-label study drug, recorded on the 
Study Drug Administration eCRF form with “Study Drug Permanently Discontinued” box 
checked for participants who prematurely discontinued open-label study drug or who completed 
open-label study drug according to the Open-Label Study Drug Completion eCRF. If the last 
dose date is missing (eg, due to lost to follow up) for participants who prematurely discontinued 
open-label study drug, or for participants who are still on open-label study drug, the latest of 
nonmissing open-label study drug start dates and end dates, the clinical visit dates and the 
laboratory visit dates excluding the dates of 24-week TFFU visits will be used to impute the last 
dose date.
Last Study Date is the latest of nonmissing study drug (blinded or open-label) start dates and 
end dates, the clinic visit and the laboratory visit dates including the 24-week TFFU visit date for 
participants who prematurely discontinued the study or who completed the study according to 
Study Completion eCRF.
Baseline value for the double-blind phase (except DXA BMD) is defined as the last 
nonmissing value obtained on or prior to Study Day 1. For DXA BMD, the baseline value is 
defined as the last nonmissing value on or prior to Study Day 14. Baseline value for the 
open-label phase (except DXA BMD) is defined as the last nonmissing value obtained on or 
prior to Open-label Study Day 1. For DXA BMD, it is defined as the last nonmissing value on or 
prior to Open-Label Study Day 14 and the last dose date of open-label study drug.


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3.6.2.
Analysis Windows
Participant visits might not occur on protocol specified days. Therefore, for the purpose of 
analysis, observations will be assigned to analysis windows. 
The following windows (shown on Table 3-1 to Table 3-7) apply to baseline and on-treatment 
assessments only. 
For participants who prematurely discontinued the blinded study drug (except participants who 
discontinue study drug after Week 48 due to HBsAg loss with confirmed seroconversion to 
anti-HBs during the double-blind phase), laboratory and DXA assessments up to and including 
the last dose date of the blinded study drug, will be considered as on-treatment during the 
double-blind phase. For participants who completed the double-blind phase, laboratory 
assessments up to and including the last dose date of the double-blind study drug + 1 day, and 
DXA assessments on or prior to the last dose date of the double-blind study drug + 14 days, will 
be considered as on-treatment during the double-blind phase.
For participants who prematurely discontinued the open-label study drug (except participants 
who discontinue study drug after Week 48 due to HBsAg loss with confirmed seroconversion to 
anti-HBs during the open-label phase), laboratory and DXA assessments up to and including the 
last dose date of the open-label study drug + 3 days, will be considered as on-treatment during 
the open-label phase. For participants completed the open-label phase, laboratory assessments up 
to and including the last dose date of the open-label study drug + 3 days, and DXA assessments 
up to and including the last dose date of the open-label study drug + 14 days, will be considered 
as on-treatment during the open-label phase. For participants who have not discontinued the 
open-label study drug permanently, data collected up to database finalization date will be 
considered as on-treatment of the open-label phase.
For participants who discontinue study drug early due to HBsAg loss with confirmed 
seroconversion, all efficacy data including data collected after the last dose date of the study drug 
will be reassigned analysis visits using the on-treatment assessment windows 
(Table 3-1, Table 3-2, and Table 3-4). 
The analysis windows for HBV DNA, hematology, serum chemistry and liver function tests, 
urinalysis, urine pregnancy test, eGFR (by CG and Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI]), renal biomarkers urine albumin to creatinine ratio (UACR), urine 
protein to creatinine ratio (UPCR), renal tubular maximum reabsorption rate of phosphate to the 
glomerular filtration rate (TmP/GFR), urine fractional excretion of filtered phosphate (FEPO4), 
fractional excretion of uric acid (FEUA), weight, and vital sign assessments are presented in 
Table 3-1. 


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Table 3-1.
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and 
Liver Function Tests, Urinalysis, Urine Pregnancy Test, eGFR 
(by CG and CKD-EPI), UACR, UPCR, TmP/GFR, FEPO4, FEUA, 
Weight, and Vital Sign Assessments
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
41
Week 8
56
42
69
Week 12
84
70
97
Week 16
112
98
125
Week 20
140
126
153
Week 24
168
154
181
Week 28
196
182
209
Week 32
224
210
237
Week 36
252
238
265
Week 40
280
266
293
Week 44
308
294
321
Week 48
336
322
363
Week 56
392
364
419
Week 64
448
420
475
Week 72
504
476
531
Week 80
560
532
587
Week 88
616
588
643
Week 96
672
644
713
Week 108
756
714
797
Week 120
840
798
881
Week 132
924
882
965
Week 144
1008
966
1091
Week 168
1176
1092
1259
Week 192
1344
1260
1427
Week 216
1512
1428
1595
Week 240
1680
1596
1763
Week 264
1848
1764
1931
Week 288
2016
1932
2099
Week 312
2184
2100
2267
Week 336
2352
2268
2435
Week 360
2520
2436
2603
Week 384
2688
2604
2771


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The analysis windows for safety ECG and fibrotest are presented in Table 3-2.
Table 3-2.
Analysis Windows for Safety ECG and Fibrotest
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 48
336
2
503
Week 96
672
504
839
Week 144
1008
840
1175
Week 192
1344
1176
1511
Week 240
1680
1512
1847
Week 288
2016
1848
2183
Week 336
2352
2184
2519
Week 384
2688
2520
2855
The analysis windows for BMD results from DXA and fasting lipid panel including direct low 
density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol to HDL ratio, are 
presented in Table 3-3.
Table 3-3.
Analysis Windows for BMD Results from DXA and Fasting Lipid 
Panel
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1(14a)
Week 24
168
2(15a)
251
Week 48
336
252
419
Week 72
504
420
587
Week 96
672
588
839 (755b)
Week 120b
840
756b
923b
Week 144
1008
840 (924b)
1175
Week 192
1344
1176
1511
Week 240
1680
1512
1847
Week 288
2016
1848
2183
Week 336
2352
2184
2519
Week 384
2688
2520
2855
a
This applies to DXA only. Upper limit for baseline DXA BMD is Day 14 and lower limit for Week 24 DXA BMD is 
Day 15.
b
This applies to the participants who consented to Amendment 3.1.


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The analysis windows for serum HBsAg (quantitative) and HBV serology are presented in 
Table 3-4.
Table 3-4.
Analysis Windows for Serum HBsAg (Quantitative) and 
HBV Serology
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 12
84
2
125
Week 24
168
126
209
Week 36
252
210
293
Week 48
336
294
391
Week 64
448
392
503
Week 80
560
504
615
Week 96
672
616
713
Week 108
756
714
797
Week 120
840
798
881
Week 132
924
882
965
Week 144
1008
966
1091
Week 168
1176
1092
1259
Week 192
1344
1260
1427
Week 216
1512
1428
1595
Week 240
1680
1596
1763
Week 264
1848
1764
1931
Week 288
2016
1932
2099
Week 312
2184
2100
2267
Week 336
2352
2268
2435
Week 360
2520
2436
2603
Week 384
2688
2604
2771
The analysis windows for fasting glucose, fasting total cholesterol, fasting triglycerides, renal 
biomarkers including urine retinol binding protein (RBP) to creatinine ratio, urine 
beta-2-microglobulin to creatinine ratio, and bone biomarkers including C-type collagen 
sequence (CTX), procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (OC), and bone 
specific alkaline phosphatase (bsAP) are presented in Table 3-5.


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Table 3-5.
Analysis Windows for Fasting Glucose, Fasting Total Cholesterol, 
Fasting Triglycerides, Renal, and Bone Biomarkers
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
55
Week 12
84
56
125
Week 24
168
126
251
Week 48
336
252
419
Week 72
504
420
587
Week 96
672
588
839 (755a)
Week 120a
840
756a
923a
Week 144
1008
840 (924a)
1175
Week 192
1344
1176
1511
Week 240
1680
1512
1847
Week 288
2016
1848
2183
Week 336
2352
2184
2519
Week 384
2688
2520
2855
a
This applies to the participants who consented to Amendment 3.1.
The analysis window for serum parathyroid hormone (PTH) is presented in Table 3-6.


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Table 3-6.
Analysis Windows for PTH
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
41
Week 8
56
42
69
Week 12
84
70
97
Week 16
112
98
125
Week 20
140
126
153
Week 24
168
154
181
Week 28
196
182
209
Week 32
224
210
237
Week 36
252
238
265
Week 40
280
266
293
Week 44
308
294
321
Week 48
336
322
363
Week 56
392
364
419
Week 64
448
420
475
Week 72
504
476
531
Week 80
560
532
587
Week 88
616
588
643
Week 96
672
644
713
Week 108
756
714
797
Week 120
840
798
881
Week 132
924
882
965
Week 144
1008
966
1175
Week 192
1344
1176
1511
Week 240
1680
1512
1847
Week 288
2016
1848
2183
Week 336
2352
2184
2519
Week 384
2688
2520
2855


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The analysis window for hepatic ultrasound for hepatocellular carcinoma (HCC) surveillance is 
presented in Table 3-7.
Table 3-7.
Analysis Windows for Hepatic Ultrasound
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 96
672
588
755
Week 120
840
756
923
Week 144
1008
924
1091
Week 168
1176
1092
1259
Week 192
1344
1260
1427
Week 216
1512
1428
1595
Week 240
1680
1596
1763
Week 264
1848
1764
1931
Week 288
2016
1932
2099
Week 312
2184
2100
2267
Week 336
2352
2268
2435
Week 360
2520
2436
2603
Week 384
2688
2604
2855
Hepatic ultrasound data was collected for the participants who consented to Amendment 3.1.
Data collected after the last dose date will be considered as post-treatment visits. Although 
there’s no participant entering TFFU phase after completing Week 384 visit, participants who 
prematurely discontinued study drug could enter TFFU phase. The analysis windows for 
post-treatment assessments are presented in Table 3-8 and Table 3-9.
Table 3-8.
Analysis Windows for Post-Treatment Assessments Except 
HBV Serology
Visit ID
Nominal Follow-Up Day
Lower Limit
Upper Limit
Follow-Up Baseline
3
Follow-Up Week 4
28
4
41
Follow-Up Week 8
56
42
69
Follow-Up Week 12
84
70
97
Follow-Up Week 16
112
98
125
Follow-Up Week 20
140
126
153
Follow-Up Week 24
168
154
181


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Table 3-9.
Analysis Windows for Post-Treatment HBV Serology
Visit ID
Nominal Follow-Up Day
Lower Limit
Upper Limit
Follow-Up Baseline
3
Follow-Up Week 12
84
4
125
Follow-Up Week 24
168
126
209
3.6.3.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values are required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. When a single value is 
needed, the following rule(s) will be used. 
For baseline of the double-blind and open-label phases, the last available record on or prior to the 
first dose of blinded and open-label study drug will be selected, respectively. For DXA BMD 
baseline, the last value on or prior to Study Day 14, and on or prior to Open-Label Study Day 14 
and the last dose date of open-label study drug will be selected for the double-blind and the 
open-label phases, respectively. If there are multiple records with the same time or no time 
recorded on the same day for numeric observations, an average will be computed for that day, 
with the exception for HBV DNA and Quantitative HBsAg for which geometric mean will be 
taken. If there are multiple records with the same time or no time recorded on the same day for 
categorical observations, the most conservative value will be taken, eg, negative will be selected 
over positive for HBeAg and HBsAg, and positive will be selected over negative for HBeAb and 
HBsAb.
The following specified rules will be used for postbaseline visits:
•
ALT: The largest value will be included in the analysis when 2 or more ALT values occur 
within the same visit window.
•
BMD: The latest record in the window will be selected.
•
HBV DNA and Quantitative HBsAg: The record closest to the nominal day for that visit 
will be selected. If there are 2 records equidistant from the nominal day, the latest will be 
selected. If there is more than 1 record on the selected day, the geometric mean will be taken.
•
Serology: For HBeAg, HBeAb, HBsAg, and HBsAb, the record closest to the nominal day 
for that visit will be selected. If there are 2 records equidistant from the nominal day, the 
latest will be selected. If there is more than 1 record on the selected day, the most 
conservative value will be taken, ie, positive will be selected over negative for HBeAg and 
HBsAg, and negative will be selected over positive for HBeAb and HBsAb.


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For all other laboratory parameters: 
•
If multiple valid nonmissing numeric observations exist in a window, then records will be 
chosen as follows:
The record closest to the nominal day for that visit will be selected. If there are 2 records 
equidistant from the nominal day, the latest will be selected. If there is more than 1 record 
on the selected day, the average will be taken.
•
If multiple valid nonmissing categorical observations (eg, safety ECG results) exist in a 
window, then records will be chosen as follows:
The most conservative value (eg, abnormal will be selected over normal for safety ECG) 
within the window will be selected. In the event that 2 values within a window are of 
equal abnormality, the value collected nearest to the nominal date will be used.


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4.
PARTICIPANT DISPOSITION
4.1.
Participant Enrollment
All necessary summaries on participant enrollment and the randomization schedule have been 
performed as part of Week 48 CSR and will not be repeated for the final CSR. 
Key study dates (first participant screened, first participant randomized, last participant 
randomized, and last participant last visit for the clinical study report) will be provided.
4.2.
Disposition of Participants
The summary of participant disposition will be provided by treatment group and overall. This 
summary will include the number of participants in the Randomized Analysis Set, participants 
randomized but not treated, participants in the Safety Analysis Set, participants in the 
Open-Label Safety Analysis Set.
In addition, the number and percentage of the participants in the following categories will be 
summarized using the Safety Analysis Set:
Double-Blind Phase
•
Prematurely discontinued double-blind study treatment (with summary of reasons for 
discontinuing treatment)
•
Completed double-blind study treatment
Open-Label Phase
•
Willing to enter open-label phase 
•
Entered open-label phase 
•
Prematurely discontinued open-label study treatment (with summary of reasons for 
discontinuing treatment)
•
Completed open-label study treatment
TFFU Phase
•
Entered TFFU period
•
Completed TFFU
•
Discontinued TFFU


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Study Completion
•
Remaining on study
•
Prematurely discontinued study (with summary of reasons for discontinuing study)
•
Started another HBV therapy
•
Completed protocol-planned duration of the study
No inferential statistics will be generated. A data listing of reasons for premature study 
drug/study discontinuation will be provided.
4.3.
Extent of Exposure
Exposure data described below will be summarized for the double-blind phase and open-label 
phase separately.
4.3.1.
Duration of Exposure to Blinded Study Drug
Duration of exposure to blinded study drug will be defined as (last dose date of blinded study 
drug – first dose date of blinded study drug + 1), regardless of temporary interruptions in study 
drug administration, and will be expressed in weeks (recorded to 1 decimal place, eg, 4.5 weeks). 
If subjects are still on blinded study drug, the latest of blinded study drug start and end dates, 
and the clinic and laboratory visit dates (excluding the open-label and 24-week treatment-free 
follow-up visit dates) will be used to impute the last dose date of blinded study drug for 
calculating the duration of blinded study drug exposure.
Duration of exposure to blinded study drug will be summarized using descriptive statistics 
(sample size, mean, standard deviation [SD], median, Q1, Q3, minimum, and maximum) and as 
the number and percentage of subjects exposed for specified periods, eg, ≥ 4 weeks (28 days), 
≥ 8 weeks (56 days), etc.
Summaries will be provided by treatment group for subjects in the Safety Analysis Set. 
No inferential statistics will be provided.


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4.3.2.
Adherence with Blinded Study Drug Regimen
Study drug regimen adherence will be computed based on tablet counts for the active drug only 
(eg, adherence in TAF group only includes TAF and not placebo for TDF). The numbers of 
tablets of study drug dispensed and returned are captured on study drug accountability forms.
Adherence (%) of study drug regimen will be calculated as follows: 
Adherence (%) =  100 ×
Number of tablets taken
Number of tablets prescribed
 =  100 ×
∑No. of tablets taken at each dispensing period  [1]
∑No. of tablets prescribed at each dispensing period  [2] + 1
[1] Number of tablets taken at a distinct dispensing period for a study drug is calculated as the minimum of (a) the daily number 
of tablets prescribed for the study drug multiplied by (the duration of treatment +1 day) at the dispensing period of the 
same dispensing date, and (b) the number of tablets taken for the study drug (number of tablets dispensed minus the number 
of tablets returned). Total number of tablets taken is determined by summing the number of tablets taken from all evaluable 
dispensing periods.
[2] Number of tablets prescribed at a distinct dispensing period for a study drug is calculated as the daily number of tablets 
prescribed for the study drug multiplied by the duration of treatment at the dispensing period of the same dispensing date. 
Total number of tablets prescribed is determined by summing the number of tablets prescribed from all evaluable dispensing 
periods.
The duration of treatment at a dispensing period for a study drug is calculated as the minimum 
of (a) the last returned date of the same dispensing period for the study drug, (b) date of 
premature discontinuation of the study drug, and (c) next dispensing date of the study drug, 
minus dispensing date of the study drug.
The next dispensing date is the following dispensing date of the study drug regardless of the 
bottle return date.
For a record where the number of tablets returned was missing (with “Yes” answered for “Was 
bottle returned?” question), it is assumed the number of tablets returned was 0. If the number of 
tablets dispensed was missing or any study drug bottle was not returned or the bottle return status 
was unknown for the same dispensing date, then all records for the same dispensing date for that 
study drug will be excluded from both denominator and numerator calculation.
Adherence up to the Week 144 Visit will be calculated for subjects in the Safety Analysis Set.
The number and percentage of subjects who return at least 1 bottle and have calculable 
adherence during the study, descriptive statistics for adherence up to Week 144 visit for a study 
drug regimen (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) along with the 
number and percentage of subjects belonging to adherence categories (eg, < 80%, ≥ 80% to 
< 90%, ≥ 90% to < 95%, ≥ 95%) will be provided by treatment group for the 
Safety Analysis Set. No inferential statistics will be provided.
( 
) 


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4.3.3.
Duration of Exposure to Open-Label Study Drug
Duration of exposure to open-label study drug will be summarized for participants in the 
Open-Label Safety Set. It is defined as (Last Dose Date of Open-Label Study Drug – First Dose 
Date of Open-Label Study Drug + 1) / 7 in weeks, regardless of temporary interruptions in study 
drug administration, and will be summarized using descriptive statistics (ie, sample size, mean, 
standard deviation [SD], median, first quartile [Q1], third quartile [Q3], minimum and 
maximum) by treatment group. The number and percentage of participants exposed will be 
summarized by prespecified period, eg, ≥ 12 weeks (84 days), ≥ 24 weeks (168 days), etc.
If participants are still on open-label study drug at the time of the data-cut, the latest date of the 
open-label study drug start and end dates, the clinic visit dates, and laboratory visit dates 
(excluding the 24-week TFFU visit dates) will be used to impute the last dose date of the 
open-label study drug for calculating the duration of the open-label study drug exposure.
4.3.4.
Adherence with Open-Label Study Drug Regimen
Study drug regimen adherence will be computed based on tablet counts for open-label study drug 
for participants in the Open-Label Safety Set. The numbers of tablets of open-label study drug 
dispensed and returned are captured on study drug accountability forms. The same formula used 
for the adherence of double-blind study drug regimen will be used for the calculation of 
adherence to the open-label study drug regimen.
The duration of treatment at a dispensing period for the open-label study drug is calculated as 
the minimum of (a) the last returned date of the same dispensing period for the open-label study 
drug, (b) date of premature discontinuation of open-label study drug, and (c) 
next dispensing date of open-label study drug, minus the dispensing date of the open-label 
study drug.
The next dispensing date is the following dispensing date of open-label study drug regardless of 
the bottle return date. 
For a record where the number of tablets returned was missing (with “Yes” answered for 
“Was bottle returned?” question), it is assumed the number of tablets returned was 0. If the 
number of tablets dispensed was missing or any open-label study drug bottle was not returned or 
the bottle return status was unknown for the same dispensing date, then all records for the same 
dispensing date for the open-label study drug will be excluded from both denominator and 
numerator calculation.
Adherence for open-label study drug will be calculated using all data from the entire open-label 
dosing period up to the date of permanent discontinuation of the open-label study drug for 
participants who prematurely discontinued open-label study drug, or completed open-label study 
drug.


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The number and percentage of participants who return at least 1 bottle and have calculable 
adherence during the open-label phase, descriptive statistics for adherence up to the visits 
mentioned above for the open-label study drug (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) along with the number and percentage of participants belonging to 
adherence categories (eg, < 80%, ≥ 80% to < 90%, ≥ 90% to < 95%, ≥ 95%) will be provided by 
treatment group for the Open-Label Safety Analysis Set. No inferential statistics will be 
provided.
4.4.
Protocol Deviations
Protocol deviations occurring after participants entered the study are documented during routine 
monitoring. The number and percentage of participants with important protocol deviations 
(e.g., at least 1, with 1, 2, 3 or more important protocol deviations), and the total number of 
important protocol deviations by deviation category (e.g., eligibility criteria, informed consent) 
will be summarized by treatment group for the Full Analysis Set. A by participant listing will be 
provided for those participants with important protocol deviations. A listing of participants who 
received the wrong study treatment will also be provided.
4.5.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (COVID-19) pandemic which had an 
impact on the study conduct. Some participants were unable to attend onsite visits due to shelter 
in place guidelines, site closures, or other reasons. This section describes how special situations 
due to COVID-19 will be handled in the analysis.
4.5.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-participant listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be provided if applicable.
4.5.2.
Protocol Deviations Due to COVID-19
A by-participant listing will be provided for participants with important protocol deviations 
related to COVID-19 if applicable. A separate listing will be provided for participants with 
non-important protocol deviations related to COVID-19 if applicable.
4.5.3.
Missed and Virtual Visits due to COVID-19
A by-participant listing of participants with missed or virtual visits due to COVID-19 will be 
provided by participant ID number in ascending order.
Information regarding missed or virtual visits due to COVID-19 will be collected as free text in 
the CRF comment fields. The determination of missed or virtual visits due to COVID-19 will be 
done using Natural Language Processing (NLP) to search the CRF comment fields. A detailed 
explanation of the algorithm is given in Appendix 2.


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4.5.4.
Adverse Events Due to COVID-19
AEs of COVID-19 will be included in analyses of AEs if applicable, which will be determined 
through COVID-19 SMQ narrow search. A by-participant listing of AEs of COVID-19 will be 
provided if applicable.
4.5.5.
Overall Assessment of COVID-19 Pandemic Impact
For participants affected by COVID-19 infection and/or pandemic while participating in the 
study, a listing of the following individual COVID-19 related outcome categories will be 
provided:
•
Death due to COVID-19
•
Adverse event of COVID-19, as determined by COVID-19 SMQ narrow search 
•
Specific adverse event directly associated with the pathogen causing COVID-19, as 
determined by Medical Search Term (MST) 
•
Hospitalization (using data from AE eCRF) due to adverse event of COVID-19 as defined 
above
•
Study drug discontinuation due to COVID-19
•
Study discontinuation due to COVID-19
•
Missed visits due to COVID-19
•
Missed key assessments due to COVID-19 (Key assessments are the assessments 
contributing to primary and key secondary end points which happened before COVID-19 
pandemic)
In addition, composite broad COVID-19 impact indicator will be derived based on the following 
individual categories defined above: death, adverse event, hospitalization, study drug 
discontinuation, study discontinuation, missed visits, and missed key assessments. Composite 
specific COVID-19 impact indicator will be derived based on death and specific adverse event.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Participant demographic data (eg, age, sex, race, and ethnicity) and baseline characteristics 
(eg, body weight, height, body mass index [BMI], and Vitamin D) will be summarized by 
treatment group and overall, using descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) for continuous data and by the number and percentage of participants 
for categorical data. Age is calculated as age in years at the first dose of study drug. 
In addition, the following baseline characteristics and medical history will be summarized:
•
BMI categories (< 18.5 kg/m2 [underweight], ≥ 18.5 - 25.0 kg/m2 [normal], 
≥ 25.0 - 30.0 kg/m2 [overweight], and ≥ 30.0 kg/m2 [obese])
•
HBV DNA (log10 IU/mL)
•
HBV DNA categories (< 7 log10 IU/mL, ≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL)
•
ALT (U/L)
•
ALT level based on central laboratory normal range (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN - 10 × ULN, > 10 ULN)
•
ALT level based on American Association for the Study of Liver Diseases (AASLD) normal 
range with the ULN as 25 U/L for female and 35 U/L for male (≤ ULN, > ULN - 5 × ULN, 
> 5 × ULN - 10 × ULN, > 10 ULN) 
•
Estimated GFR by CG, CKD-EPI creatinine, and CKD-EPI Cystatin C methods
•
HBeAg status (positive, negative)
•
Previous oral nucleoside/nucleotide treatment experience (yes, no)
•
Previous interferon experience (yes, no)
•
Years positive for HBV 
•
HBV Genotype (A, B, C, D, E, F, etc)
•
FibroTest score
•
Fibrosis stage by fibrotest score (0 - 0.48, 0.49 - 0.74, 0.75 - 1)
•
Cirrhosis history (yes, no, indeterminate/unknown)


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•
Proteinuria by urinalysis (dipstick) (Grade 0, Grade 1, Grade 2, Grade 3)
•
Medical history: diabetes mellitus (yes, no), hypertension (yes, no), cardiovascular disease 
(yes, no), and hyperlipidemia (yes, no) 
•
Clinical BMD status (normal, osteopenia, osteoporosis)
•
IL28B Genotype 
Diabetes mellitus, hypertension, cardiovascular disease, and hyperlipidemia above are 
determined by medical history and/or concomitant medication data, which will be reviewed by 
the Gilead medical monitor before unblinding.
5.2.
Medical History
A listing of medical history data will be provided for the Randomized Analysis Set.


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6.
EFFICACY ANALYSES
For the final analyses, efficacy data will be summarized for the double-blind and open-label 
phase up to Week 384 using Missing = Failure (M = F) based on participants in the FAS and 
Missing = Excluded (M = E) approach based on participants in the FAS if applicable.
No statistical comparisons will be performed for the efficacy analyses. All efficacy data up to the 
week 384 (i.e., final) data finalization including data collected during 24-week TFFU period for 
participants who prematurely discontinued study drug will be listed.
HBV DNA lab values based on the Roche COBAS® Taqman® assay (with LLOQ of 29 IU/mL, 
on or before Week 64 visit), Roche AmpliPrep/COBAS® TaqMan® 2.0 assay (with LLOQ of 
20 IU/mL, after Week 64 visit) and Roche COBAS 6800 assay (with LLOQ of 10 IU/mL, at 
Week 360 and 384 visits) will be used for HBV DNA analysis. If the value in IU/mL (TaqMan) 
is above the upper limit of quantification, the corresponding diluted value (TaqDil), if available, 
will be used.
6.1.
Primary Efficacy Endpoints
The primary efficacy end point is the proportion of participants with HBV DNA < 29 IU/mL at 
Week 48, which has been analyzed in the previous Week 48 interim analysis, and will not be 
repeated for this final analysis (refer to Week 48 SAP for the statistical analysis method for the 
primary efficacy end point).
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
For the definitions below, double-blind baseline will be used.
The secondary efficacy end points are as follows:
•
The proportion of participants with plasma HBV DNA < 29 IU/mL at Weeks 96, 144, 240, 
and 384
•
The proportion of participants with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96, 144, 240, and 384
•
The proportion of participants with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 48, 96, 144, 240, and 384
•
The proportion of participants with HBsAg loss at Weeks 48, 96, 144, 240, and 384
•
The proportion of participants with HBsAg seroconversion to anti- HBs at Weeks 96, 144, 
240, and 384


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•
The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96, 144, 240, 
and 384
•
The incidence of drug resistant mutations at Weeks 48, 96, 144, 240, and 384
•
The change from baseline in log10 (HBV DNA) (IU/mL) at Weeks 48, 96, 144, 240, and 384
•
The change from baseline in log10 (HBsAg) (IU/mL) at Weeks 48, 96, 144, 240, and 384
•
The change from baseline in ALT at Weeks 48, 96, 144, 240, and 384
Incidence of drug resistant mutations will be reported in a separate virology report.
For the final analysis, the following definitions will be used:
•
HBsAg loss is defined as HBsAg test result changes from HBsAg positive at baseline to 
HBsAg negative at a postbaseline visit with baseline HBsAb negative or missing
•
HBsAg seroconversion is defined as HBsAg loss and HBsAb test result changes from 
HBsAb negative or missing at baseline to HBsAb positive at a postbaseline visit 
•
ALT normalization is defined as ALT > ULN (by central laboratory normal range or AASLD 
normal range) at baseline but within normal range at a postbaseline visit
Both baseline and postbaseline borderline serology results will be imputed using the following 
rules:
•
HBsAg and HBeAg borderline/equivocal will be considered as HBsAg positive and HBeAg 
positive
•
HBsAb and HBeAb borderline/equivocal will be considered as HBsAb negative and HBeAb 
negative


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6.2.2.
Analysis Methods for Secondary Efficacy End points
The analyses for the secondary efficacy endpoints will be conducted using the FAS. All the 
secondary efficacy endpoints involving proportions will be analyzed using the same statistical 
method (M = F) applied to the analysis of the primary efficacy endpoint. Sensitivity analyses will 
be performed using the M = E approach as well. No statistical comparisons will be performed.
The change from baseline in log10 (HBV DNA) (IU/mL), log10 (HBsAg) (IU/mL), and ALT 
will be summarized by visit using observed data (ie, missing will be excluded). In addition, the 
proportion of participants with HBV DNA < 29 IU/mL (M = F and M = E), ALT normalization 
(M = F and M = E), mean change from double-blind baseline in log10 (HBV DNA) (IU/mL), 
log10 (HBsAg) (IU/mL), and ALT (U/L) will be plotted over time for participants in the FAS. 
Fibrosis assessed by FibroTest® at each visit and the change from baseline in FibroTest score 
will be summarized using descriptive statistics (sample size, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment group. A shift table of fibrosis stage based on FibroTest 
score by visit will also be provided. Mean change from double-blind baseline in FibroTest score 
will be plotted with 95% CI over time using observed data for participants in the FAS. No 
statistical comparisons will be performed. A listing of fibrosis assessment by FibroTest® will 
also be provided.
6.3.
Changes From Protocol-Specified Efficacy Analyses
Change from baseline in log10 (HBV DNA) (IU/mL), log10 (HBsAg) (IU/mL), and ALT were 
added in the SAP as secondary efficacy end points to fully explore the treatment effect of TAF 
versus TDF. The Randomized Analysis Set was not defined in the protocol but is added in the 
SAP. All these changes which were previously documented in the Week 48 China Analysis SAP 
have been carried over to this SAP.


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7.
SAFETY ANALYSES
For the Final analysis, cumulative safety data (AEs, laboratory abnormalities, etc.) and exposure 
data will be summarized for (1) participants in the Safety Analysis Set during the double-blind 
phase, (2) participants in the Open-Label Safety Analysis Set during the open-label phase.
By-visit summary tables will be presented for the entire study treatment period (double-blind and 
open-label phase combined), based on participants in the Safety Analysis Set, starting from the 
double-blind phase baseline. No by-visit summaries for safety measurements will be generated 
for the TFFU phase.
For the analyses of events occurring during open-label phase, baseline will be reset as the last 
nonmissing value obtained on or prior to Open-Label Study Day 1 except for DXA BMD, which 
is defined as the last nonmissing value obtained on or prior to Open-Label Study Day 14.
All safety data, including data collected during the TFFU period for participants prematurely 
discontinued study drug, will be included in data listings.
7.1.
Adverse Events
7.1.1.
Adverse Event Dictionary
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.
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 5 of the 
clinical study protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and 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 “Yes” 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
AEs for which ‘Yes’ is marked for question ‘Related to Study Procedures?’ in the eCRF will be 
identified and included in AE listing.


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7.1.5.
Serious AEs
Serious AEs are those identified as serious in the eCRF, where ‘Yes’ was marked for 
‘AE serious’. The clinical database will be reconciled with the serious AE database (from the 
Drug Safety and Public Health Department) before database finalization.
7.1.6.
Treatment-Emergent AEs
7.1.6.1.
Definition of Treatment-Emergent
Summaries of treatment-emergent AEs are defined for the double-blind and the open-label 
phases separately.
Treatment-emergent AEs occurring during the double-blind phase are defined as:
•
Any AE with an onset date on or after the blinded study drug start date and no later than the 
blinded study drug stop date for those who discontinued blinded study drug, or 
•
Any AE leading to blinded study drug discontinuation.
Treatment-emergent AEs occurring during the open-label phase are defined as:
•
Any AE with an onset date on or after the open-label study drug start date and no later than 
the open-label study drug stop date + 3 days for those who discontinued open-label study 
drug, or
•
Any AE leading to open-label study drug discontinuation. 
7.1.6.2.
Incomplete Dates
If an AE onset date is incomplete or completely missing, the following rules will be used to 
define treatment-emergent AE during the double-blind and open-label phases: 
Events with Missing Onset Day and/or Month
The event is treatment-emergent during the double-blind phase if the following 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 the blinded study drug, and
•
For those who discontinued the blinded study drug permanently only: the month and year 
(or year) of onset date is the same as or before the month and year (or year) of the date of the 
last dose of the blinded study drug, and 
•
End date is as follows:
The (complete) end date is on or after the first dose date of the blinded study drug, 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 the blinded study drug, or
End date is completely missing


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The event is treatment-emergent during the open-label phase if the following 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 the open-label study drug, and
•
For those who discontinued the open-label study drug permanently only: the month and year 
(or year) of onset date is the same as or before the month and year (or year) of the date of the 
last dose of the open-label study drug + 3 days, and 
•
End date is as follows:
The (complete) end date is on or after the first dose date of the open-label study drug, 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 the open-label 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 treatment-emergent AE during the 
double-blind phase if end date is as follows:
•
The (complete) end date is on or after the first dose date of the blinded study drug, 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 the blinded study drug, or
•
End date is completely missing
An AE with a completely missing onset date is defined as treatment-emergent AE during the 
open-label phase if end date is as follows:
•
The (complete) end date is on or after the first dose date of the open-label study drug, 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 the open-label study drug, or
•
End date is completely missing
7.1.7.
Summaries of AEs and Deaths
Adverse events will be summarized for (1) participants in the Safety Analysis Set during the 
Double-Blind phase, and (2) participants in the Open-Label Safety Analysis Set during the 
open-label phase. The full set of AE summaries as described below will be generated for both 
(1) and (2).


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A brief summary of AEs (ie, the number and percentage of participants) will be presented by 
treatment group for the double-blind and open-label phases separately for the following: (1) any 
treatment-emergent AE, (2) any Grade 3 or 4 treatment emergent AE, (3) any Grade 2, 3 or 
4 treatment-emergent AE, (4) any treatment emergent study drug-related AE, (5) any Grade 3 
or 4 treatment-emergent study drug-related AE, (6) any Grade 2, 3 or 4 treatment-emergent 
study drug-related AE, (7) any treatment-emergent serious adverse event (SAE), (8) any 
treatment-emergent study drug-related SAE, (9) any treatment-emergent AE leading to 
premature study drug discontinuation, (10) any treatment emergent AE leading to dose 
modification or study drug interruption, and (11) any treatment-emergent death.
Treatment-emergent death refers to death that occurs between the first dose date and the last dose 
date + 3 days (inclusive).
Summaries (number and percentage of participants) of AEs (by SOC, HLT [if specified below], 
and PT) will be provided by treatment group and overall for the double-blind phase on Safety 
Analysis Set and the open-label phase based on the Open-Label Safety Analysis Set as follows:
•
All treatment-emergent AEs summarized by SOC, HLT, and PT
•
Any Grade 3 or 4 treatment-emergent AEs
•
Any Grade 2, 3, or 4 treatment-emergent AEs
•
All treatment-emergent study drug-related AE summarized by SOC, HLT, and PT
•
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 leading to premature discontinuation from study drug
•
All treatment-emergent AEs leading to dose modification or study drug interruption
Multiple events will be counted once only per participant in each summary. For data 
presentation, SOC (and HLT) 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 by-treatment summaries, data listings will be provided for the following:
•
All AEs (including AEs in the TFFU phase)
•
Grade 3 and 4 AEs


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•
SAEs
•
Study drug-related SAEs
•
Deaths
•
AEs leading to premature discontinuation of study drug
•
AEs leading to dose modification or study drug interruption
7.1.8.
Potential Uveitis Events
Analysis will be performed to detect AEs where the symptoms reported may potentially 
represent uveitis. The list of PTs for potential uveitis events were defined as events from the 
predefined MST list consisting of ocular PTs, initially reviewed by an external ophthalmologist, 
and maintained by Patient Safety (PS) through MedDRA upversioning for safety monitoring of 
posterior uveitis.
A summary (number and percentage of participants) of treatment-emergent potential uveitis 
events by PT will be provided by treatment group for the double-blind phase on Safety Analysis 
Set and the open-label phase based on the Open-Label Safety Analysis Set. A data listing of 
potential uveitis events will be provided.
7.1.9.
Potential Cardiovascular Events
Potential cardiovascular events are defined as events with predefined list of MedDRA PTs based 
on 3 MedDRA SMQs based on the latest MedDRA version: Ischemic central nervous system 
vascular conditions, Other ischemic heart disease, and Myocardial infarction. 


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A summary (number and percentage of participants) of potential treatment-emergent 
cardiovascular events and serious cardiovascular events by PT will be provided by treatment 
group for the double-blind phase on Safety Analysis Set and the open-label phase based on the 
Open-Label Safety Analysis Set. data listing of potential cardiovascular events will be provided.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of graded laboratory data will be provided for 
double-blind phase on Safety Analysis Set and the open-label phase based on the Open-Label 
Safety Analysis Set. Summaries of numerical laboratory data by visit will be provided for the 
entire study period for participants in the Safety Analysis Set from baseline to Week 384.
The analyses will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.4.
A by-participant listing for laboratory test results will be provided by participant ID number and 
visit in chronological order for hematology, serum chemistry, urine chemistry, and urinalysis 
separately. Values falling outside of the relevant reference range and/or having a severity grade 
of 1 or higher on the Gilead Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities will be flagged in the data listings, as appropriate.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will be 
provided by treatment group for each laboratory test during the entire study period 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 3.6.3.
Median (Q1, Q3) change from the double-blind baseline in selected safety end points including 
the fasting lipid panel parameters, and fasting glucose over time will be plotted by treatment 
group for the entire study treatment period (double-blind and open-label phases combined), for 
participants in the Safety Analysis Set.


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7.2.1.1.
Metabolic Assessments
For the lipid panel and glucose measurements, only those under fasting status will be 
summarized. 
Fasting lipid data (including total cholesterol, LDL, HDL and triglycerides) will also be analyzed 
using the following National Cholesterol Education Program (NCEP) Adult Treatment Panel 
(ATP) III categories {National Cholesterol Education Program (NCEP) 2001}:
•
For total cholesterol (mg/dL): < 200 (desirable), 200-239 (borderline high), and 
≥ 240 (high)
•
For LDL (mg/dL): < 100 (optimal), 100-129 (near optimal/above optimal), 
130-159 (borderline high), 160-189 (high), and ≥ 190 (very high)
•
For HDL (mg/dL): < 40 (low), 40-59 (normal), and ≥ 60 (high)
•
For triglycerides (mg/dL): < 150 (normal), 150-199 (borderline high), 200-499 (high), and 
≥ 500 (very high)
The number and proportion of participants for the above categories of each lipid parameter will 
be summarized by its baseline category for each treatment group at each visit for the entire study 
treatment period.
7.2.1.2.
Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized. 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))
When albumin value is ≥ 4.0 g/dL, the actual calcium results will be used. 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, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or Grade 4 (life-threatening). 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; analysis for each direction 
(ie, increased, decreased) will be presented separately. 
For triglycerides, LDL, and total cholesterol, the protocol-specified toxicity grade scale is for 
fasting test values; non-fasting lipid results (or lipid results without known fasting status) will not 
be graded or summarized by toxicity grades. 


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If any laboratory toxicity grading scale overlaps with normal reference ranges (eg, Grade 1 scale 
overlaps with normal reference ranges), laboratory values within normal range will not be graded 
except for lipid tests. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities occurring in the double-blind phase are defined as 
values that increase by at least 1 toxicity grade from baseline at any postbaseline visit up to and 
including the last does date of the blinded study drug (or ‘last dose date of the blinded study 
drug + 1’ for those who enter the open-label phase) for those who discontinued blinded study 
drug permanently, or values that increase by at least 1 toxicity grade from baseline at any 
postbaseline visit for those who are still on the blinded study drug. If the relevant baseline 
laboratory data are missing, any laboratory abnormality of at least Grade 1 will be considered 
treatment-emergent.
Treatment-emergent laboratory abnormalities occurring in the open-label phase are defined as 
values that increase by at least 1 toxicity grade from the open-label baseline at any open-label 
postbaseline visit up to and including the last dose date of open-label study drug + 3 days for 
those who discontinued open-label study drug prematurely (or ‘last dose date of the open-label 
study drug + 3 days’ for those who completed the open-label phase), or values that increase by at 
least 1 toxicity grade from the open-label baseline at any open-label postbaseline visit for those 
who are still on the open-label study drug. For the analyses of abnormalities occurring during 
open-label treatment, baseline will be the last available record on or prior to Open-Label Study 
Day 1. 
Fasting glucose and nonfasting glucose are graded based on different grading scales. 
Treatment-emergent laboratory abnormalities will be summarized for fasting glucose. Since 
nonfasting glucose was not assessed at baseline, the maximum postbaseline grade will be 
summarized.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Treatment-emergent marked laboratory abnormalities occurring in the double-blind phase are 
defined as values that worsen by at least 3 grades from baseline at any postbaseline visit up to 
and including the last dose date of the blinded study drug for those who discontinued blinded 
study drug prematurely (or ‘last dose date of the blinded study drug + 1 day’ for those who 
completed double -blind phase), or values that worsen by at least 3 grades from baseline at any 
postbaseline visit for those who are still on blinded study drug. If relevant baseline laboratory 
data are missing, any laboratory abnormalities of at least Grade 3 or 4 will be considered as 
treatment-emergent marked laboratory abnormalities.
Treatment-emergent marked laboratory abnormalities occurring in the open-label phase are 
defined as values that worsen by at least 3 grades from the open-label baseline at any open-label 
postbaseline visit up to and including the last dose date of open-label study drug + 3 days for 
those who discontinued open-label study drug prematurely (or ‘last dose date of the open-label 
study drug + 3 days’ for those who completed the open-label phase), or values that worsen by at 
least 3 grades from the open-label baseline at any open-label postbaseline visit for those who are 
still on open-label study drug.


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7.2.2.3.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of participants) of laboratory abnormalities 
will be provided by treatment group (participants categorized according to most severe 
abnormality grade) for the double-blind and open-label phase:
•
Treatment-emergent laboratory abnormalities
•
Treatment-emergent Grade 3 and 4 laboratory abnormalities
•
Treatment-emergent marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of participants 
with any nonmissing postbaseline (or open-label postbaseline) value in the given study period. A 
listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be provided.
7.2.3.
ALT Elevation
An ALT elevation is defined as serum ALT > 2 × baseline value and > 10 × ULN, with or 
without associated symptoms. Confirmed ALT elevation (ALT flare) is defined as ALT 
elevations at 2 consecutive postbaseline visits. All treatment-emergent ALT elevations including 
confirmed ALT elevations will be summarized for the double blind and the open-label phases 
separately. For analyses of ALT elevation during open-label treatment, baseline will be the last 
available record on or prior to Open-Label Study Day 1. All treatment emergent and 
nontreatment-emergent ALT elevations will be included in a listing.
7.3.
Bone Safety Analyses
The BMD-related analyses for the entire study treatment period will be based on participants in 
the Hip or Spine DXA Analysis Set. The analyses of fracture events and bone events during 
double-blind phase will be based on the Safety Analysis Set, and the summaries for the 
open-label phase will be based on Open-Label Safety Analysis Set.
7.3.1.
Bone Mineral Density (BMD)
Observed BMD values will be used for all the analyses described below: Percentage change from 
baseline in hip BMD and spine BMD during the entire study treatment period will be 
summarized by treatment group and visit using descriptive statistics for participants in the Hip 
and Spine DXA Analysis Sets. 
For each participant and each visit, the clinical BMD status will be defined for hip and spine 
BMD based on the corrected t-score in Table 7-1.


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Table 7-1.
Normal, Osteopenia, and Osteoporosis as Defined by T-Score
Clinical Status
BMD T-Score
Normal
t-score ≥ -1.0
Osteopenia
-2.5 ≤ t-score < -1.0
Osteoporosis
t-score < -2.5
The number and percentage of participants in each clinical BMD status (normal, osteopenia, and 
osteoporosis) will be summarized by visit and by baseline clinical status for both hip and spine. 
The number and percentage of participants in each category based on percentage change from 
baseline in hip BMD and spine BMD (> 7% decrease, > 5% to ≤ 7% decrease, > 3% to ≤ 5% 
decrease, > 1% to ≤ 3% decrease, > 0 to ≤ 1% decrease, 0 to ≤ 1% increase, > 1% to ≤ 3% 
increase, > 3% to ≤ 5% increase, > 5% to ≤ 7% increase, > 7% increase) will be summarized by 
treatment group and visit. 
The number and percentage of participants in each category based on percentage change from 
baseline in femoral neck (≥ 7% decrease, ≥ 5% to < 7% decrease, ≥ 3% to < 5% decrease, 
≥ 1% to < 3% decrease, ≥ 0 to < 1% decrease, ≥ 0 to < 1% increase, ≥ 1% to < 3% increase, 
≥ 3% to < 5% increase, ≥ 5% to < 7% increase, ≥ 7% increase) will be summarized by treatment 
group and visit. 
Median (Q1, Q3) and mean (95% CIs) of percentage change from the double-blind baseline in 
observed hip BMD and spine BMD over time will be plotted by treatment group for the entire 
study treatment period for participants in the DXA Analysis Set.
7.3.2.
Bone Biomarkers
Bone biomarkers include serum CTX, P1NP, PTH, OC, and bsAP.
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone 
biomarkers will be summarized by treatment group and visit using descriptive statistics. 
Median (Q1, Q3) percentage change from the double-blind baseline in each bone biomarker over 
time will be plotted by treatment group for the entire study treatment period for participants in 
the Safety Analysis Set.
7.3.3.
Fracture Events
The PTs for fracture events were defined based on HLGT of Fractures from latest version of 
MedDRA. The number and percentage of subjects who experienced fracture events will be 
summarized by treatment group for the double-blind and the open-label phase separately. A data 
listing of fracture events will be provided.


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7.3.4.
Bone Events
The PTs for bone events were defined based on the broad search for bone mineral density and 
bone-disorder-related PTs, including fractures, using the latest version of MedDRA. The number 
and percentage of participants who experienced treatment-emergent bone events will be 
summarized by treatment group for the double-blind and the open-label phase separately. A data 
listing of bone events will be provided.
7.4.
Renal Safety Analyses
7.4.1.
Confirmed Renal Abnormalities
Confirmed renal abnormalities are defined as follows:
•
Confirmed increase from baseline in creatinine of at least 0.5 mg/dL or
•
Confirmed CLCr by CG below 50 mL/min or
•
Confirmed phosphorus < 2 mg/dL
Treatment-emergent confirmed renal abnormalities will be summarized for the double-blind and 
the open-label phase separately. For analyses of confirmed renal abnormalities during the open 
label treatment, baseline will be the last available record on or prior to Open-Label Study Day 1. 
All confirmed renal abnormalities including those that occur during the TFFU period will be 
listed. 
7.4.2.
Serum Creatinine
The baseline and change from baseline in serum creatinine will be summarized using descriptive 
statistics. 
Median (Q1, Q3) and mean (95% CIs) of change from the double-blind baseline in observed 
serum creatinine over time will be plotted by treatment group for the entire study treatment 
period for participants in the Safety Analysis Set.
A positive shift in serum creatinine values was observed due to a lot calibration change on 
01 July, 2018, occurring across Covance laboratory sites worldwide. A correction was therefore 
applied to records on or after 01 July, 2018 to serum creatinine, following the regression 
equation specified in Table 7-2. The corrected serum creatinine values will be used for the 
analyses of serum creatinine, serum creatinine toxicity, eGFR estimated by the Cockcroft Gault 
formula, eGFR by the CKD-EPI method and other relevant parameters. 


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The corrected values must be in the same unit as the original values after going through the 
regression formula in Table 7-2.
•
If the unit of serum creatinine is “μmol/L”, then use the formula directly. 
•
If the unit of serum creatinine is “mg/dL”, the values should be converted to “μmol/L” before 
using the formula. 
After the correction, unit of serum creatinine should be converted back to “mg/dL” for summary 
and comparison purpose. 
Table 7-2.
Method of Serum Creatinine Correction
Regional Lab Center
Accession Numbera
Regular Regression for Serum 
Creatinine (μmol/L)b, c
Indianapolis 
starts with 65
Y=1.002×X+1.77
Geneva 
starts with 62 or 63
Y=1.025×X+2.62
Shanghai 
starts with 67
Y=0.971×X+5.42
Singapore 
starts with 64 or 66
Y=1.009×X−1.42
Japan 
start with 68
Y=1.033×X+7.25
a
Accession numbers specified which regional lab center tested the sample. For example, samples with accession number 
starting with 65 were tested in Indianapolis Auto Chemistry Center.
b
X and Y are the serum creatinine values from previous lot before 01 July, 2018 and serum creatinine values from new lot on 
or after 01 July, 2018, respectively. 
c
The serum creatinine correction is based on the unit of umol/L. The unit should be converted to mg/dL for summary 
purposes. 
7.4.3.
Estimated Glomerular Filtration Rate
The following formulae will be used to calculate eGFR: 
•
CG:
eGFRCG (mL/min) = [(140 – age (yrs)) × weight (kg) × (0.85 if female)] / (SCr (mg/dL) × 72),
where weight is actual total body mass in kilograms, and SCr is serum creatinine.
•
CKD-EPI Creatinine Based:
eGFRCKD-EPI, creatinine (mL/min/1.73 m2) = 141 × min(SCr/κ,1)α × max(SCr/κ,1)-1.209 × 0.993Age × 
1.018 (if female) × 1.159 (if black),
where κ is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, 
min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1 
{Levey 2009}.


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•
CKD-EPI Cystatin C based:
eGFRCKD-EPI, cysC (mL/min/1.73 m2) = 133 × min(SCys/0.8, 1)-0.499 × max(SCys/0.8, 1)-1.328 × 
0.996age [× 0.932 if female],
where SCys is serum cystatin C.
Change from baseline in eGFRCG and eGFRCKD-EPI, creatinine at each postbaseline visit during the 
entire study treatment period will also be provided. 
The number and proportion of participants with decrease from baseline of ≥ 25% and ≥ 50% in 
eGFRCG and eGFRCKD-EPI, creatinine will be summarized by treatment groups for the double-blind 
phase and the open-label phase. Baseline for the open-label phase will be the last available 
record on or prior to the first dose date of open-label study drug.
The number and proportion of participants in each stage of chronic kidney disease (CKD) will be 
summarized by double-blind baseline stages of CKD at the entire study period based on 
participants in the Safety Analysis Set. 
The stages of CKD are defined as follows:
•
Stage 1: eGFRCG ≥ 90 mL/min
•
Stage 2: eGFRCG ≥ 60 and < 90 mL/min
•
Stage 3: eGFRCG ≥ 30 and < 60 mL/min
•
Stage 4: eGFRCG ≥ 15 and < 30 mL/min
•
Stage 5: eGFRCG < 15 mL/min
Cystatin C will be collected for each participant at baseline visit (Amendment 2 and after) and 
whenever their postbaseline eGFR by CG < 50 mL/min. Therefore, eGFRCKD-EPI, cysC will be 
summarized as the baseline disease characteristics only. All postbaseline eGFRCKD-EPI, cysC with 
percentage change from baseline will be listed.
Median (Q1, Q3) change from the double-blind baseline in eGFR by CG and CKD-EPI 
creatinine methods over time will be plotted by treatment group for the entire study treatment 
period (double-blind and open-label phases combined) for participants in the 
Safety Analysis Set.
7.4.4.
Treatment-Emergent Proteinuria (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) will be summarized by treatment group 
for the double-blind and the open-label phase separately. A listing of participants with 
treatment-emergent proteinuria will be provided.


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7.4.5.
Urine Creatinine, Urine RBP to Creatinine Ratio and Beta-2-Microglobulin 
to Creatinine Ratio
Baseline, postbaseline, change from baseline and percentage change from baseline in urine 
creatinine, urine RBP to creatinine ratio and beta-2-microglobulin to creatinine ratio will be 
summarized by treatment group and visit using descriptive statistics, during the entire study 
treatment period. 
Median (Q1, Q3) percentage change from the double-blind baseline in the 2 ratios over time will 
be plotted by treatment group for the entire study treatment period, for participants in the 
Safety Analysis Set.
7.4.6.
Proteinuria by Quantitative Assessment
Baseline, postbaseline, changes from baseline, and percentage change from baseline in UPCR 
and UACR will be summarized by treatment group and visit using descriptive statistics, for the 
entire study treatment period.
The number and proportion of participants with UPCR ≤ 200 mg/g versus > 200 mg/g will be 
summarized by baseline category for each postbaseline visit during the entire study treatment 
period {KDIGO Guideline Development Staff 2013}.
The number and proportion of participants with UACR < 30 mg/g versus ≥ 30 mg/g will be 
summarized by baseline category for each postbaseline visit during the entire study treatment 
period {KDIGO Guideline Development Staff 2013}.
Median (Q1, Q3) percentage change from the double-blind baseline in the 2 ratios over time will 
be plotted by treatment group for the entire study treatment period for participants in the 
Safety Analysis Set.
7.4.7.
Other Renal Biomarkers
Other renal biomarkers include TmP/GFR, FEPO4, and FEUA.
TmP/GFR based on serum creatinine {Barth 2000} will be calculated as follows:


86
.0
)
8.0
(
1
/
3.0
/
86
.0
/
4
4









TRP
if
SPO
TRP
TRP
GFR
TmP
TRP
if
SPO
TRP
GFR
TmP
where TRP (tubular reabsorption of phosphate) is calculated by:
UCr
SCr
SPO
UPO
TRP



4
4
1


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where SCr is serum creatinine concentration (mg/dL), UPO4 is urine phosphate concentration 
(mg/dL), SPO4 is serum phosphate concentration, and UCr is urine creatinine concentration 
(mg/dL).
Urine FEPO4 will be calculated as follows:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Urine FEUA will be calculated as follows:
FEUA (%) = (SCr × UUa) / (SUa × UCr) × 100 (%)
Where UUa and SUa are urine and serum uric acid (mg/dL), respectively. 
The baseline, postbaseline, and change from baseline in TmP/GFR, FEPO4, and FEUA will be 
summarized by treatment group and visit using descriptive statistics, during the entire study 
treatment period. 
Median (Q1, Q3) change from the double-blind baseline in TmP/GFR, FEPO4, and FEUA over 
time will be plotted by treatment group for the entire study treatment period, for participants in 
the Safety Analysis Set.
7.5.
Ophthalmologic Assessment
As no Ophthalmologic assessment was performed in China, no analysis will be conducted.
7.6.
Body Weight
Body weight at each visit and change from baseline in body weight will be summarized using 
descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) by 
treatment group for each postbaseline analysis window, during the entire study treatment period. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3.
7.7.
Prior Hepatitis B Medications
Prior HBV medications will be summarized by treatment group. No inferential statistics will be 
computed. A listing of prior HBV medications will also be provided.
7.8.
Concomitant Medications
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 for the 
double-blind, the open-label phases, and will be summarized (number and percentage of 
participants) separately by treatment group and WHO drug class and preferred name. Multiple 
drug use (by preferred name) will be counted only once per participant. The summary will be 
sorted alphabetically by drug class and then by decreasing total frequency within a class. 


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If the start or stop date of concomitant medications is incomplete, the month and year 
(or year alone if month is not recorded) of start or stop date will be used to determine if the 
medications are concomitant as follows. The medication is concomitant for the double-blind 
phase 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 blinded 
study drug
•
The month and year of stop of the medication is before the date of the first dose of blinded 
study drug
The medication is concomitant for the open-label phase 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 open-label 
study drug
•
The month and year of stop of the medication is before the date of the first dose of open-label 
study drug
If both the start and stop date of the medication are missing, the medication will be considered as 
concomitant during both double-blind and open-label phases.
If the start and stop date of the medications are not missing, and the start date is not after the last 
dose date of the blinded study drug and the stop date is not before the first dose date of the 
blinded study drug, or the medications are marked as ongoing and start date is on or before the 
last dose date of the blinded study drug, the medications are considered concomitant during the 
double-blind phase.
Similarly, if the start and stop date of the medications are not missing, and the start date is not 
after the last dose date of the open-label study drug and the stop date is not before the first dose 
date of the open-label study drug, or the medications are marked as ongoing and start date is on 
or before the last dose date of the open-label study drug, the medications are considered 
concomitant during the open-label phase.
Summaries of concomitant medications will be provided for the double-blind phase using the 
Safety Analysis Set and the open-label phase using the Open-Label Safety Analysis Set. 
No inferential statistics will be provided. Participants with any concomitant medication use will 
also be listed.


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7.9.
Electrocardiogram (ECG) Results
The number and percentage of participants in the Safety Analysis Set with an investigator’s ECG 
assessment of normal, abnormal but not clinically significant, or abnormal and clinically 
significant will be summarized by treatment group and by baseline result for each visit, during 
the entire study period. No inferential statistics will be provided. 
A by-participant listing of safety ECG results will be provided including treatment, assessment 
date and time, and ECG results.
7.10.
Other Safety Measures
A data listing will be provided for participants experiencing pregnancy during the study. 
Listings of cirrhosis and hepatocellular carcinoma assessment results will be provided.
Alcohol use at baseline will also be listed.
7.11.
Changes From Protocol-Specified Safety Analyses
Treatment-emergent proteinuria was not included as a key secondary safety end point in 
Protocol Amendment 3.1 and is added in the SAP. 
As no Ophthalmologic assessment was performed in China, no analysis will be conducted.
Comparison of the safety and tolerability of TAF versus TDF for the treatment of HBeAg 
negative, CHB beyond Week 48 during the double-blind phase in treatment-naive and 
treatment-experienced participants was not included as a secondary objective of this study 
and was documented in the Week 48 China Analysis SAP and is carried over to this SAP.


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8.
REFERENCES
Barth JH, Jones RG, Payne RB. Calculation of renal tubular reabsorption of phosphate: the 
algorithm performs better than the nomogram. Ann Clin Biochem 2000;37 ( Pt 
1):79-81.
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the 
Evaluation and Management of Chronic Kidney Disease. Kidney international. 
Supplement 2013;3 (1):v-150.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150 (9):604-
12.
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. 
National Institute of Health May, 2001.


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9.
SOFTWARE
nQuery Advisor® (Statistical Solutions Ltd., Version 6.0, Cork, Ireland) was used for the sample 
size and power calculation.
SAS® (SAS Institute Inc., Version 9.4, Cary, NC) is to be used for all programming of tables, 
listings, and figures.


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10.
SAP REVISION
Revision Date
(dd month yyyy)
Section
Summary of Revision
Reason for Revision


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11.
APPENDICES
Appendix 1.
Adverse Events of COVID-19
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19


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Appendix 1.
Adverse Events of COVID-19
An adverse event record will be flagged as adverse events for COVID-19 if its Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term (PT) is included in the 
pre-specified PT list, which includes all PTs from the narrow search of the following COVID-19 
SMQs under based the latest MedDRA version provided by Gilead GLPS (search name: 
COVID-19 (SMQ) – Narrow) and reviewed by Gilead medical monitors.
SMQ Source
AEs for COVID-19 
COVID-19 (SMQ) (Narrow Scope)


TAF
GS-US-320-0108 Final China
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 63
20 December 2023
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm that will be used to determine which visits 
are missing and which visits are virtual.
Data Collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by 
Clinical Data Management to instruct clinical trial sites with data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites were instructed to enter 
“Visit missed due to COVID-19” and if an in-person visit was conducted virtually, sites were 
instructed to enter “Virtual visit due to COVID-19”.
Determination of Missed and Virtual Visits
Natural Language Processing (NLP) will be used to search the CRF comment fields to identify 
instances of “COVID-19”, “Virtual”, or synonyms (see Table 11-1). The search terms will be 
maintained in a global lookup table and can be modified to tune the NLP model. Any comments 
with COVID-19 search terms, “Missed visit” or “Virtual visit” will be assigned as follows:
i.
If COVID-19 terms are identified through NLP and the visit date is missing, then result is 
“Missed Visit”
ii. If COVID-19 and Virtual terms are identified through NLP for a visit, then result is “Virtual 
Visit”. When there are multiple records for the same participant and the same visit, if one 
record could be categorized as “Virtual Visit”, all records associated with this participant and 
this visit will be categorized as “Virtual Visit”
iii. Otherwise result is missing
Table 11-1.
Example Search Terms for “COVID-19” and “Virtual” Used to 
Identify Missed/Virtual Visits
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
CORONA
CORONAVIRUS
PANDEMIC
OUTBREAK
CRISIS
LOCKDOWN
QUARANTINE
SHELTER
VIRTUAL
TELEMED
TELEHEALTH
TELEPHONE
REMOTE
TELEMEDICINE
TELECONSULTATION
TELEPHONICALLY
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-320-0108 SAP Final China
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
20-Dec-2023
18:39:50
Clinical Development
eSigned
04-Jan-2024
16:25:23
PPD
PPD

Prot_003.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director: 
Gilead Sciences 
Medical Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy of Tenofovir Alafenamide (T AF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (IDF) 300 mg QD for the 
Treatment ofHBeAg-Negative, Chronic Hepatitis B 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
115,561 
2013-000626-63 
NCT0 1940341 
HBeAg-negative Chronic Hepatitis B 
GS-US-320-0108 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Name: 
Telephone: 
Fax (paper): 
Email: 
Amendment 3 .4: 
John Flahert l.> Pharm D 
PPD 
PPD 
PPD 
PPD 
PPD 
25 September 2019 
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. 


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
Gilead Sciences, lnc. 
Final 
Amendment 3 .4 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 19 
I. 
INTRODUCTION .............................................................................................................................................. 23 
1.1. 
Background ............................................................................................................................................ 23 
1.2. 
Tenofovir Alafenamide (TAF, GS-7340) ............................................................................................... 25 
1.2.1. 
General Information ............................................................................................................. 25 
1.2.2. 
Preclinical Pharmacology and Toxicology ........................................................................... 26 
1.2.3. 
Clinical Trials ofTenofovir Alafenamide (TAF, GS-7340) ................................................. 29 
1.2.4. 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(EiC/FIT AF) ......................................................................................................................... 41 
1.3. 
Rationale for This Study ........................................................................................................................ 49 
1.3. I. 
Tenofovir Alafenamide (T AF) for Treatment of Chronic Hepatitis B ................................. 49 
1.3.2. 
Rationale for the Current Study ............................................................................................ 50 
1.3 .3. 
Rationale for Dose Selection ................................................................................................ 52 
1.4. 
Compliance ............................................................................................................................................ 53 
2. 
OBJECTIVES ..................................................................................................................................................... 54 
3. 
STUDY DESIGN ................................................................................................................................................ 56 
3. I. 
Treatment Plan and Regimen ................................................................................................................. 56 
3.2. 
Biomarker Testing .................................................................................................................................. 57 
3.2.1. 
Biomarker Sam les to Address the Stud Ob·ectives: ......................................................... 57 
3.2.2. 
I 
4. 
SUBJECT POPULATION .................................................................................................................................. 60 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 60 
4.2. 
Inclusion Criteria .................................................................................................................................... 60 
4.3. 
Exclusion Criteria ................................................................................................................................... 6 1 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 63 
5.1. 
Randomization and Blinding .................................................................................................................. 63 
5.1.1. 
Procedures for Breaking Treatment Codes ........................................................................... 63 
5.2. 
Description and Handling ofTenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate 
(TDF) and Matched Placebos ................................................................................................................. 64 
5.2.1. 
Formulation .......................................................................................................................... 64 
5.2.2. 
Packaging and Labeling ....................................................................................................... 65 
5.2.3. 
Storage and Handling ........................................................................................................... 65 
5.3. 
Dosage and Administration ofT AF and TDF and Matched Placebos ................................................... 65 
5.4. 
Prior and Concomitant Medications ....................................................................................................... 66 
5.5. 
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos ................................................................................................................................... 68 
5.5.1. 
lnvestigational Medicinal Product Return or Disposal ......................................................... 68 
6. 
STUDY PROCEDURES .................................................................................................................................... 69 
CONFIDENTIAL 
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Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
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Final 
Amendment 3 .4 
7. 
6.1. 
Subject Enrollment and Treatment Assignment ..................................................................................... 69 
6.2. 
Pretreatment Assessments ...................................................................................................................... 69 
6.3. 
6.4. 
6.5. 
6.6. I 
6.2.1. 
Screening Visit ..................................................................................................................... 69 
6.2.2. 
Baseline Assessments ........................................................................................................... 70 
Treatment Assessments .......................................................................................................................... 71 
6.3.1. 
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144) ...................................................................................................... 71 
6.3.2. 
Open Label Visits ................................................................................................................. 81 
Post-treatment Assessments ................................................................................................................... 83 
6.4.1. 
HBsAg Loss and Seroconversion Subjects .......................................................................... 83 
6.4.2. 
All other subjects who discontinue study dtug ..................................................................... 83 
6.4.3. 
Follow up visit assessments (all subjects) ............................................................................ 83 
Early Discontinuation (ED) from Study ................................................................................................. 84 
Criteria for Discontinuation of Stud Treatment .................................................................................... 84 
Resistance urve1 ance .......................................................................................................................... 6 
6.10. 
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance ........................................................... 86 
6.11 . 
End of Study ........................................................................................................................................... 86 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 87 
7. I. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 87 
7. I. I. 
Adverse Events ..................................................................................................................... 87 
7 .1.2. 
Serious Adverse Events ........................................................................................................ 87 
7.1.3. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 88 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 88 
7 .2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 88 
7 .2.2. 
Assessment of Severity ........................................................................................................ 89 
7.3. 
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO ......................................................................................................... 89 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 92 
7.5. 
Toxicity Management ............................................................................................................................ 92 
7.5.1. 
Grades I and 2 Laboratory Abnormality or Clinical Event... ............................................... 93 
7.5.2. 
Grade 3 Laboratoty Abnormality or Clinical Event ............................................................. 93 
7.5.3. 
Grade 4 Laboratoty Abnormality or Clinical Event ............................................................. 93 
7.5.4. 
Management of Bone Evaluation ......................................................................................... 94 
7.5.5. 
Management of Potential Nephrotoxicity ............................................................................. 94 
7.5.6. 
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management ......................................................................................................................... 95 
7.5.7. 
Management of Potential Posterior Uveitis Cases ................................................................ 97 
7 .6. 
Special Situations Reports ...................................................................................................................... 97 
7 .6.1. 
Definitions of Special Situations .......................................................................................... 97 
7.6.2. 
lnsttuctions for Reporting Special Situations ....................................................................... 98 
8. 
STA TIS TI CAL CONSIDERATIONS .............................................................................................................. I 00 
8.1. 
Analysis Objectives and Endpoints ...................................................................................................... I 00 
8.1.1. 
Analysis Objectives ............................................................................................................ I 00 
8.1.2. 
Primary Endpoint ............................................................................................................... IO I 
8.1.3. 
Secondary Endpoints .......................................................................................................... IOI 
8.1.4. 
Other Endpoints of Interest ................................................................................................ IO I 
8.2. 
Analysis Conventions ........................................................................................................................... I 02 
8.2.1. 
Analysis Sets ...................................................................................................................... I 02 
8.2.2. 
Data Handling Conventions ............................................................................................... I 03 
CONFIDENTIAL 
Page 3 
25 September 2019 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
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Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
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25 September 2019
8.3.
Multiplicity Adjustments......................................................................................................................103
8.4.
Demographic Data and Baseline Characteristics .................................................................................104
8.5.
Efficacy Analysis .................................................................................................................................104
8.5.1.
Primary Analysis................................................................................................................104
8.5.2.
Analyses of Other Endpoints of Interest.............................................................................105
8.6.
Safety Analysis.....................................................................................................................................105
8.6.1.
Key Secondary Safety Analyses.........................................................................................105
8.6.2.
Extent of Exposure.............................................................................................................106
8.6.3.
Adverse Events...................................................................................................................106
8.6.4.
Laboratory Evaluations ......................................................................................................106
8.7.
Pharmacokinetic Analysis....................................................................................................................107
8.7.1.
Biomarker Analysis............................................................................................................107
8.8.
Sample Size..........................................................................................................................................107
8.9.
Data Monitoring Committee ................................................................................................................108
9.
RESPONSIBILITIES........................................................................................................................................109
9.1.
Investigator Responsibilities ................................................................................................................109
9.1.1.
Good Clinical Practice........................................................................................................109
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................109
9.1.3.
Informed Consent...............................................................................................................109
9.1.4.
Confidentiality....................................................................................................................110
9.1.5.
Study Files and Retention of Records ................................................................................110
9.1.6.
Case Report Forms.............................................................................................................111
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................112
9.1.8.
Inspections..........................................................................................................................112
9.1.9.
Protocol Compliance..........................................................................................................112
9.2.
Sponsor Responsibilities ......................................................................................................................113
9.2.1.
Protocol Modifications.......................................................................................................113
9.2.2.
Study Report and Publications ...........................................................................................113
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................113
9.3.1.
Access to Information for Monitoring................................................................................113
9.3.2.
Access to Information for Auditing or Inspections ............................................................114
9.3.3.
Study Discontinuation........................................................................................................114
10.
REFERENCES .................................................................................................................................................115
11.
APPENDICES ..................................................................................................................................................117
Appendix 1.
Investigator Signature Page..................................................................................................118
Appendix 2.
Study Procedures Table........................................................................................................119
Appendix 3.
 Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])............................................................................125
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................126
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............127
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations.........................................................................................149
CCI


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Gilead Sciences, Inc.
Amendment 3.4
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LIST OF IN-TEXT TABLES
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection......................................30
Table 1-2.
GS-US-320-0101: Baseline Demographics and Disease Characteristics ...............................33
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and Laboratory 
Abnormalities: Overall Summary, Safety Analysis Set..........................................................34
Table 1-4.
GS-US-320-0101: HBV DNA Results: Median Change from Baseline at Day 15 
and Day 29 by Treatment Group ............................................................................................37
Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on Day 1 ........................39
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on Day 1 ........................40
Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: Overall Summary, Safety 
Analysis Set............................................................................................................................44
Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities, 
Safety Analysis Set.................................................................................................................45
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine and Hip Bone 
Mineral Density at Week 24, DXA Analysis Set ...................................................................47
Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by Gradation at Week 
24, DXA Analysis Set ............................................................................................................48
Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover Markers, 
Safety Analysis Set.................................................................................................................49
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution Due to the 
Potential for Drug-Drug Interaction with Study Medication..................................................67
LIST OF IN-TEXT FIGURES
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance (Cockcroft-Gault
Method) in GS-US-320-0101.................................................................................................35
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV DNA (Log10
IU/mL) by Treatment Group ..................................................................................................36
Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: TAF (GS-
7340), Linear Scale.................................................................................................................38
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: 
Tenofovir, Linear Scale..........................................................................................................39
Figure 1-5.
GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
Cockcroft-Gault by Visit, Safety Analysis Set.......................................................................46
Figure 3-1.
Study Schema.........................................................................................................................57


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 6
25 September 2019
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Title of Study:
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg-Negative, Chronic Hepatitis B
IND Number:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
115,561
2013-000626-63
NCT01940341
Study Centers Planned:
Approximately 160 centers worldwide
Objectives:
The primary objectives of this study are as follows:

To compare the efficacy of tenofovir alafenamide (TAF) 
25 mg QD versus tenofovir disoproxil fumarate (TDF) 300 mg 
QD for the treatment of HBeAg-negative, chronic hepatitis B 
at Week 48 in treatment-naïve and treatment-experienced 
subjects. The primary efficacy parameter is the proportion of 
subjects with plasma HBV DNA levels below 29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD 
versus TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows:

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the percent change from baseline in hip 
and spine bone mineral density (BMD) at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the change from baseline in serum 
creatinine at Week 48


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 7
25 September 2019
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF
300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48, 96,
and 144

To compare the serological response (loss of HBsAg with 
seroconversion to anti-HBs) of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest®
of TAF 25 mg QD versus TDF 300 mg QD for the treatment 
of HBeAg-negative, chronic hepatitis B at Weeks 48, 96,
and 144

To compare the incidence of drug resistant mutations of TAF 
25 mg QD versus TDF 300 mg QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic 
findings by fundoscopic examination of TAF 25 mg QD 
versus TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in a 
subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir 
(TFV) and determine intracellular concentrations of tenofovir 
diphosphate (TFV-DP) within peripheral blood mononuclear 
cells (PBMCs) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy , safety, and 
incidence of drug resistance mutations of TAF 25 mg QD in 
subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD and then 
switched to open-label TAF 25 mg QD


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.4
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Study Design:
This is a randomized, double-blind, non-inferiority study to 
compare the antiviral activity of TAF 25 mg QD versus TDF 
300 mg QD. Approximately 390 subjects will be randomized in 
a 2:1 ratio (A:B) to the treatment arms and will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
> 7 log10 IU/mL
< 8 log10 IU/mL, > 8 log10 IU/mL) and oral 
antiviral treatment status (treatment-naïve vs. 
treatment-experienced).
Treatment Arm A: 260 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD
For China, approximately 150 additional subjects 
(100 in Treatment Arm A and 50 in Treatment Arm B) will be 
enrolled for local registration purposes.
The duration of double-blind treatment is 144 weeks (96 weeks 
under Amendment 2.1). All subjects who complete the double-
blind period of treatment are eligible for participation in the open 
label TAF 25 mg QD extension period for an additional 
240 weeks (through Week 384/ED). Subjects already assigned to 
open-label TAF 25 mg QD at Week 96 per Amendment 2.1 will 
continue on open-label TAF 25 mg QD through Week 384/ED. 
For the entire duration of the study, subjects and investigators will 
remain blinded to the initial treatment regimen to which they were 
randomized.
Subjects with a confirmed creatinine clearance (CLCr) 
< 50 mL/min, and > 20 % decline in eGFR by CKD-EPI 
(cystatin C), at any time during the double blind period of the 
study will be required to undergo dose modification to every other 
day dosing of study drug. Subjects with confirmed creatinine 
clearance < 30 mL/min at any time during the study will have the 
study drug permanently discontinued.
The primary analysis will occur at Week 48 with the primary 
efficacy endpoint being the proportion of subjects with complete 
viral suppression, i.e., plasma HBV DNA level below 29 IU/mL.
Subjects who permanently discontinue study drug 
(either prematurely or at the end of study [Week 384]) for reasons 
other than HBsAg loss with confirmed seroconversion to anti-HBs 
will be followed every 4 weeks for 24 weeks off treatment or until 
initiation of alternative, commercially available, HBV therapy, 
whichever occurs first. Use of commercial therapy is strongly 
encouraged.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
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Gilead Sciences, Inc.
Amendment 3.4
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Subjects with HBsAg loss with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of seroconversion to anti-HBs. Subjects 
with HBsAg loss with confirmed seroconversion to anti-HBs prior 
to Week 48 are not permitted to discontinue study drug prior to 
the Week 48 visit. Subjects who discontinue study drug for 
confirmed seroconversion to anti-HBs will be followed off 
treatment every 4 weeks for 12 weeks and then per the study visit 
schedule (Appendix 2) through Week 384/ED. Discontinuation of 
study drug for subjects experiencing HBsAg loss with confirmed 
seroconversion, who have known bridging fibrosis or cirrhosis, 
should be considered on a case by case basis.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will review the progress and safety of this 
study approximately every 24 weeks following the time of 
randomization of the first subject during the double blind period 
of the study. During the open-label duration of the study (Weeks 
144 to 384), the DMC will convene approximately every 
48 weeks. At each meeting, the DMC will review routine safety 
and dual energy X-ray absorptiometry (DXA) data and will make 
recommendations regarding modification of the study treatment.
Number of Subjects 
Planned:
390 subjects (260 subjects TAF 25 mg QD and matched placebo 
of TDF 300 mg QD, and 130 subjects TDF 300 mg QD and 
matched placebo of TAF 25 mg QD)
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of 
TAF 25 mg QD) will be enrolled.
Target Population:
Subjects, who are 18 years of age and older, with HBeAg-
negative, chronic hepatitis B
Duration of 
Treatment:
The duration of the double-blind treatment is 144 weeks
(96 weeks under Amendment 2.1). After completing the double-
blind period of treatment, all subjects remaining on treatment will 
be eligible to receive open label TAF 25 mg QD for up to an 
additional 240 weeks (Week 144 through Week 384). Subjects 
already assigned to open-label TAF 25 mg QD at Week 96 per 
Amendment 2.1 will continue on open-label TAF through Week 
384/ED. Subjects who lose HBsAg with confirmed
seroconversion to anti-HBs should discontinue study drug within 
3-6 months following confirmation of seroconversion to anti-HBs, 
or after Week 48, if seroconversion occurs prior to this visit. 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
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Diagnosis and Main 
Eligibility Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible to participate in the study.
1) Must have the ability to understand and sign a written 
informed consent form, which must be obtained prior to 
initiation of study procedures.
2) Male and non-pregnant, non-lactating female subjects, 
18 years of age and older, based on the date of the screening 
visit. A negative serum pregnancy test at Screening is required 
for female subjects of childbearing potential (as defined in 
Appendix 6).
3) Documented evidence of chronic HBV infection 
(e.g. HBsAg positive for more than 6 months)
4) HBeAg-negative, chronic hepatitis B with all of the following:
a) HBeAg-negative and HBeAb positive at Screening (if the
subject is deemed ineligible for this study by HBV 
serology [i.e. HBeAg positive CHB], this information may 
be used to determine eligibility for GS-US-320-0110 
[another Gilead Sciences Phase 3 study in HBeAg-
positive, CHB subjects; this study must also be IRB/EC 
approved at the participating center])
b) Screening HBV DNA ≥ 2 × 104 IU/mL 
c) Screening serum ALT level > 60 U/L (males) or > 38 U/L 
(females) and ≤10 × ULN (by central laboratory range)
5) Treatment-naïve subjects (defined as < 12 weeks of oral 
antiviral treatment with any nucleoside or nucleotide 
analogue), OR treatment-experienced subjects (defined as 
subjects meeting all entry criteria [including HBV DNA and 
serum ALT criteria] and with ≥12 weeks of previous treatment 
with any nucleoside or nucleotide analogue) will be eligible 
for enrollment. Treatment-experienced subjects receiving oral 
antiviral treatment at Screening must continue their treatment 
regimen until the time of randomization, when it will be 
discontinued.
6) Any previous treatment with interferon (pegylated or 
non-pegylated) must have ended at least 6 months prior to the 
baseline visit.


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7) Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the 
Cockcroft-Gault method) based on serum creatinine and actual 
body weight as measured at the Screening evaluation, as 
follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8) Normal ECG (or if abnormal, determined by the investigator
not to be clinically significant)
9) Must be willing and able to comply with all study 
requirements.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not 
to be enrolled in the study.
1) Pregnant women, women who are breastfeeding or who 
believe they may wish to become pregnant during the course 
of the study.
2) Males and females of reproductive potential who are unwilling 
to use an “effective”, protocol-specified method(s) of 
contraception during the study. For a list of protocol-specified 
contraceptive methods, refer to Appendix 6.
3) Co-infection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by 
recent imaging)
5) Any history of, or current evidence of, clinical hepatic 
decompensation (e.g., ascites, encephalopathy or 
variceal hemorrhage).
6) Abnormal hematological and biochemical parameters, including:
a) Hemoglobin < 10 g/dL 
b) Absolute neutrophil count < 750/mm3
c) Platelets ≤50,000/mm3
d) AST or ALT > 10 × ULN
e) Total bilirubin > 2.5 × ULN
f)
Albumin < 3.0 g/dL
g) INR > 1.5 × ULN (unless stable on anticoagulant regimen)
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator


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9) Significant bone disease (eg, osteomalacia, chronic 
osteomyelitis, osteogenesis imperfecta, osteochrondroses), or 
multiple bone fractures
10) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical 
resection (basal cell skin cancer, etc). Subjects under 
evaluation for possible malignancy are not eligible
11) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), investigational agents, nephrotoxic 
agents, or agents capable of modifying renal excretion
12) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
13) Current alcohol or substance abuse judged by the investigator 
to potentially interfere with subject compliance
14) Any other clinical condition or prior therapy that, in the 
opinion of the investigator, would make the subject unsuitable 
for the study or unable to comply with dosing requirements.
15) Subjects on prohibited concomitant medications (See Table 5-1). 
Subjects on prohibited medications, otherwise eligible, will 
need a wash out period of at least 30 days.
Study Procedures/
Frequency:
Laboratory analyses (serum chemistry, liver tests, hematology, 
urinalysis, plasma HBV DNA levels, pregnancy testing [for 
females of childbearing potential]), vital signs, adverse events and 
concomitant medications will be performed at Screening, 
Baseline, and every 4 weeks thereafter through Week 48, every 
8 weeks through Week 96, every 12 weeks through Week 144, 
and every 24 weeks through Week 384/Early Discontinuation 
(ED) visit. HBV serology (HBeAg and HBeAb, HBsAg and 
reflex HBsAb [anti-HBs]) will be performed at Screening and 
Baseline, HBsAg and reflex HBsAb will be performed every 
12-16 weeks until Week 144, every 24 weeks until Week 384/ED 
and at Follow Up Weeks 12 and 24. Quantitative serum HBsAg 
will be assessed at Screening, Baseline, and every 12-16 weeks
until Week 144, every 24 weeks until Week 384/ED, and at 
Follow Up visits. Bone and renal biomarker testing will be 
performed at Baseline and then at defined intervals (see Schedule 
of Assessments, Appendix 2) throughout the study. IL28B 
polymorphism genotype, HBV genotyping and vitamin D level 
will be performed at Baseline only. Fibrotest® will be performed 
at Baseline and every 48 weeks until Week 384/ED. Fasting 
metabolic assessments (fasting glucose and lipid panel) will be 


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conducted at Baseline, every 24 weeks until Week 240, and every 
48 weeks m1til Week 384/ED visit. 
Complete physical examinations will be perfonned at Screening, 
Baseline, and Weeks 24, 48, 72, 96, 144, 240 and Week 384/ED. 
Height assessment will be conducted at Screening only. Symptom 
directed physical exams with body weight assessment will be 
conducted at all other visits. ECG will be perfonned at Screening 
and every 48 weeks thereafter. At sites in China with the 
capability only, DXA scans of the hip and spine will be conducted 
during the screening period, and should be conducted at least 
14 days prior to the first dose of study drug, and will be 
subsequently conducted at Weeks 24, 48, 72, 120, 96, 144, every 
48 weeks until Week 384, and the ED visit, if not done within the 
last 24 weeks. Hepatic ultrasound for surveillance of 
hepatocellular carcinoma will be perfonned starting at Week 96 
and then every 24 weeks until Week 384/ED. 
Genotypic analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance will be perfonned at Baseline 
for all subjects and attempted for all viremic subjects (HBV DNA 
69 IU/mL) at Weeks 48, 96, 144 and every 48 weeks until 
Week 384/ED. As it may not be known at the time of the visit 
whether a patient is viremic or if it will be their last study visit, a 
separate virology sample for potential resistance surveillance will 
be collected at each study visit. Plasma, serum, and urine will be 
collected at Baseline and at every visit thereafter for storage. 
A single phannacokinetic (PK) blood sample will be collected at 
all study visits from Weeks 4 through 48 for all subjects. At the 
Week 4 and 12 visits, dosing will occur in-clinic and a single PK 
blood sample will be collected between 15 minutes and 4 hours 
post-dose. It is preferred that subjects take their study drug 
according to a morning dosing schedule; however, evening dosing 
is allowable. Subjects who elect to dose in evening are not 
required to have in-clinic dosing and the single PK blood sample 
collection perfonned at the Week 4 and 12 visits. 
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Test Product, Dose, and 
Mode of 
Administration:
Double-Blind Treatment:

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 
and matched placebo of Tenofovir DF (TDF) 300 mg QD, 
oral administration
Open-Label Treatment:

Tenofovir alafenamide (TAF) 25 mg QD, oral administration
Reference Therapy, 
Dose, and Mode of 
Administration:
Double-blind Treatment:

Tenofovir DF 300 mg QD, oral administration and matched 
placebo of Tenofovir alafenamide (TAF) 25 mg QD, 
oral administration
Open-label Treatment: NA
Criteria for Evaluation:
Safety:
Key secondary safety endpoints include the percent change from 
baseline at Week 48 in hip and spine BMD, and change from 
baseline at Week 48 in serum creatinine.
If a subject has confirmed creatinine clearance (CLCr) 
< 50 mL/min, and > 20% decline in eGFR by CKD-EPI (cystatin 
C), at any time during the double-blind period of the study, the 
subject will be required to undergo dose modification to every 
other day dosing of study drug. Subjects with confirmed 
creatinine clearance < 30 mL/min at any time during the study
will have the study drug permanently discontinued.
The proportion of subjects in each treatment arm with tolerability 
failure (defined as an adverse event [AE] leading to permanent 
discontinuation of study drug) at Weeks 48, 96, 144, 240, and 384
will be summarized. Change from baseline in serum creatinine 
will be assessed at every visit and summarized through 
Week 384/ED. Change from baseline in BMD by DXA of the 
spine and hip will be assessed at Weeks 24, 48, 72, 96, 120, and 
144, and every 48 weeks until Week 384/ED. Fracture Risk 
Assessment will be evaluated at Baseline.
Ophthalmologic changes from baseline by fundoscopic 
examination at Weeks 24, 48, 72, 96, and 144 (or ED if prior to 
Week 144 and more than 24 weeks since the last exam) will be 
summarized for a subset of subjects (n = 30). In addition, for any 
subject who develops signs or symptoms of posterior uveitis, the 
investigator should contact the Gilead Medical Monitor to discuss 
the need for additional ophthalmologic evaluation including 
dilated fundoscopy and optical coherence tomography (OCT).


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Adverse events and clinical laboratory tests will be collected at 
every visit and summarized through Week144. Additionally, 
summaries of AEs, discontinuations due to AEs, and laboratory 
data including BMD measurements (via DXA scans, serum 
creatinine and creatinine clearance by Cockcroft-Gault) by 
original treatment arms (TAF versus TDF) will continue through 
Week 384. Fracture risk assessment will be evaluated at Baseline.
In China, this fracture risk assessment will be evaluated at sites 
with DXA capability only.
Efficacy:
The primary efficacy endpoint is the proportion of subjects with 
plasma HBV DNA levels below 29 IU/mL at Week 48. 
Other secondary efficacy endpoints are:

The proportion of subjects with plasma HBV DNA 
< 29 IU/mL at Weeks 96, 144, 240, and 384

The proportion of subjects with plasma HBV DNA 
< 29 IU/mL (target not detected) at Weeks 48, 96, 144, 240,
and 384

The proportion of subjects with ALT normalization (by central 
laboratory and American Association for the Study of Liver 
Diseases [AASLD] criteria) at Weeks 48, 96, 144, 240,
and 384

The proportion of subjects with HbsAg loss at 
Weeks 48, 96, 144, 240, and 384

The proportion of subjects with HbsAg seroconversion to 
anti-HBs at Weeks 48, 96, 144, 240, and 384

The change from baseline in fibrosis as assessed by 
FibroTest® at Weeks 48, 96, 144, 240, and 384

The incidence of drug resistant mutations at 
Weeks 48, 96, 144, 240, and 384
Pharmacokinetics:
The following TAF and TFV plasma pharmacokinetic parameters 
will be calculated for the 
population (n = 30): 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½
Single PK plasma samples collected at Weeks 4-48 may be used 
for estimation of population pharmacokinetics of TAF and TFV.
Single PBMC samples at selected PK substudy sites collected at 
the intensive PK substudy visit will be used for TFV-DP 
concentration determination
CCI


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Statistical Methods:
The primary analysis will be performed when approximately 
390 subjects complete 48 weeks of the double-blind treatment 
period or discontinue prematurely. The analysis will compare the 
TAF arm to the TDF arm.
Analysis Methods:
A two-sided 95% confidence interval, based on large sample 
theory, adjusted for the randomization stratification factors, for 
the difference (TAF-TDF) between treatments will be evaluated to 
compare treatment groups with respect to the primary efficacy 
endpoint. A missing equals failure approach will be employed for 
the primary analysis. Non-inferiority will be declared if the lower 
bound of this confidence interval exceeds 0.10 (i.e., 10% 
non-inferiority margin). If non-inferiority is established, the lower 
bound of the 95% confidence interval (CI) will be compared to 0; 
if the lower bound of the 95% CI is greater than 0, then 
superiority of TAF over TDF will be established using the same 
CI.
The percent change from baseline in hip and spine BMD at 
Week 48 will be analyzed using an analysis of variance 
(ANOVA) model. The model will include treatment group as a 
fixed effect. The details are provided in the Statistical Analysis 
Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be 
analyzed using an analysis of covariance (ANCOVA) model with 
baseline serum creatinine as a covariate, and treatment group as a 
fixed effect. The details are provided in the SAP.
All secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum). All categorical secondary endpoints 
will be summarized by number and percentage of subjects who 
meet the endpoint.
Sample Size:
With respect to the primary efficacy endpoint of proportion of 
subjects with plasma HBV DNA levels below 29 IU/mL at 
Week 48, when the sample sizes are 260 (TAF 25 mg arm) and 
130 (TDF 300 mg arm), a two-group, large-sample normal 
approximation test of proportions with a one-sided 0.025 
significance level will have 90% power to reject the null 
hypothesis, that the TAF 25 mg arm is inferior to the TDF 300 mg 
arm (the difference in proportions [TAF-TDF] having a lower 
bound of the one-sided 97.5% confidence interval of less than 
0.10, i.e., 10%) in favor of the alternative hypothesis that the 
TAF 25 mg arm is not inferior to the TDF 300 mg arm. This 
assumes the expected difference (TAF-TDF) in proportion of 


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subjects with HBV DNA < 29 IU/mL is 0 and the proportion of 
subjects with HBV DNA < 29 IU/mL in the TDF 300 mg arm is 
0.91.
The TDF virologic rate of 0.91 was calculated using the observed 
rate in Study GS-US-174-0102. 
This sample size also provides 90% power to detect a 1% 
difference in the percentage change from baseline in hip BMD at 
Week 48 (assuming a 1.17% change from baseline in TDF 
300 mg arm and 0.17% change in TAF 25 mg arm, with a 
common standard deviation of 2.20% and a two-sided α = 0.025); 
a 77% power to detect a 1% difference in the percentage change 
from baseline in spine BMD at Week 48 (assuming a 1.69% 
change from baseline in the TDF 300 mg arm and 0.69% change 
in the TAF 25 mg arm, with a common standard deviation of 
3.08% and a two-sided α = 0.025); a 52% power to detect a 
0.03 mg/dL difference in the change from baseline in serum 
creatinine at Week 48 (assuming a 0.04 mg/dL change from 
baseline in the TDF 300 mg arm and 0.01 mg/dL change from 
baseline in the TAF 25 mg arm, with a common standard 
deviation of 0.12). These assumptions were derived from studies 
GS-98-437, GS-98-438, GS-US-174-0102, GS-US-174-0103, and 
GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of TAF 25 mg 
QD) will be enrolled.
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
AASLD
American Association for the Study of Liver Diseases
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
AST
Aspartate aminotransferase (SGOT)
AUCinf
Area under the concentration versus time curve extrapolated to infinite time, calculated 
as AUC0last + (Clast/z)
AUCtau
Area under the plasma concentration versus time curve over the dosing interval (tau)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKF-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI / C
Cobicistat
CRF/eCRF
Case report form(s)/electronic case report form(s)
CRO
Contract (or clinical) research organization
CTX
C-type collagen sequence
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
PVE
Pharmacovigilance and Epidemiology
DXA
Dual energy x-ray absorptiometry


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E2
Estradiol
EC
Ethics committee
EudraCT
European clinical trials database
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HbeAb
Hepatitis B e antibody
HbeAg
Hepatitis B e antigen
HbsAb
Hepatitis B surface antibody
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)


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IRB
Institutional review board
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure


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STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
Tenofovir Alafenamide, GS-7340
TAF Fumarate
Tenofovir Alafenamide Fumarate, GS-7340-03
TDF
Tenofovir Disoproxil Fumarate
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TLOVR
Time to loss of virologic response
Tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
T3
Triiodothyronine
TSH
Thyroid stimulating hormone
UACR
Urine albumin-to-creatinine ratio
UGT1A1
Uridine glucuronosyltransferase 1 family, polypeptide A1 
ULN
Upper limit of the normal range
UPCR
Urine protein-to-creatinine ratio
US
United States
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a serious global health care problem and one of the principal causes 
of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Of the estimated 
2 billion people worldwide who have been acutely infected with the hepatitis B virus (HBV), 
approximately 400 million have developed CHB, and approximately 1 million people die 
annually from complications of CHB {World Health Organization (WHO) 2000}. Despite the 
availability of HBV vaccine programs in many countries, new HBV infections are still common 
even in areas of low endemicity. For example, approximately 80,000 people in the United States 
(US) become acutely infected each year, according to an estimate from the Centers for Disease 
Control and Prevention {Centers for Disease Control and Prevention (CDC) 2003}. Following 
acute HBV infection, approximately 5% to 10% of adults and up to 90% of children fail to 
produce an immune response adequate to clear the infection; these individuals become chronic 
carriers of the virus {Zuckerman 1996}.
Chronic hepatitis B has a broad clinical spectrum, ranging from asymptomatic, slowly 
progressive illness to severe, and more rapidly progressive liver disease. Chronic hepatitis B may 
remain quiescent for many years and represent a risk factor for progression to cirrhosis, liver 
failure, and death within a few years. Approximately 25% of subjects with CHB will ultimately 
develop serious liver disease such as hepatic decompensation, cirrhosis, or HCC {Zuckerman 1996}. 
The development of nucleos(t)ide analogues has been a major breakthrough for the treatment of 
CHB, providing effective suppression of viral replication and reducing the risk of long term 
complications. However, if viral replication resumes as a result of resistance mutation 
development, the clinical benefit is lost. The rate of resistance development in treatment-naive 
subjects varies depending on the treatment: up to 70% after 4 years with lamivudine (LAM), up 
to 29% after 5 years with adefovir dipivoxil (ADV), 25%/11% in hepatitis B e antigen 
positive/negative (hepatitis B e antigen [HBeAg]+/) subjects after 2 years with telbivudine 
(LdT), and 1.2% after 5 years with entecavir (ETV). To date, resistance to TDF has not been 
documented {Marcellin 2011}.
Tenofovir DF (Viread®) 300 mg once daily was first approved for the treatment of CHB in 
Turkey on 28 March 2008, and is currently approved in 101 countries, including the US, Canada, 
and Europe. Approval of TDF for CHB was based primarily on 48 week data from 375 adult 
subjects with HBeAg  CHB and 266 subjects with HBeAg+ CHB who enrolled in the similarly 
designed pivotal studies GS-US-174-0102 (HBeAg  subjects) and GS-US-174-0103 
(HBeAg+ subjects). In study GS-US-174-0102, TDF 300 mg once daily was shown to be 
superior to ADV 10 mg once daily for the treatment of HBeAg/antibody to hepatitis B e antigen 
(anti-HBe)-positive (presumed precore mutant) chronic HBV infection. At 48 weeks, 
70.8% of subjects in the TDF group (n = 250) had a complete response (plasma HBV 
deoxyribonucleic acid [DNA] < 69 IU/mL [400 copies/mL] and histologic improvement 
characterized by ≥2 point reduction in the Knodell necroinflammatory score and no worsening 
of Knodell fibrosis), compared to 48.8% of subjects in the ADV group (n = 125; p < 0.001) 
{Marcellin 2007}. In study GS-US-174-0103 (HBeAg+ subjects), at 48 weeks, 


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66.5% of subjects in the TDF group (n = 176) had a complete response, compared to 12.2% in 
the ADV group (n = 90; p < 0.001) {Heathcote 2007}. Subjects in both studies who completed 
the 48-week double-blind treatment period (including the end-of-blinded-treatment biopsy) were 
eligible to continue in an open-label (OL) extension phase consisting of treatment with TDF up 
to Week 480 (Year 10).
In both Phase 3 studies, for viremic subjects originally randomized to ADV who rolled over to 
open-label TDF at Week 48, HBV DNA values decreased sharply during the first 16 weeks of 
TDF therapy. At Week 96, the percentages of subjects with plasma HBV DNA < 400 copies/mL 
were not significantly different between treatment groups in both studies. Viral suppression was 
maintained through Week 240 of these 2 pivotal studies in those subjects receiving continued 
treatment with TDF for 240 weeks (TDFTDF group), and in those subjects who received 
192 weeks of TDF treatment following an initial 48 weeks of treatment with ADV 
(ADVTDF group). Based on results from a pooled histology analysis at Year 5 for these 
2 studies, 96.2% of subjects on open-label TDF experienced either improvement or no change in 
fibrosis (by Ishak fibrosis scoring). Further, of the 96 subjects with cirrhosis at baseline 
(Ishak fibrosis score 5-6), 25% experienced no change in Ishak fibrosis score while 73% 
experienced reversal of cirrhosis by Week 240 with a reduction in Ishak fibrosis score of at least 
2 points (missing = excluded [M = E], data after addition of emtricitabine [FTC] included) 
{Marcellin 2013}. Importantly, viral suppression (HBV DNA < 69 IU/mL or < 400 copies/mL 
was documented in 330/334 (99%) of subjects with available histology who were maintained on 
therapy with an available HBV DNA measurement at Week 240. No mutations associated with 
TDF resistance developed in subjects treated with TDF for up to 5 years in the pivotal studies
{Marcellin 2013}. No phenotypic resistance to TDF has been observed among subjects with 
virologic breakthrough or who developed conserved-site changes in the HBV polymerase 
(pol)/reverse transcriptase (RT) during TDF treatment for up to 5 years. Continued treatment 
with TDF for 5 years revealed no new adverse reactions inconsistent with the known safety 
profile of TDF. Importantly, these results demonstrate that achievement and maintenance of long 
term viral suppression with TDF translates into a histological benefit (i.e. fibrosis regression) in 
the majority of subjects.
While liver biopsy provides important information regarding severity of necroinflammatory 
activity and fibrosis in diseases such as CHB, it is no longer considered routine in clinical 
practice for ongoing disease monitoring, and the procedure itself is challenging to perform within 
the context of clinical trials. Additionally, liver biopsy is costly and limited by sampling error as 
well as patient reluctance to undergo this invasive procedure. With the availability of 
non-invasive tests, including FibroTest® (also known as FibroSURE in the U.S.) and Fibroscan®, 
which have been shown to correlate with histology in liver diseases such hepatitis B 
{Poynard 2005}, hepatitis C {Ngo 2006}, and non-alcoholic fatty liver disease {Poynard 2007}, 
the need for liver biopsy has been largely replaced, particularly for ongoing monitoring of 
changes in fibrosis.
Tenofovir DF is also approved worldwide in many markets for administration in combination 
with other antiretroviral agents for treatment of human immunodeficiency virus (HIV)-1 
infection (first approval in 2001). Tenofovir DF is also a component of Truvada®
(FTC 200 mg/TDF 300 mg), a marketed fixed-dose combination product for treatment of HIV-1 


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infection in combination with other antiretroviral agents. More recently, TDF has been included 
in single tablet regimens (STRs) for treatment of HIV infection. Three STRs are currently 
approved for once-daily administration in the treatment of HIV-1 infection, efavirenz 
(EFV)/FTC/TDF (Atripla®), FTC/rilpivirine (RPV)/TDF (Complera®/Eviplera), and more 
recently, elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TDF (Stribild™). The newly approved 
Stribild™STR tablet, which contains a fixed-dose combination of E/C/F/TDF 
(150/150/200/300 mg), has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HIV-1 infection in treatment-naïve adults. E/C/F/TDF 
is the first approved STR that combines an integrase strand transfer inhibitor (elvitegravir) with a 
nucleoside reverse transcriptase inhibitor (NRTI) backbone into a once-daily tablet. Since 
Viread® was first marketed on 31 October 2001, the overall exposure to TDF up to 31 May 2013 
from branded Viread®, Truvada®, Atripla®, Complera® and Stribild®, combined up to 
31 May 2013, is estimated to be in excess of 6 million patient years
TDF is a preferred oral N(t)RTIs for treatment of CHB infection by all current treatment 
guidelines. For the majority of CHB subjects, life-long treatment is required as only a small 
percentage (< 10%) of subjects experience sustained loss of hepatitis B surface antigen (HBsAg), 
and as a consequence, achieve an effective cure of the disease. Though highly effective, long 
term use of TDF is associated with nephrotoxicity and reduced bone mineral density in some 
subjects {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. Thus, alternative 
therapies with high antiviral potency, a high genetic barrier to resistance development, and 
improved long term safety and tolerability are needed in order to further advance treatment of 
chronic HBV infection worldwide.
Tenofovir alafenamide (TAF), a novel “intracellular” prodrug of tenofovir (TFV), has the 
potential to advance treatment of chronic HBV infection. In contrast to TDF, an oral prodrug that 
is rapidly cleaved by esterases in the intestines and plasma to TFV, TAF has been specifically 
synthesized to be more stable in resisting early enzymatic cleavage following oral administration 
and remain mostly intact until penetrating target cells. By virtue of this key distinguishing 
property, TAF when administered at a lower dose than TDF, is capable of efficiently delivering 
active drug (e.g. tenofovir diphosphate [TFV-DP]) to the cells where it is needed 
(e.g. HBV-infected hepatocytes, HIV-infected lymphoid cells) while systemic exposures of TFV 
are greatly reduced in comparison to oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication and an 
improved tolerability and safety profile.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is a next generation oral 
prodrug of TFV, a nucleotide analog that inhibits reverse transcription in HIV-1 and HBV. TFV
is metabolized intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) and HBV pol/RT that terminates the 
elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance 


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have been used in various studies: GS-7340, synonym for GS-7340 as the free base; 
GS-7340-02, synonym for TAF monofumarate (1:1); and GS-7340-03 as the hemifumarate (2:1). 
GS-7340-03, also known as TAF fumarate, the form being used in GS-US-292-0102 
(Phase 2 study in HIV subjects) and GS-US-320-0101 (Phase 1b study in HBV subjects), is 
considered comparable to GS-7340-02 based on physical/chemical properties of GS-7340-02, the 
form that has been used in previous studies and a number of currently ongoing studies. 
Importantly, both GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in 
blood and biological fluids.
For further information on TAF (GS-7340), please refer to the latest Investigator’s Brochure for 
GS-7340.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
TAF is converted intracellularly by cathepsin A (CatA) and carboxylesterase-1 (Ces1) to form 
TFV (i.e, a nucleoside monophosphate analog) which is not dependent on an intracellular 
nucleoside kinase activity for the first step in the conversion to the active metabolite, and is 
subsequently converted to TFV-DP by cellular kinases. The cellular enzymes responsible for 
TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) {Robbins 1995}
and nucleotide diphosphate kinase, which are highly active and ubiquitous. AK exists as multiple 
isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most efficiently by AK2. 
Analysis of primary cells showed that CatA activity varied minimally in both human cluster of 
differentiation 4 (CD4+) T-lymphocytes and macrophages. CatA activity was equivalent in 
resting and activated CD4s and approximately 2-fold higher in macrophages. Intracellular 
metabolites of TAF were similar among individual donors in both CD4+ T-cells and 
macrophages. Carboxylesterease-1 (Ces1) which is highly expressed in liver, contributes to TAF 
conversion to TFV, particularly in hepatocytes {Bam 2012, Birkus 2012}.
The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T-cells, NK cells, B-cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite 
TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations. 
Additionally, a 24-hour continuous incubation of TAF in primary human hepatocytes in vitro 
resulted in approximately 120- or 5-fold higher levels of TFV-DP compared to incubation of 
TFV or TDF, respectively (AD-120-2017).
1.2.2.2.
Safety Pharmacology
TAF monofumarate (GS-7340-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006) and 
gastrointestinal systems (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). GS-7340-02 (at 1000 mg/kg) reduced 
distal transit and increased stomach weights starting 2 hours post dosing with reversibility 


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beginning by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. The 
IC50 for the inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current was 
estimated to be greater than 10 μM.
1.2.2.3.
Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate (GS-7340-02), and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of GS-7340-02 is equivalent to 80 mg of the GS-7340 free 
base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours.
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with 
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted), and 8.1 to 
12.5 hours in rhesus monkeys.
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the 
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that 
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug based on 
IV studies of TFV. Following oral administration of GS-7340-02, approximately 15% of a 
radiolabeled dose is recovered in dog urine in 24 hrs. TFV was the major species present in the 
urine (90%), with about 3.4% of TAF also present. Biliary excretion of TFV in dogs and fecal 
elimination of TFV in rats and dogs are negligible.
Tenofovir was the only species found in the intestinal contents and feces. In human systems, 
TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed 
oxidation (AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4, inhibition 
or induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has 
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1 
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or 
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma 
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by 
clinically relevant drug-drug interactions is very low.
The hepatic extraction of TAF was estimated to be 70% suggesting that TAF was rapidly cleaved 
by hepatic hydrolases including Ces1 and CatA {Babusis 2013}. An in vitro study to evaluate 
effects of inhibitors of CatA or Ces1 on TAF metabolism in primary human hepatocytes is 
ongoing. Single and repeat dose dog liver pharmacokinetic studies are planned.


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1.2.2.4.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months and was negative in genetic toxicology studies.
In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. GS-7340-02 also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above. In chronic 
studies in dogs after 9 months of treatment with GS-7340-02, the primary target organs were 
kidney and bone.
GS-7340-02 had no discernible electrocardiograph (ECG/EKG) effect at the low dose of 
2 mg/kg/day and slightly prolonged PR intervals at 6 and 18/12 mg/kg/day (started at 
18 mg/kg/day, then reduced to 12 mg/kg/day at Weeks 7-8). Additionally, at Week 39, 
GS-7340-02 appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but was 
reversible at the 3 month recovery period. Minor hematological and biochemistry parameters 
changes were observed but remained within normal historical ranges with the following 
exceptions: AST (~ 100% increase) and total bilirubin (~ 40% increase). There were no clear 
treatment-related effects observed in monkeys following 28 days of treatment, including no 
changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day 
(tenofovir AUC = 3758 ng•h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day 
(tenofovir AUC = 1180 ng•h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (tenofovir AUC = 5870 ng•h/mL). In conjunction with the nonclinical data with 
TDF and the clinical experience with TDF and TAF, these toxicology studies support studies in
humans of doses up to 150 mg/day (equivalent to 120 mg free base, the highest anticipated 
human dose) for chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable TFV exposures 
less than previously tested in chronic and carcinogenicity studies with TDF, carcinogenicity 
studies in mice and rats with TAF are currently not required per agreement with FDA and EMA.
Also, TAF does not need to be evaluated in perinatal-postnatal reproductive toxicology studies
per agreement with FDA and EMA. Reproductive tissues were examined in repeat-dose 
toxicology studies in the rat, dog, and monkey. There were no clearly treatment-related 
histologic alterations or changes in organ weights in the rat and the dog following chronic daily 
dosing, or in the monkey.
The TAF fumarate (GS-7340-03) oral rat fertility study is ongoing (Report No. TX-120-2012;
report in progress).


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1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
To date, a total of 8 Phase 1 and Phase 1/2, or Phase 2, clinical trials of tenofovir alafenamide 
(TAF) have been conducted or are ongoing in 528 subjects. This includes seven HIV studies 
(total of 477 subjects; 2 completed Phase 1/2 studies [68 subjects], 3 completed Phase 1 studies 
[83 subjects], and 2 ongoing Phase 2 studies [326 subjects]), and 1 Phase 1b HBV study 
(completed enrollment; 51 subjects). TAF is presently in Phase 3 for treatment of HIV-1 
infection in combination with E, C and F, and a Phase 1b study has completed enrollment and 
dosing for treatment of chronic HBV.
Clinical trials entailing the use of TAF (dose[s] studied) for HIV-1 infection and other Phase 1 
studies include:

GS-120-1101, a Phase 1/2 study of the pharmacokinetics and antiviral activity of TAF 
(GS-7340 [50 mg and 150 mg]) in HIV infected subjects (completed)

GS-US-120-0104, a Phase 1b study of the pharmacokinetics and antiviral activity of 
GS-7340 (8 mg, 25 mg, 40 mg) in HIV infected subjects (completed)

GS-US-120-0107, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-7340 (25 mg and 150 mg) on the QT/QTc interval in 
healthy subjects (completed)

GS-US-120-0108, A Phase 1, Open-Label, Parallel-Design Study to Evaluate the 
Pharmacokinetics of GS-7340 (25 mg) in Subjects with Severe Renal Impairment 
(completed)

GS-US-120-0109, A Phase 1 Study to Evaluate the Pharmacokinetics, Metabolism and 
Excretion of GS-7340 (25 mg [completed])
Further details regarding these studies are provided in the table below (Table 1-1). In Phase 1/2 
studies in HIV-infected subjects (Studies 120-1101 and 120-0104), the short-term 
safety/tolerability, PK, and antiviral activity of TAF when given as a stand alone agent (SA) 
were evaluated over a range of doses. In Study 120-0104, at TAF doses of 25 mg or higher, 
near-maximal HIV RNA suppression was observed at Day 10, and importantly, single dose PK 
assessments of TAF (8 mg, 25 mg, or 40 mg) and TDF (300 mg) demonstrated that the 
TAF-generated TFV systemic exposures (AUCinf) were markedly lower (approximately 90% 
lower at TAF 25 mg) than the TFV exposure generated with TDF 300 mg. For HIV Phase 2 
(and Phase 3) studies, however, a 10 mg dose of TAF was selected for inclusion as a component 
of the elvitegravir (E)/ cobicistat (COBI, or “C”)/emtricitabine(F)/TAF single tablet regimen 
(STR) in comparison to the E/C/F/TDF STR control arm. A reduction in dose from 25 mg to
10 mg of TAF in the E/C/F/TAF STR is required based on a drug-drug interaction between TAF 
and COBI resulting in increased exposures of both TAF and TFV which is likely a consequence 
of Pgp-mediated inhibition of TAF and TFV efflux within the gut by COBI. Importantly, the 
resultant TFV exposures when TAF is dosed at 10 mg with COBI in the E/C/F/TAF STR 
formulation are similar to TFV exposures generated with TAF 25 mg given as a SA. Given that 
TAF exposures with E/C/F/TAF.


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10 mg are comparable to those with TAF given alone, safety results in HIV trials using this 
formulation are being assessed at a TAF dose that is considered therapeutically equivalent to 
TAF 25 mg. Thus, HIV studies conducted at TAF exposures similar to those expected in HBV 
provide the basis for supporting safety data for the TAF HBV development program.
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection
Study #
Population
Design
Dosing/Duration
Rationale
HIV Studies (Phase 1/2)
120-1101
N = 30
Treatment naïve
Dose escalation
3 treatment cohorts
TAF 50 mg, 150 mg, 
TDF 300 mg; multiple 
dosing for 14 days
Short-term proof of 
concept study;
safety, PK, and antiviral 
efficacy
120-0104
N = 38
Treatment naïve
(no ARV within 
90 days of screening)
Randomized 
(2:2:2:1:2) 
partially blinded
TAF 8 mg, 25 mg, 40 mg, 
TDF 300 mg, or placebo 
(PBO) for 10 days; off 
treatment follow up to 
Day 21
Confirmatory study for 
Study 1101 using a TAF 
reformulation; more 
rigorous design, evaluate 
lower TAF doses
Ongoing Supportive Phase 1 Studies
120-0107
N = 48
Males/females, 
age 18-45
Thorough QT 
(TQT)
TAF 25 mg, 125 mg;
each subject dosed 3 
times for 37 days (with 10 
day wash-out period)
Regulatory requirement
120-0108
N = 27 
(14 with severe renal 
impairment [CrCL 
15-29 mL/min] and 
13 matched controls 
[CrCL ≥90 mL/min])
PK in Renal 
impairment
TAF 25 mg single dose 
with 14 days of follow up
Characterizing TAF and 
TFV PK in severe renal 
impairment 
(to demonstrate no need 
for TAF dose 
adjustment)
120-0109
N = 8
healthy volunteer, 
male subjects
Mass Balance
Single radio-labeled TAF 
25 mg dose with 21 days 
of follow up
Regulatory requirement
Clinical trials entailing the use of TAF for the treatment of CHB virus:

GS-US-320-0101 A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess 
the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naïve Adults 
with Chronic Hepatitis B (CHB) Infection (enrollment and dosing completed)
The two proof-of concept studies, GS-120-1101 and GS-US-120-0104, as well as 
GS-US-292-0101, a STR bioequivalence study, were performed using TAF monofumarate
(GS-7340-02). All subsequent studies discussed herein were performed using TAF fumarate 
(GS-7340-03).
GS-120-1101 was a Phase 1/2 randomized double-blind, active-controlled, dose escalation study 
of the safety, tolerance, pharmacokinetics, and antiviral activity of TAF in antiretroviral-naïve 
subjects who are chronically infected with HIV-1. The subjects were randomized to receive 


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14 days of monotherapy, fasting, with GS-7340-02 50 mg (40 mg GS-7340 [free base]
equivalent) QD, 150 mg (120 mg GS-7340 [free base] equivalent) QD, or tenofovir DF 300 mg 
QD (n = 10 per group). TAF was rapidly absorbed into the systemic circulation, and 
subsequently following attainment of Cmax, was eliminated rapidly with a short plasma half-life 
(20-40 minutes). Compared with TDF, GS-7340-02 50 mg provided a ~16-fold lower TFV Cmax
(207 ng/mL vs 13 ng/mL), about 2-fold longer elimination half-life (26 hours vs 48 hours) and 
lower overall systemic tenofovir exposure (AUCinf: 1814 ng.h/mL vs 383 ng.h/ml). TAF 
monofumarate 150 mg provided lower Cmax (42 ng/mL), but comparable AUCinf: (1740 ng.h/mL) 
as TDF. In PBMCs, TFV was detected earlier, more frequently, and in higher concentrations 
following dosing of TAF monofumarate as compared to TDF. The intracellular delivery of TFV
is approximately 30-fold greater for GS-7340-02 versus TDF. The decrease from Baseline to 
Day 14 in plasma HIV-RNA levels was greater for groups treated with GS-7340-02 50 mg 
(p = 0.02757) or 150 mg (p = 0.0010) than the group that received TDF 300 mg. The median 
changes from baseline in plasma HIV-1 RNA after 14 days of monotherapy were 
0.96 log10 copies/mL for TDF 300 mg, 1.65 log10 copies/mL for GS-7340-02 50 mg, and 
1.68 for GS-7340-02 150 mg.
A second proof-of-concept study, GS-US-120-0104, evaluated monotherapy, fasting, with three 
lower doses of TAF compared with TDF 300 mg, or placebo, administered for 10 days. Potent 
antiviral activity was achieved with TAF in treatment-naïve HIV-1 infected subjects; mean viral 
load declines for both the 25 mg and 40 mg doses were statistically better than the 8 mg dose. 
TAF exposure (AUC) was best associated with antiviral activity despite its short plasma half-life 
(~ 30 min). TFV AUC values were 97%, 87%, and 80% lower at 8 mg, 25 mg, and 40 mg TAF
respectively, compared to TDF administration. When compared to 40 mg and historical 120 mg 
data, 25 mg TAF provides near maximal anti-HIV-1 activity. From this PK-PD analysis, a target 
exposure of a dose of 25 mg TAF monotherapy is expected to provide near maximal antiviral 
activity and ~ 90% reduction in circulating TFV.
Study GS-US-120-0107 is a Phase 1, partially-blinded, randomized, placebo- and 
positive-controlled study to evaluate the effect of TAF on the QT/QTc interval in healthy 
subjects. This was a negative thorough-QTc study. No effect of TAF was observed on the QTcF 
interval (ie, no QTc interval prolongation > 10 msec at any time point post-dose and assay 
sensitivity was confirmed via the positive control [moxifloxacin]). As such, these findings satisfy 
the guidelines set forth in the International Conference on Harmonization (ICH) E14 guidance 
and support the conclusion that there is no significant effect of TAF on the QT/QTc interval.
Study GS-US-120-0108 is a Phase 1, open-label, parallel-design study to evaluate the PK of TAF 
in subjects with severe renal impairment. TAF was well tolerated in the study. Subjects with 
severe renal impairment had < 2-fold higher TAF and 5-6 fold higher TFV systemic exposures as 
assessed by AUC relative to subjects with normal renal function. TFV exposures in subjects with 
severe renal impairment are comparable to those with normal renal function receiving 300 mg 
TDF QD. Given the extensive safety data available for TDF at a dose of 300 mg, TFV exposures 
in severely renally impaired subjects similar to those associated with TDF 300 mg are deemed 
appropriate for further study of TAF in HIV-infected subjects without TAF dose modification.


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Preliminary results from Study GS-US-120-0109, a Phase 1 PK, metabolism and excretion study 
demonstrated that TAF is eliminated in both feces and urine. TAF and its metabolites are 
eliminated in both feces and urine. The predominant species detected in feces and urine is TFV, 
accounting for 31.4% ± 10.4% and 22.2% ± 4.47% respectively of the total radioactive dose.
These human data are consistent with the established preclinical profile of TAF. Following
administration of TAF, plasma [14C] radioactivity showed a time dependent profile with TAF as 
the most abundant species in the initial few hours and uric acid, a byproduct of TAF metabolism, 
in the remaining period. The whole blood-to-plasma concentration ratio of [14C] radioactivity 
increased from 0.511 at 0.25 hours post dose to 2.32 at 216 hours post dose, suggesting a 
relatively slower clearance of [14C] radioactivity from blood cells relative to the plasma 
[14C] radioactivity time-course. In addition to TFV and uric acid, additional low quantities of 
metabolites were formed, including xanthine, hypoxanthine, and adenine. They are identical to 
the endogenous products of purine metabolism and therefore should not cause any safety risk. 
TAF 25 mg tablets administered together with tracer dose of [14C] radiolabeled TAF as a single 
oral tablet, were well tolerated.
HBV Study – GS-US-320-0101
In HBV subjects, a 28 day Phase 1b study (GS-US-320-0101), was conducted to evaluate 
safety/tolerability, pharmacokinetics, and antiviral activity of TAF at doses of 8 mg, 25 mg, 
40 mg, and 120 mg compared to TDF 300 mg control in 50 subjects (10/cohort). As of 
April 2, 2013, enrollment was completed (n = 51) and all subjects have completed study drug 
dosing through Day 29.
Preliminary data suggest that all treatment groups were generally well matched (Table 1-2) and 
representative of the chronic HBV population. Overall, the majority of subjects were male 
(66.7%), and of Asian descent (56.9%). Of the 51 randomized subjects, 27 (53%) and 24 (47%)
were HBeAg-negative and HBeAg-positive, respectively. Median age ranged among groups 
from 34 years in the 8 mg and 25 mg TAF groups to 40 and 42 years in the 40 mg and 120 mg 
TAF groups, respectively; median age in the TDF group was 34 years. The most common HBV 
genotype at enrollment was genotype C (16/51; 31%), the proportions of other genotypes were: 
A (7/51; 14%), B (10/51; 20%), D (9/51; 18%), and E (9/51; 18%). The distribution of HBV 
genotypes was similar within groups, with the exception of a higher proportion (5 of 11 [45.5%]) 
of subjects in the 40 mg TAF group having genotype B.


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Table 1-2.
GS-US-320-0101: Baseline Demographics and Disease Characteristics
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(N = 10)
TDF 300 mg
(N = 10)
Male sex, n (%) 
4 (40%)
8 (80%)
8 (73%)
8 (80%)
6 (60%)
Median (range) age, yr
34 (19 – 57)
34 (23 – 42)
40 (19 – 60)
42 (25 – 51)
34 (25 – 49)
Race, n (%)
Asian
)
Black or African American
White
Native Hawaiian or 
Other Pacific Islander
Median (range) BMI, kg/m2
26.6
(17.9 - 32.3)
25.9
(20.2 – 46.0)
24.1
(21.0 – 31.8)
24.5
(19.8 – 34.0)
25.6
(19.6 – 31.8)
Median (range) body weight, kg
69.7
(49.9 – 94.0)
74.7
(61.0 –
134.4)
62.5
(56.0 –
104.1)
71.2
(54.0 –
110.0)
78.3
(47.2 – 98.8)
Median (range) CLCr, mL/min
107.1
(88.8 -
158.0)
121.7
(84.8 -
239.1)
117.9
(75.6 - 153.8)
107.6
(81.3 -
143.5)
127.1
(64.2 -
196.4)
Median (range) HBV DNA, 
log10 IU/mL
6.26
(3.73 – 8.98)
6.35
(3.56 – 8.93)
5.37
(3.27 – 8.57)
5.98
(3.71 – 9.74)
4.78
(3.97 – 8.85)
Median (range) HBsAg,
log10 IU/mL
4.10
(1.55 – 4.72)
3.59
(1.47 – 4.72)
3.64
(1.67 – 4.72)
3.84
(2.64 – 4.72)
3.93
(2.95 – 4.72)
Median (range) ALT, U/L
41.0
(23 - 83)
52.5
(33 - 106)
50.0
(11 - 169)
43.0
(26 - 114)
27.5
(11 - 107)
HBeAg-negative, n (%)
5 (50%)
4 (40%)
8 (73%)
5 (50%)
5 (50%)
HBV genotype, n (%)
A
1 (10%)
1 (10%)
1 (9%)
1 (10%)
3 (30%)
B
1 (10%)
2 (20%)
5 (45%)
1 (10%)
1 (10%)
C
2 (20%)
4 (40%)
3 (27%)
3 (30%)
4 (40%)
D
3 (30%)
2 (20%)
1 (9%)
3 (30%)
0
E
3 (30%)
1 (10%)
1 (9%)
2 (20%)
2 (20%)
Preliminary safety results are summarized in the table (Table 1-3) below. Overall, TAF was safe 
and well tolerated in HBV subjects. No subjects experienced a serious adverse event (SAE), or 
Grade 3 or 4 treatment emergent adverse event, and no subjects required treatment 
discontinuation for an AE. Treatment emergent AEs were generally mild to moderate, and 
included gastrointestinal complaints (nausea, vomiting, diarrhea, epigastric discomfort), fatigue, 
lethargy, headache, and dizziness. Grade 3 laboratory abnormalities were seen in 3 subjects in 
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the TAF 40 mg group (1 subject each with creatine kinase elevation, glycosuria, and hematuria), 
2 subjects in the TAF 120 mg group (1 subject each with elevated transaminases [both AST and 
ALT occurring during treatment follow-up], and amylase elevation), and in 1 subject in the TDF 
arm (amylase elevation). The subject with Grade 3 glycosuria in the TAF 40 mg group, 
experienced this abnormality at Day 29 which was associated with a corresponding serum 
glucose elevation (212 mg/dL); the subject also had a history of diabetes mellitus.
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and 
Laboratory Abnormalities: Overall Summary, Safety Analysis Set
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(N = 10)
TDF 300 mg
(N = 10)
Subjects Experiencing Any 
Treatment-Emergent Adverse Event
7 (70%)
6 (60%)
6 (55%)
8 (80%)
5 (50%)
Subjects Experiencing Any 
Treatment-Emergent 
Study Drug-Related Adverse Event
2 (20%)
4 (40%)
3 (27%)
4 (40%)
5 (50%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Adverse Event
1 (10%)
1 (10%)
0
4 (40%)
2 (20%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Study Drug-Related Adverse Event
0
0
0
3 (30%)
1 (10%)
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Laboratory Abnormality
0
0
3 (27%)
2 (20%)
1 (10%)
Subjects Experiencing Any 
Treatment-Emergent 
Serious Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Treatment-Emergent Adverse Event 
Leading to Premature Study Drug 
Discontinuation
0
0
0
0
0
Given the significantly smaller declines in creatinine clearance (CLCr) observed at Week 24 with 
TAF relative to TDF in the HIV Phase 2 study (GS-US-209-0102; Section 1.2.4), changes in 
CLCr were also assessed in HBV subjects participating in GS-US-320-0101. After 4 weeks of 
dosing, numerically smaller changes in CLCr at Day 29 were seen in HBV subjects receiving 
TAF compared with TDF (Figure 1-1). At Day 29, median (range) change from baseline in CLCr
was 2.0 ( 13.2, 9.6) mL/min for the TAF 25 mg group compared with a change of 
10.4 ( 35.7, 13.0) mL/min in the TDF group. Further, there were no notable differences in CLCr


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change among the two lowest dose groups (TAF 8 mg and TAF 25 mg), and the highest dose 
group (120 mg). An early decline in CLCr, similar to that observed in the TDF group was noted 
in the TAF 40 mg group; however, by Day 29 the change in CLCr was similar to the other TAF 
groups. These results are consistent with findings in HIV subjects receiving the E/C/F/TAF 
10 mg STR and provide additional evidence to support the concept that lower TFV exposures 
with TAF relative to TFV exposures with TDF are associated with notable differences in renal 
function as determined by estimated CLCr.
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance 
(Cockcroft-Gault Method) in GS-US-320-0101
Baseline is defined as Day 1.
Over 28 days of study drug treatment, similar median declines in HBV DNA levels were 
observed among treatment groups (Figure 1-2). Overall, viral decay results among subjects who 
received treatment with TAF demonstrated the absence of a dose effect. In addition, the HBV 
DNA declines with TAF (n = 41) over 28 days of dosing were similar to HBV DNA declines 
observed in the TDF 300 mg group (n = 10). A summary of change from baseline in HBV DNA 
results at Day 15 and Day 29 is provided in the table below (Table 1-4) below. Among TAF 
groups, median change from baseline in HBV DNA at Day 29 ranged from 1.98 log10 IU/mL
for the TAF 40 mg group to 2.76 log10 IU/mL for the TAF 8 mg group. For TAF 25 mg, the 
change from baseline in HBV DNA at Day 29 was 2.67 log10 IU/mL. Consistently smaller 
declines in HBV DNA over time, and slightly lower median change from baseline in HBV DNA
 
 
 
   
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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were observed in the TAF 40 mg group at Day 29. The reason for this is unclear and possibly 
related to a lower median HBV DNA value at Baseline (Table 1-4). In this group, 
5/11 (45.5%) subjects had a baseline HBV DNA value below 5.0 log10 IU/mL. In comparison to 
TAF groups, the change from baseline in HBV DNA at Day 29 was 2.60 log10 IU/mL with 
TDF 300 mg.
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV 
DNA (Log10 IU/mL) by Treatment Group
Baseline is defined as Day 1/pre-dose.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-4. 
GS-US-320-0101: HBV DNA Results: Median Change from Baseline 
at Day 15 and Day 29 by Treatment Group 
TAF 8 mg 
TAF 25 mg 
TAF 40 mg 
TAF 120 mg 
TDF 
(N = IO) 
(N = IO) 
(n = 11) 
(N = IO) 
(N = IO) 
HBV DNA (Log10 IU/mL) at 
6.26 
6.35 
5.37 
5.98 
4.78 
Baseline (Day I), 
- -
(3.42, 7.78) - -
Median (QI, Q3), [Min, Max] 
[3.27, 8.57] 
n = 
10 
10 
9 
10 
10 
Change from Baseline in 
-2.41 
-2.14 
-1.84 
-2.43 
-2.55 
HBV DNA (Log10 IU/mL) at ... ... 
(-2. 18, - 1.68) ... ... 
Day 15, Median (QI , Q3), 
[Min, Max] 
[-2.8 I, -0.98] 
n = 
10 
10 
9 
9 
10 
Change from Baseline in 
-2.76 
-2.67 
-1.98 
-2.70 
-2.60 
HBV DNA (Log10 IU/mL) at 
(-3.17, -2.48) ... 
(-2.65, - 1.82) ... ... 
Day 29, Median (QI , Q3), 
[Min, Max] 
[-3.11 , - 1.67] 
Plasma concentration-time profiles were generated after intensive phannacokinetic sampling 
following a single dose on Day 1 for subjects who were randomized to receive T AF 8, 25, 40, or 
120 mg, or TDF 300 mg (N=51). The respective plasma concentration-versus-time profiles are 
shown in Figure 1-3 and Figure 1-4 (TFV). Phannacokinetic parameters were calculated via 
non-compartmental analysis. 
TAF Pharmacokinetic Results 
In general, the concentration-time profiles for T AF over the range of doses studied in CHB 
subjects were consistent with previous results in the healthy volunteers and HIV subjects 
receiving TAF either as a single agent or as a component of the E/C/F/TAF STR. 
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Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: TAF (GS-7340), Linear Scale
TAF plasma pharmacokinetic parameters are summarized in Table 1-5. Day 1 pharmacokinetic 
results in CHB subjects participating in GS-US-320-0101 are consistent with previously reported 
results in the HIV Phase 1/2 study GS-US-120-0104, which evaluated TAF single-dose 
pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 40 mg (n=8), versus TDF 
300 mg (n=6). In GS-US-120-0104, mean (%CV) AUC0-last was 38.4 (80.6) ng∙h/mL, 
139.7 (57.8) ng∙h/mL, and 322.1 (42.0) ng∙h/mL after single doses of TAF 8 mg, 25 mg, and 
40 mg, respectively. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to the results generated in GS-US-120-0104.
Similar findings to the present study were also observed when TAF pharmacokinetic parameters 
were assessed after multiple doses at steady-state in the ongoing Phase 2 study, 
GS-US-292-0102, which compares STRs of E/C/F/TAF 10 mg to E/C/F/TDF 300 mg in HIV-1 
infected, treatment-naive subjects. Mean (%CV) AUClast, and Cmax values for TAF at the 10 mg 
dose in combination with COBI were 230.4 (47.3) ng∙h/mL and 232.8 (64.6) ng/mL, 
respectively. As TAF exposures at the 10 mg dose, when included as a component of the 
E/C/F/TAF STR, have been shown to be comparable to those with TAF 25 mg given as the 
stand-alone agent, these results indicate similar TAF exposures in both subjects infected with 
HIV and those infected with HBV.
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on 
Day 1
TAF PK Parameter
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(N = 11)
TAF 120 mg
(N = 10)
AUC0-last (ngh/mL)
59.2 (54.1)
153.0 (41.1)
328.1 (58.4)
832.4 (39.1)
AUCinf (ngh/mL)
60.6 (52.8)
154.4 (41.0)
329.8 (58.1)
834.6 (38.9)
Cmax (ng/mL))
83.2 (46.3)
249.5 (45.9)
527.4 (50.6)
1128.7 (33.7)
Tmax (h) median
0.5
0.5
0.5
0.5
T1/2 (h)
0.36 (23.8)
0.51 (32.6)
0.59 (30.7)
0.76 (30.8)
All results expressed as mean (%CV) unless otherwise stated
TFV Pharmacokinetic Results
Mean (SD) plasma concentration versus time profiles for TFV following single dose 
administration of ascending doses of TAF and TDF 300 mg are shown in Figure 1-4. At each 
TAF dose evaluated, plasma TFV concentrations resulting from TAF administration were lower 
than plasma TFV concentrations following TDF administration. The TFV concentrations 
achieved from all TAF dose levels in HBV subjects in GS-US-320-0101 are comparable to TFV 
concentrations achieved after TAF administration in the HIV program.
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: Tenofovir, Linear Scale
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Tenofovir (TFV) plasma pharmacokinetic parameters are summarized in Table 1-6. As with 
TAF, Day 1 TFV pharmacokinetic results in CHB subjects participating in GS-US-320-0101 are 
consistent with those previously reported in the HIV Phase 1/2 study GS-US-120-0104, which 
evaluated TAF single-dose pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 
40 mg (n=8), versus TDF 300 mg (n=6). In GS-US-120-0104, mean (%CV) AUCinf for TFV 
were 49.4 (30.3) ng∙h/mL, 195.9 (27.2) ng∙h/mL, and 287.3 (33.7) ng∙h/mL after single doses of 
TAF 8 mg, 25 mg, and 40 mg, respectively. Mean (%CV) AUCinf for TFV following TDF 
300 mg was 1719.2 ng∙h/mL. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to results seen in HIV subjects in GS-US-120-0104. As stated 
earlier, When TAF is included as a component of the E/C/F/TAF STR, a reduced dose (10 mg) is
required due to a drug-drug interaction (inhibition of P-gp in the gut by cobicistat) that results in
increased exposures of both TAF and TFV (see Section 1.2.4).
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on 
Day 1
TFV PK Parameter
TAF 8 mg
(n=10)
TAF 25 mg
(n=10)
TAF 40 mg
(n=11)
TAF 120 mg
(n=10)
TDF 300 mg
(n=10)
AUC0-last (ngh/mL)
32.9 (35.0)
90.6 (25.8)
213.4 (40.2)
607.7 (35.4)
1682.1 (28.0)
AUCinf (ngh/mL),
74.0 (41.2)
171.4 (29.9)
444.6 (43.0)
1572.0 (47.2)
2309.8 (27.9)
Reduction in AUCinf, 
TAF/TDF (%)
97
93
81
32
N/A
Cmax (ng/mL),
3.0 (34.5)
8.3 (41.6)
20.3 (43.2)
61.0 (33.5)
306.8 (24.5)
Reduction in Cmax, 
TAF/TDF (%)
99
97
93
80
N/A
Tmax (h) median
1.25
1.0
1.0
1.0
1.0
t1/2 (h)
26.7 (23.4)
20.7 (39.6)
26.3 (33.8)
31.4 (38.6)
10.8 (17.4)
The following Section (1.2.4) provides a summary of experience with TAF in HIV-1 infection, 
including the final Week 24 analysis results for TAF when used as a component of the 
E/C/F/TAF STR in the HIV Phase 2 study GS-US-292-0102. Because TAF exposures in this 
ongoing trial are similar to those expected in the TAF HBV development program, these results 
provide important supporting safety data.


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1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)
Phase 1 and 2 clinical trials using TAF, coformulated into the E/C/F/TAF STR for the treatment 
of HIV-1 infection include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI when administered as E/C/F/TAF STR relative to E/C/F/TDF or 
TAF (completed)

GS-US-292-0103, a Phase 1 healthy volunteer study to evaluate the pharmacokinetics and 
relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
GS-7340 doses of 10 mg (STR) or 25 mg SA (completed)

GS-US-292-0102, a Phase 2 randomized, double-blinded study of the safety and efficacy of 
E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, antiretroviral treatment-naive 
adults (ongoing)
1.2.4.1.
Summary of Phase 1 Studies (Study GS-US-292-0102, GS-US-292-0103)
Study GS-US-292-0101 is a completed Phase 1 study of 40 subjects evaluating the relative 
bioavailability of two different formulations of E/C/F/TAF STR, each with TAF dose of 25 mg 
or 40 mg, versus E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, and FTC 
were comparable between E/C/F/TAF vs E/C/F/TDF regardless of formulation (monolayer or 
bi-layer). In contrast, TAF exposures were ~2.2-fold higher (and corresponding tenofovir 
exposures ~ 3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 25 mg for both 
formulations of the E/C/F/TAF. This is likely mediated by inhibition of Pgp-mediated intestinal 
secretion of TAF by COBI and consistent with data from Study GS-US-311-0101 described 
below.
Study GS-US-292-0103 is a completed Phase 1 healthy volunteer study which evaluated the PK 
and relative bioavailability of the E/C/F/TAF STR relative to the individual components at TAF 
doses of 10 mg (as STR) or 25 mg SA. Results indicate that when dosed as the E/C/F/TAF 
10 mg STR, TAF and TFV exposures were comparable to those observed with TAF 25 mg dosed 
alone. Exposures of EVG, COBI, and FTC were also comparable between the STR and 
individually dosed formulations.
1.2.4.2.
Week 24 Summary of Phase 2 Study (Study GS-US-292-0102)
GS-US-292-0102 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of E/C/F/TAF STR versus E/C/F/TDF in 
HIV-1 infected, antiretroviral treatment-naive adults with plasma HIV-1 RNA levels 
≥5,000 copies/mL at Screening.


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Eligible subjects were randomized in a 2:1 ratio to 1 of the following 2 treatment arms and 
randomization was stratified by HIV-1 RNA level (≤ 100,000 copies/mL or > 100,000 copies/mL) 
at Screening:

Treatment Arm 1: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TAF 10 mg 
(E/C/F/TAF) + placebo-to-match STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TDF 300 mg (E/C/F/TDF) once daily (n = 100)

Treatment Arm 2: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TDF 300 mg 
(E/C/F/TDF) + placebo-to-match STR EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TAF 10 mg (E/C/F/TAF) once daily (n = 50)
The Independent Data Monitoring Committee (IDMC) reviewed the safety and study conduct at 
Week 12 and determined that no changes were required for study GS-US-292-0102. Interim data 
at Week 24 is presented below.
1.2.4.3.
Week 24 Subject Disposition and Demographics
A total of 170 subjects were randomized and treated in this study: 112 subjects in the E/C/F/TAF 
group and 58 subjects in the E/C/F/TDF group. The full analysis set (FAS) and safety analysis 
set (SAS) each included all randomized and treated subjects from each group. A total of 
24 subjects were included in the pharmacokinetic substudy analysis set. At the time of the 
Week 24 data analysis, 6 subjects (2.4%) had been discontinued from treatment and 4 subjects 
(2.4%) had been discontinued from study.
Of the 170 subjects in the FAS and SAS, 165 (97.1%) were male; 115 (67.6%) were white and 
50 (29.49%) were black; and the mean age was 36 years (range: 18 to 71 years). Demographic 
and baseline disease characteristics were similar between the 2 treatment groups.
1.2.4.4.
Week 24 Efficacy Results
Proportion of Subjects with Plasma HIV-1 RNA < 50 copies/mL at Week 24
The proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at Week 24 was 86.6% in 
the E/C/F/TAF group and 89.7% in the E/C/F/TDF group, with a stratum-adjusted difference in 
the response rate between the 2 treatment groups of 4.9% (95% CI: 15.7% to 5.9%; p = 0.36).
Results of the secondary efficacy endpoint confirmed those of the primary analysis. The 
proportion of subjects with suppression of plasma HIV-1 RNA < 50 copies/mL at Week 24 
(time-to-loss of virologic-response [TLOVR] analysis) was 88.4% (99/112) in the E/C/F/TAF 
group and 84.5% (49/58) in the E/C/F/TDF group. The stratum-adjusted difference in the 
response rate between the 2 treatment groups was 0.1% (95% CI: 10.4% to 10.2%; p = 0.99).
The mean increase in CD4 cell count from baseline to Week 24 was 163 cells/μL in the 
E/C/F/TAF group and 177 cells/μL in the E/C/F/TDF group (-6 difference in LSM, 95% CI 
44 to 33).


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1.2.4.5.
Week 24 Pharmacokinetic Results
Results from the intensive 
 demonstrated that, consistent with data in 
healthy subjects and HIV-infected subjects treated with TAF monotherapy, E/C/F/TAF (10 mg) 
produced substantially lower tenofovir systemic exposures than E/C/F/TDF (TDF 300 mg). TAF 
exhibited a short median (min-max) plasma half-life of 0.47 (0.37 to 0.87) hours with no 
detectable drug after 8 hours post-administration. Steady-state mean (CV%) AUCtau was 
230 ng•hr/mL (47%). PK results for the other components EVG, COBI and FTC were similar to 
historical data for these agents when administered as E/C/F/TDF (data not shown). In addition, 
TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) in subjects in the 
E/C/F/TAF group showed that TFV-DP was detectable within PBMCs at greater exposures 
(approximately 5-fold) after administration of E/C/F/TAF than with E/C/F/TDF.
1.2.4.6.
Week 24 Safety Results
1.2.4.6.1.
Overall Safety
At the time of the 24-week interim analysis, 112 subjects had been treated with E/C/F/TAF for a 
median duration of 21.1 weeks and 58 subjects had been treated with E/C/F/TDF for a median 
duration of 21.3 weeks. The overall subject incidence of treatment-emergent adverse events 
(AEs) was balanced between treatment groups (81.3% E/C/F/TAF, 81.0% E/C/F/TDF) 
(Table 1-7). The most frequent treatment-emergent AEs (> 10% in either treatment group) were 
(17.9% E/C/F/TAF, 12.1% E/C/F/TDF) nausea, diarrhea (11.6% E/C/F/TAF, 12.1%
E/C/F/TDF), fatigue (11.6% E/C/F/TAF, 8.6% E/C/F/TDF), upper respiratory tract infection 
(7.1% E/C/F/TAF, 12.1% E/C/F/TDF), and headache (9.8% E/C/F/TAF, 10.3% E/C/F/TDF), 
respectively.
Most treatment-emergent AEs were assessed as Grade 1 or Grade 2 in severity. The incidence of 
Grade 3 or 4 AEs was higher in the E/C/F/TAF group (7.1%) compared to the E/C/F/TDF group 
(3.4%). No Grade 3 or 4 event occurred in > 1 subject; the system organ class (SOC) with the 
highest subject incidence of Grade 3 or 4 events was Nervous System Disorders 
(2.7% E/C/F/TAF, 0% E/C/F/TDF). The only Grade 3 or 4 event that was considered by the 
investigator to be related to investigational product was Grade 3 diarrhea in 1 subject (0.9%) in 
the E/C/F/TAF group; there were no treatment-related Grade 3 or 4 AEs in the E/C/F/TDF 
group. Based on these data, there do not appear to be any signature, higher grade AEs associated 
with the use of E/C/F/TAF through 24 weeks of treatment.
More subjects in the E/C/F/TAF group compared to the E/C/F/TDF group also had 
treatment-emergent serious AEs (SAEs) (5.4% vs 3.4%) or AEs leading to premature treatment 
discontinuation (3.6% vs 0). None of these events occurred in > 1 subject, and none of the SAEs 
were considered by the investigator to be related to treatment with investigational product. The 
system organ class (SOC) with the highest subject incidence of treatment-emergent SAEs was 
Infections and Infestations (4.5% E/C/F/TAF, 0% E/C/F/TDF). No deaths or pregnancies 
occurred.
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Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: 
Overall Summary, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Subjects Experiencing Any Treatment-Emergent Adverse Event
91 (81.3%)
47 (81.0%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Adverse Event
42 (37.5%)
17 (29.3%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Adverse Event
8 (7.1%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related Adverse 
Event
38 (33.9%)
15 (25.9%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Study-Drug-
Related Adverse Event
6 (5.4%)
1 (1.7%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Study-Drug-Related 
Adverse Event
1 (0.9%)
0
Subjects Experiencing Any Treatment-Emergent Serious Adverse Event
6 (5.4%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related 
Serious Adverse Event
0
0
Subjects Experiencing Any Treatment-Emergent Adverse Event Leading to 
Premature Study Drug Discontinuation
4 (3.6%)
0
Subjects who had Treatment-Emergent Death
0
0
Treatment-emergent death refers to a death occurring between the first dose date and the last dose date plus 30 days (inclusive).
At least 1 treatment-emergent laboratory abnormality (ie, at least 1 grade level increase in graded 
abnormality) was reported for 103/111 subjects (92.8%) in the E/C/F/TAF group and 
46/58 subjects (79.3%) in the E/C/F/TDF group. The majority of laboratory abnormalities were 
Grade 1 or 2 in severity. Subject incidence of Grade 3 or 4 treatment-emergent laboratory 
abnormalities is summarized in Table 1-8.


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Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Maximum Post-Baseline Toxicity Grade 3 or 4
19 (17.1%)
8 (13.8%)
Neutrophils
5 (4.5%)
1 (1.7%)
WBC
1 (0.9%)
0
Amylase
2 (1.8%)
1 (1.7%)
Creatine Kinase (CK)
6 (5.4%)
2 (3.4%)
Lipase
0
1 (12.5%)
Serum Glucose (Hyperglycemia)
0
1 (1.7%)
Total Cholesterol (Fasting, Hypercholesterolemia)
1 (0.9%)
0
Triglycerides (Fasting)
1 (0.9%)
1 (1.7%)
LDL (Fasting)
7 (6.4%)
2 (3.4%)
Urine Protein (Proteinuria)
1 (0.9%)
0
Urine RBC (Hematuria, Quantitative)
1 (0.9%)
0
Denominator for percentage is the number of subjects in the SAS with at least 1 post-baseline laboratory value (for the test).
Subjects were counted once for the maximum postbaseline severity for each laboratory test.
Lipase test was only performed for subjects with serum amylase > 1.5 × upper limit of normal.
Urine RBC (hematuria, quantitative) was graded based on DAIDS grading scale (with the modification of urine RBC 
> 75 cells/HPF as Grade 3).
For Urinalysis (i.e., urine glucose, urine protein, and urine RBC), the highest grade is up to Grade 3.
No clinically significant changes in mean thyroid function tests (TSH, free T3, free T4) or serum 
immunoglobulins (IgG and IgM) were observed.
1.2.4.6.2.
Renal Safety
On multiple objective laboratory tests of renal function, subjects receiving E/C/F/TAF had a 
lower magnitude of change than subjects receiving E/C/F/TDF through 24 weeks.
The change from baseline in serum creatinine (sCr) was lower in the E/C/F/TAF group compared 
to the E/C/F/TDF group at most assessments through Week 24. At Week 24, median change 
from baseline in serum creatinine was 0.07 mg/dL (range through Week 24: 
0.05 mg/dL to 0.08 mg/dL) for the E/C/F/TAF group and 0.11 mg/dL (range through Week 24: 
0.08 mg/dL to 0.11 mg/dL) for the E/C/F/TDF group (Week 24 p = 0.016).
Accordingly, the decrease from baseline in estimated glomerular filtration rate (GFR) by 
Cockcroft-Gault formula for CLCr was lower in the E/C/F/TAF group compared to the 
E/C/F/TDF group at most assessments through Week 24 (Figure 1-5). At baseline, the mean 
(SD) estimated GFRC-G was similar between groups (120.1 [30.22] (mL/min) for subjects in the 
E/C/F/TAF group and 114.7 [21.68] (mL/min) for subjects in the E/C/F/TDF group. At Week 24, 


Tenofovir Alafenamide (T AF) 
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median change from baseline estimated GFRc-G was 6.6 mL/min for the E/C/F/TAF group and 
10.6 mL/min for the E/C/F/TDF group (p = 0.009). At Week 24, 3 (5.2%) subjects in the 
E/C/F/TDF group would be classified as new Stage 3 CKD (eGFR 30-59 mL/min) vs. 
1 (1.0%) subjects in the E/C/F/TAF group, and 15 (14.4%) subjects in the E/C/F/TAF group 
would be classified as new Stage 2 CKD (eGFR 60-89 mL/min) vs. 20 (34.5%) subjects in the 
E/C/F/TDF group. 
Figure 1-5. 
GS-US-292-0102: Median (Ql, Q3) of Change from Baseline in 
Estimated GFR by Cockcroft-Gault by Visit, Safety Analysis Set 
-
10 
10 
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112 
109 
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O 
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58 
54 
58 
8 
110 
58 
12 
107 
58 
16 
Week 
107 
58 
24 
104 
58 
32 
18 
11 
At Week 24, a trend towards reduced proteinuria was observed in the E/C/F/TAF group. By 
urine dipstick, the frequency of maximum post-baseline proteinuria (any grade) was 13.5% in 
E/C/F/TAF vs. 20.7% in E/C/F/TDF. The median change from baseline in urine albmn in to 
creatinine ratio (UACR) was 0.84 mglg in E/C/F/TAF vs 0.07 in EICIF!TDF. The median 
change from baseline in urine protein to creatinine ratio UPCR was 5.6 m 
and 1.6 mglg in 
the E/C/F/T AF and E/C/F/TDF 
ou s res ectivel . 
At Week 24, median change from baseline 
beta-2-microglobulin to creatinine ratio was 35.9 µgig for EICIF!TAF vs 1.1 µgig for 
E/C/F/TDF (p = 0.004), and median change from baseline in retinol binding protein to creatinine 
ratio was 0.7 µgig for E/C/F/TAF vs 11.9 µgig for E/C/F/TDF (p = 0.006). 
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A treatment difference for other laboratory markers of kidney function were not observed, 
including median change from baseline for serum phosphate and fractional excretion of 
phosphate (fractional excretion of phosphate [FEPO4] using adjusted sCr).
1.2.4.6.3.
Bone Safety
DXA scans of the spine and hip were performed at the Baseline and Week 24 visits (and at the 
early study drug discontinuation visit, if applicable) to measure changes from baseline in BMD.
The percent changes from baseline in BMD values in the lumbar spine and hip are summarized 
in Table 1-9. The median percentage decrease from baseline was significantly less for subjects in 
the E/C/F/TAF group compared with that for subjects in the E/C/F/TDF group for both spine 
(p = 0.002) and hip (p < 0.001) BMD. 
The categorical distribution of subjects in each treatment group with percentage changes in BMD 
from baseline within specified ranges at Week 24 is summarized for spine and hip in Table 1-10. 
At Week 24, a significantly higher proportion of subjects in the E/C/F/TAF group than in the 
E/C/F/TDF group had no decreases in BMD at the hip (40.6% vs 22.8%; p < 0.001) and spine 
(37.5% vs 12.1%; p = 0.003). Substantially fewer subjects in the E/C/F/TAF group had decreases 
in BMD of >3% at the hip than in the E/C/F/TDF group (3.0% vs 31.6%) at Week 24.
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine 
and Hip Bone Mineral Density at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Change at Week 24
Spine
N
104
58
0.002
Mean (SD)
-0.84 (3.411)
-2.48 (2.519)
Median (Q1, Q3)
-0.92 (-3.00, 0.99)
-2.34 (-3.65, -
0.33)
Min, Max
-8.49, 17.12
-10.37, 2.43
Hip
N
101
57
< 0.001
Mean (SD)
-0.30 (1.774)
-2.103 (2.677)
Median (Q1, Q3)
-0.42 (-1.44, 0.71)
-2.08 (-3.60, -
0.48)
Min, Max
-4.68, 7.84
-8.55, 4.86
P-values were from the Wilcoxon rank sum test.
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 E/C/F/TDF post baseline visit were 
included in the 
 analysis set.
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Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by 
Gradation at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Percentage Change at Week 24
Spine
No Decrease
39/104 (37.5%)
7/58 (12.1%)
0.003
> 0 to < = 1% Decrease
14/104 (13.5%)
11/58 (19.0%)
> 1 to < = 3% Decrease
25/104 (24.0%)
17/58 (29.3%)
> 3 to < = 5% Decrease
18/104 (17.3%)
15/58 (25.9%)
> 5% Decrease
8/104 (7.7%)
8/58 (13.8%)
Hip
No Decrease
41/101 (40.6%)
13/57 (22.8%)
< 0.001
> 0 to < = 1% Decrease
23/101 (22.8%)
7/57 (12.3%)
> 1 to < = 3% Decrease
34/101 (33.7%)
19/57 (33.3%)
> 3 to < = 5% Decrease
3/101 (3.0%)
12/57 (21.1%)
> 5% Decrease
0/101
6/57 (10.5%)
P-value was from the CMH test for ordinal data (row mean scores differ statistic was used).
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 postbaseline visit were included in 
 analysis set.
Clinical BMD status was assessed using BMD T-scores. Changes from baseline in BMD status 
at Week 24 were determined using T-scores. At Week 24, 6 of 99 subjects (6.1%) in the 
E/C/F/TAF group and 2 of 58 subjects (3.4%) in the E/C/F/TDF group showed a deterioration 
from baseline in spine BMD T-score category, and 1 of 99 subjects (1.1%) in the E/C/F/TAF 
group and 5 of 54 subjects (9.3%) in the E/C/F/TDF group showed a deterioration from baseline 
in hip BMD T-score category. In the E/C/F/TAF group at Week 24, 5 subjects had improvement 
in spine BMD T-score category and 1 subject had improvement in hip BMD T-score category. 
One subject in the E/C/F/TDF group showed improvement in the hip BMD T-score category. As 
a continuous variable, median decrease from baseline BMD T-score was significantly less for 
E/C/F/TAF vs E/C/F/TDF at both spine (-0.08 vs. 0.22, p = 0.005) and hip ( 0.03 vs 0.14, 
p < 0.001).
Bone turnover markers, including one for bone resorption (C-type collagen sequence [CTX]) and 
three for formation (bone specific alkaline phosphatase [bsAP], osteocalcin [OC], and 
procollagen type 1 N-terminal propeptide [P1NP]), were assessed to support the BMD data. 
Comparisons of percent change from baseline for each bone turnover marker at Weeks 12 and 24 
demonstrated statistically significantly less change in the E/C/F/TAF arm, and provide evidence 
of less bone turnover at both timepoints in the E/C/F/TAF arm vs the E/C/F/TDF arm 
(Table 1-11). These results are consistent with the observations made in the BMD analyses.
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Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover 
Markers, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
E/C/F/TAF vs E/C/F/TDF
p-value
Week 12
CTx, % change in mean (SD)
37.9 (62.0)
103.7 (109.1)
<0.001
bsAP, % change in mean (SD)
-13.4 (16.0)
2.0 (16.3)
<0.001
OC, % change in mean (SD)
22.0 (32.5)
46.9 (49.1)
<0.001
P1NP, % change in mean (SD)
2.6 (32.2)
30.1 (36.1)
<0.001
Week 24
CTx, % change in mean (SD)
39.2 (79.2)
94.8 (107.9)
<0.001
bsAP, % change in mean (SD)
4.1 (17.2)
25.3 (24.9)
<0.001
OC, % change in mean (SD)
30.3 (43.5)
71.0 (74.3)
<0.001
P1NP, % change in mean (SD)
10.6 (38.7)
58.8 (61.4)
<0.001
P-values were from the Wilcoxon rank sum test; CTx = Type 1 collagen crosslinked C-telopeptide; 
bsAP = serum bone specific alkaline phosphatase; OC = osteocalcin; P1NP = procollagen Type 1 N-terminal propeptide.
1.2.4.6.4.
Week 24 Conclusions
Key conclusions from the Week 24 analysis of Study GS-US-292-0102 included the following:

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 24 was similar 
between treatment groups

Treatment was generally well tolerated as most AEs were mild and not associated with 
treatment discontinuation. No new or unexpected adverse events occurred.

The data shows that subjects taking E/C/F/TAF had more modest changes in creatinine and 
in bone mineral density than subjects taking E/C/F/TDF. The differences were statistically 
significant and may have important clinical relevance for individual subjects.
Other than renal lab abnormalities and biomarkers and bone biomarkers, the frequency and type 
of laboratory abnormalities was comparable between the two treatment arms.
1.3.
Rationale for This Study
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B
Approximately one-third of the world’s population has serological evidence of past or present 
HBV infection with over 350 million people globally who are chronic HBV surface antigen 
(HBsAg) carriers. The disease burden for HBV varies regionally, with greater than 50% of all 
subjects residing in Asian countries with the highest prevalence (e.g. China, India, Vietnam, 
Indonesia, South Korea, Taiwan, the Philippines, and Pakistan). The primary goal of treatment is 
to achieve and maintain virologic suppression, without resistance, which has been shown to 


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translate to improvement in liver disease outcomes. Current guidelines recommend treatment for 
subjects with evidence of ongoing viral replication along with liver injury based on elevated 
levels of serum ALT. 
TDF and ETV are highly potent first line therapies for CHB; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically 
lamivudine-experienced/resistant subjects {Baldick 2008, Tenney 2009}. The latter is a key 
limitation for ETV use as LAM remains one of the most commonly prescribed HBV treatments 
in most regions of the world. Thus, despite the availability of effective treatments there remains a 
clear need for newer oral HBV agents that are safe and well tolerated for long term use, and 
capable of achieving high rates of viral suppression with little or no potential for resistance 
development.
Tenofovir alafenamide (TAF), a novel prodrug of TFV, has the potential to further advance the 
treatment of chronic HBV infection. In contrast to TDF, an agent that is rapidly and completely 
cleaved by intestinal and plasma esterases to TFV, TAF is a more stable prodrug that efficiently 
resists early enzymatic cleavage following oral administration and remains more fully intact until 
it is taken up by target cells. As a consequence, TAF, when given at a lower dose than TDF, is 
capable of efficiently delivering active drug (e.g. TFV-DP) to the virally-infected cells 
(e.g. HBV-infected hepatocytes and HIV-infected lymphoid cells) while systemic exposures of 
TFV are reduced compared with oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication, and an 
improved tolerability and safety profile.
Results from GS-US-320-0101, a Phase 1b study evaluating the short-term (28 day) safety, 
efficacy (HBV DNA suppression), and PK of TAF at 4 dose levels (8 mg, 25 mg, 40 mg, 
and 120 mg) compared to TDF 300 mg, has shown no dose effect in regard to viral suppression, 
and similar short-term safety and tolerability compared with TDF. Intensive PK results show 
93% or greater reductions in TFV exposures with doses of TAF 25 mg or lower compared to the 
TFV exposures generated with TDF 300 mg. These results, taken together with 24 weeks safety 
results from the HIV Phase 2 study GS-US-292-0102, which directly compares TAF to TDF 
(each included as a component of an STR), suggest that TAF is safe and well tolerated and may 
have a lower potential for renal- and bone-related AEs compared to TDF. Importantly, TFV 
exposures for E/C/F/TAF 10 mg are comparable to TFV exposures generated with TAF 25 mg 
given as a stand alone agent.
1.3.2.
Rationale for the Current Study
TDF and ETV are highly potent first line therapies for chronic HBV; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically lamivudine 
(LAM)-experienced/resistant subjects. Thus, despite the availability of effective treatments there 
remains a clear need for newer oral HBV agents that are safe and well tolerated for long term 
use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development. TAF has the potential to address each of these requirements. 


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The current study is designed to evaluate non-inferiority of TAF compared to TDF in regard to 
the proportion of subjects with HBV DNA levels below 29 IU/mL at Week 48. The durability of 
TAF compared to TDF in regard to the proportion of subjects with HBV DNA < 29 IU/mL at 
Weeks 96 and 144 will also be assessed in a double blind fashion. In addition to treatment naïve 
subjects, treatment experienced CHB subjects who are viremic and with elevated ALT levels at 
screening are included. This is based on given results from GS-US-174-0106 (ADV suboptimal 
responders) and GS-US-174-0121 (LAM-resistant subjects) which demonstrated in viremic 
patients comparable rates of HBV DNA suppression, as described below, in comparison to 
results in mostly treatment naïve subjects participating in pivotal studies GS-US-174-0102 
(HBeAg-negative subjects) and GS-US-174-0103 (HBeAg-positive subjects). Given the unique 
properties of TAF (efficient delivery of the active moiety, TFV-DP, to HBV-infected 
hepatocytes with reduced systemic TFV exposures), this study will also evaluate the potential 
safety differences (e.g. renal- and bone-related complications) of TAF relative to TDF at
Week 48 and long term comparative safety at Week 96 and 144, after which subjects will be 
further evaluated for longer-term safety and efficacy of TAF in an open-label TAF 25 mg QD 
extension phase through Week 384. The extension phase is important as it will enable the 
evaluation of subjects treated for the entire 384 week period with TAF as well as those who 
received 144 weeks of TDF initially in a double-blinded fashion followed by an additional 
240 weeks of open-label TAF. The latter group will allow an ongoing assessment, including 
possible resolution, of any potential bone- and/or renal-related (or other) complications during 
TAF treatment that might have arisen under initial treatment with TDF.
The primary endpoint of this study is the proportion of subjects with HBV DNA < 29 IU/mL at 
Week 48; the lowest limit of susceptibility of the polymerase chain reaction (PCR) assay to be 
employed (Roche COBAS® Taqman® HBV test for use with the High Pure System). A
histological component of treatment response is not included. Alternatively, non-invasive means 
(i.e. Fibrotest®) will be used to assess the degree of fibrosis at baseline and the change in fibrosis 
on an annual basis for all subjects participating in the trial. In support of this, 48 week results 
from studies, GS-US-174-0102 and GS-US-174-0103, which formed the basis for TDF approval 
for CHB, showed TDF to be superior to ADV based on a “complete response” to treatment 
(a composite endpoint of HBV DNA suppression and histologic improvement based on repeat 
liver biopsy). In GS-US-174-0102, conducted in HBeAg-negative (presumed pre-core mutant) 
subjects, 70.8% and 48.8% of subjects randomized to TDF and ADV, respectively, achieved a 
complete response at Week 48 (treatment difference: 23.5%; p < 0.001). Of the components, 
HBV DNA suppression (< 69 IU/mL) was achieved in 94.4% and 64.0% (treatment difference: 
30.3%; p < 0.001), while histologic improvement was achieved in 74.2% and 68.8% 
(treatment difference: 5.2%; p = 0.292) of TDF- and ADV-treated subjects, respectively. Thus, 
the greater potency of TDF relative to ADV resulting in a significantly higher rate of viral 
suppression was the primary element associated with the superior treatment response at 48 weeks
{Marcellin 2007, Marcellin 2008}. Similar findings were observed in HBeAg-positive subjects 
in GS-US-174-0103.
After 48 weeks, subjects in GS-US-174-0102 and GS-US-174-0103 were eligible to continue 
open-label treatment with TDF. At Year 5 (Week 240), 331/641 (52%) of subjects on TDF 
(without addition of FTC) underwent a repeat liver biopsy, and regression of fibrosis 


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(improvement in Ishak fibrosis score of ≥1 point) was seen in 52% (172/331) of subjects. 
Furthermore, in 94/331 (28%) subjects with cirrhosis (Ishak score ≥5) at baseline, 73% (69/94) 
were no longer cirrhotic at year 5 (≥1 unit decrease in Ishak score). These results confirm the 
benefits of long term viral suppression with TDF in terms of regression of fibrosis and reversal 
of cirrhosis in the majority of TDF-treated subjects {Marcellin 2013}.
The efficacy of TDF in viremic treatment experienced CHB populations has been shown to be 
similar to treatment naïve subjects. In a prospective, randomized (1:1), double-blind, Phase 3b 
study (GS-US-174-0121) which compared TDF alone to the combination of FTC/TDF in 
280 HBeAg-positive and HBeAg-negative subjects receiving treatment with LAM and having 
HBV DNA > 3 log10 IU/mL with documented LAM-resistance (rtM204I/V ± rtL180M 
mutation[s]), 89.4% of TDF-treated subjects vs. 86.3% treated with FTC/TDF had HBV DNA 
< 69 IU/mL at Week 96 (primary endpoint, missing equals failure analysis; p = 0.43). BMD was 
also assessed in GS-US-174-0121, and small declines in BMD (< 2%) of both hip and spine were 
seen with equal frequency in both groups which occurred by Week 24 (spine) and Week 72 
(hip). In another prospective, randomized, double-blind study of TdF vs. FTC/TDF in 
105 HBeAg-positive and HBeAg-negative subjects with a prior suboptimal response to ADV 
(GS-US-174-0106), no differences in HBV DNA suppression (proportion less than 69 IU/mL) 
were seen between treatment groups (82.4% TDF vs. 84.0% FTC/TDF; ITT, non-completer 
equals failure; p = 0.78). Taken together, these studies support the efficacy of TDF in treatment 
experienced subjects as being similar to results seen in treatment naïve subjects.
1.3.3.
Rationale for Dose Selection
In the Phase 1b study, GS-US-320-0101, which has completed enrollment, 4 doses 
(8, 25, 40, and 120 mg) of TAF monotherapy, and TDF 300 mg were evaluated in 
51 treatment naïve CHB subjects. To date, all subjects have completed the 28 day dosing period. 
Results demonstrate that TAF when given in doses over a range of 8 to 120 mg results in similar 
HBV DNA declines over 28 days. Furthermore, HBV DNA suppression with TAF is comparable 
to that of TDF 300 mg. In GS-US-320-0101, increased rates of viral suppression were not 
observed with higher TAF doses (40 mg, 120 mg) relative to lower TAF doses 
(8 mg and 25 mg), and similar safety profiles were observed among TAF treatment groups. PK 
results demonstrate a 93% reduction in TFV exposures relative to TDF 300 mg when TAF is 
dosed at 25 mg. These results in CHB subjects are consistent with data in healthy volunteers and 
HIV-infected subjects given TAF 25 mg as a stand alone agent. Importantly, as previously 
stated, the TFV exposures seen with TAF 25 mg in CHB subjects are therapeutically comparable 
to those in HIV patients receiving E/C/F/TAF 10 mg (due to an inhibitory drug-drug interaction 
between TAF and COBI when these agents are included in the E/C/F/TAF STR) which provide 
safety data (from Phase 2 study GS-US-292-0102) supporting the development of TAF for 
hepatitis B at the 25 mg dose level. Further, in CHB subjects participating in the Phase 1b study 
who were dosed at the lowest TAF dose (8 mg), a 97% reduction in TFV exposures relative to 
TDF 300 mg was observed, representing an incremental reduction in TFV exposure of only 
5% at this dose level relative to TAF 25 mg.


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Importantly, the TFV exposures at a 25 mg dose when given alone are consistent with TAF 
exposures generated with the E/C/F/TAF 10 mg STR currently in Phase 3 development for 
treatment of HIV infection. Thus, the efficacy and safety of TAF in HIV is also being evaluated 
at a dose level that is therapeutically equivalent to the dose selected for study GS-US-320-0108.
Final Week 24 results from GS-US-292-0102, a phase 2 study being conducted in HIV-1 
treatment naïve subjects, demonstrated similar safety and tolerability of TAF vs. TDF when each 
is included as a component of STRs containing elvitegravir, cobicistat, and emtricitabine. At 
Week 24, significant differences were noted between arms in regard to smaller declines in hip 
BMD, estimated CLCr (Cockcroft-Gault), and changes in various biomarkers of bone and renal 
function which are suggestive of differences in bone and renal tolerability of TAF vs. TDF. 
Similar assessments are included in the present trial in HBeAg-negative, chronic HBV subjects, 
and the study is sufficiently powered to demonstrate a potentially superior safety profile for TAF 
relative to TDF in regard to these bone and renal parameters.
In summary, a 25 mg dose was selected for TAF for use in this non-inferiority trial based upon 
the safety profile for TAF in treatment naïve HIV-1-infected subjects from GS-US-292-0102, 
which utilizes a therapeutically equivalent TAF dose (10 mg as a component of the E/C/F/TAF 
STR), the viral suppression results in chronic HBV subjects in GS-US-320-0101 showing 
comparable rates of HBV DNA decline for a TAF 25 mg dose compared to TDF 300 mg 
(the approved dose for treatment of HBV), and the reduced systemic TFV exposures (~93%) 
seen with TAF relative to TDF 300 mg, when dosed at this level.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative,
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and 
treatment experienced subjects
The key secondary safety objectives of the study are:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization by central laboratory and AASLD criteria) 
response of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144


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
To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72 , 96, and 144 
(or ED visit if prior to Week 144 and more than 24 weeks since prior exam) in a subset of 
subjects

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and the incidence of drug resistance 
mutations of TAF 25 mg QD in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD and then switched to open-label 
TAF 25 mg QD


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a randomized, double-blind, non-inferiority study to compare the antiviral activity of 
TAF 25 mg QD versus TDF 300 mg QD. Approximately three hundred ninety (390) subjects 
will be randomized in a 2:1 ratio (A:B) to the treatment arms for 144 weeks (96 weeks under 
Amendment 2.1), and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced).
For China, approximately 150 additional subjects will be randomized in a 2:1 ratio (A: B) to the 
treatment arms for 96 weeks, and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced).
If the subject is deemed ineligible for this study by HBV serology (i.e. HBeAg positive CHB), 
this information may be used to determine eligibility for GS-US-320-0110 
(another Gilead Sciences Phase 3 study in HBeAg positive, CHB subjects; this study must also 
be IRB/EC approved at the participating center). 
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD
For China, approximately 150 additional subjects (100 in Treatment Arm A and 50 in 
Treatment Arm B) will be enrolled for local registration purposes.
Subjects with a history of or current diagnosis of compensated cirrhosis are eligible for 
enrollment. Acceptable diagnostic criteria for cirrhosis include a Metavir or Knodell fibrosis 
score ≥4 or Ishak fibrosis score ≥ 5 by liver biopsy, or previous Fibroscan result > 12kPa 
(in countries where locally approved). Available information regarding the presence or absence 
of cirrhosis by these criteria will be captured in the electronic case report forms at Baseline, and 
any other time during the trial should an investigator opt to undertake additional studies. 
Importantly, the change in fibrosis as assessed by Fibrotest® will be performed in all subjects 
participating in the trial at Baseline, and annually thereafter through Week 384/ED.
The duration of double-blind treatment is 144 weeks (96 weeks under Amendments 2.1). At 
Week 144, all subjects remaining on blinded treatment will be switched to the open-label TAF 
25 mg QD extension period for up to an additional 240 weeks (Week 144 through 
Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at Week 96 per 
Amendment 2.1 will continue on open-label TAF 25 mg QD through Week 384/ED. All subjects 
who complete the double-blind period of treatment are eligible for participation in the open label 
TAF 25 mg QD extension period. Subjects who permanently discontinue study drug 
(either prematurely [ED] or at the end of study [Week 384]) for reasons other than HBsAg loss 
with confirmed seroconversion to anti-HBs, will be followed every 4 weeks for 24 weeks off 
treatment or until initiation of alternative, commercially available HBV therapy, whichever 
occurs first.


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Subjects with HBsAg loss with confinned seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confinned seroconversion to anti-HBs prior to Week 48 are not pennitted to 
discontinue study drug prior to the Week 48 visit. After Week 48, these subjects who discontinue 
study drug will be followed off treatment every 4 weeks for 12 weeks and then per the study visit 
schedule (Appendix 2) through Week 384/ED. Discontinuation of study drug for subjects 
experiencing HBsAg loss with confinned seroconversion to anti-HBs, who have known bridging 
fibrosis or cirrhosis, should be considered on a case by case basis. 
Figure 3-1. 
Study Schema 
I 
Screening 
I 
Randomization 2:1 (A:B) 
I 
I 
Arm A: TAF 25 mg QD and placebo to 
Arm B: TDF 300 mg QD and placebo to 
match of TDF 300 mg QD 
match ofTAF 25 mg QD 
I 
I 
I 
Week96 Open Label TAF25 mg QD (Amendment2.l) 
Week 144 Open Label TAF 25 mg QD (Amendment 3.1) 
I 
I 
Week 384 / Early Discontinuation Visit 
I 
Follow up -
Every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first 
3.2. 
Biomarker Testing 
3.2.1. 
Biomarker Samples to Address the Study Objectives: 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 390 subjects, who are 18 years of age and older, with HBeAg-negative chronic 
hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 300 mg 
matched placebo (n = 260) or TDF 300 mg and TAF 25 mg matched placebo (n = 130) for 
144 weeks (96 weeks under Amendment 2.1).
For China, approximately 150 subjects, who are 18 years of age and older, with HBeAg-negative 
chronic hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 
300 mg matched placebo (n = 100) or TDF 300 mg and TAF 25 mg matched placebo (n = 50) 
for 96 weeks.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures.
2) Male and non-pregnant, non-lactating female subjects, 18 years of age and older, based on 
the date of the screening visit. A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in Appendix 6).
3) Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 
6 months).
4) HBeAg-negative, chronic hepatitis B with all of the following:
a) HBeAg-negative and HBeAb-positive at Screening (if the subject is deemed ineligible for 
this study by HBV serology [i.e. HBeAg-positive CHB], this information may be used to 
determine eligibility for GS-US-320-0110 [another Gilead Sciences Phase 3 study in 
HBeAg-positive, CHB subjects; this study must also be IRB/EC approved at the 
participating center])
b) Screening HBV DNA ≥ 2 × 104 IU/mL
c) Screening serum ALT level 60 U/L (males) or > 38 U/L (females) and ≤10 × ULN 
(by central laboratory range)
5) Treatment-naïve subjects (defined as < 12 weeks of oral antiviral treatment with any 
nucleoside or nucleotide analogue), OR treatment-experienced subjects (defined as subjects 
meeting all entry criteria [including HBV DNA and serum ALT criteria] and with 
> 12 weeks of previous treatment with any nucleoside or nucleotide analogue) will be 


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eligible for enrollment. Treatment-experienced subjects receiving oral antiviral treatment at 
Screening must continue their treatment regimen until the time of randomization, when it will 
be discontinued.
6) Any previous treatment with interferon (pegylated or non-pegylated) must have ended at 
least 6 months prior to the baseline visit. 
7) Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the Screening evaluation, 
as follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8) Normal ECG (or if abnormal, determined by the investigator not to be clinically significant)
9) Must be willing and able to comply with all study requirements.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study.
2) Males and females of reproductive potential who are unwilling to use an “effective”, 
protocol-specified method(s) of contraception during the study. For a list of 
protocol-specified contraceptive methods, refer to Appendix 6.
3) Co-infection with HCV, HIV, or HDV.
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5) Any history of, or current evidence of, clinical hepatic decompensation 
(e.g., ascites, encephalopathy or variceal hemorrhage).  
6) Abnormal hematological and biochemical parameters, including:
a) Hemoglobin < 10 g/dL
b) Absolute neutrophil count < 750/mm3
c) Platelets ≤50,000/mm3
d) AST or ALT > 10 × ULN


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e) Total Bilirubin > 2.5 × ULN
f)
Albumin < 3.0 g/dL
g) INR > 1.5 × ULN (unless stable on anticoagulant regimen)
7) Received solid organ or bone marrow transplant.
8) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator.
9) Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures.
10) Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
11) Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational
agents, nephrotoxic agents, or agents capable of modifying renal excretion.
12) Known hypersensitivity to study drugs, metabolites, or formulation excipients.
13) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance.
14) Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
15) Subjects on prohibited concomitant medications (See Table 5-1). Subjects on prohibited 
medications, otherwise eligible, will need a wash out period of at least 30 days.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
A centralized randomization procedure via an Interactive Voice/Web Response System 
(IVRS/IWRS) will be used for this study, whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. If the subject is deemed ineligible for this study by HBV serology 
(i.e. HBeAg-positive CHB), this information may be used to determine eligibility for 
GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg-positive, CHB subjects; this 
study must also be IRB/EC approved at the participating center). Eligible subjects will be 
randomized 2:1 to receive either blinded TAF 25 mg and TDF matched placebo or TDF 300 mg 
and TAF matched placebo for 144 weeks (96 weeks under Amendment 2.1). Subjects will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, ≥7 log10 IU/mL - < 8 log10 IU/mL, 
≥8 log10 IU/mL) and oral antiviral treatment status (treatment-naïve vs. treatment-experienced). 
At Week 144, all subjects will be switched to open label TAF 25 mg QD up to an additional
240 weeks (Week 144 through Week 384/ED). Subjects already assigned to open-label 
TAF 25 mg QD at Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED.
For the entire duration of the study, subjects and investigator will remain blinded to the initial 
treatment regimen to which the subjects were randomized.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IVRS/IWRS
for that subject. Gilead recommends, but does not require that the investigator contact the 
Gilead Medical Monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report form/ 
electronic case report form (CRF/eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead Medical Monitor promptly in 
case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Pharmacovigilance and Epidemiology (PVE)may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (TAF). The tablets are yellow, round-shaped, and film-coated. 
The tablets are debossed with “GSI” on one side and “25” on the other side. In addition to the 
active ingredient, each film-coated tablet contains the following inactive ingredients: 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. 
5.2.1.2.
Placebo to match TAF Tablets
Placebo tablets to match TAF 25 mg are yellow, round-shaped, and film-coated. The tablets are 
debossed with “GSI” on one side and “25” on the other side. Each tablet contains the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
yellow iron oxide. 
5.2.1.3.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF)
TDF 300 mg tablets contain 300 mg of tenofovir disoproxil fumarate (TDF), which is equivalent 
to 245 mg of tenofovir disoproxil. The tablets are light blue, almond-shaped, plain-faced, and
film-coated. Each tablet contains the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose (hydroxypropyl methylcellulose), 
glycerol triacetate, titanium dioxide, and indigo carmine aluminum lake.
5.2.1.4.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF) to be Used in 
Developing Markets
TDF 300 mg tablets to be used in developing markets contain 300 mg of tenofovir disoproxil 
fumarate (TDF), which is equivalent to 245 mg of tenofovir disoproxil. The tablets are white, 
almond-shaped, film-coated, debossed with “GILEAD” and “4331” on one side and plain-faced 
on the other side. Each tablet contains the following inactive ingredients: microcrystalline 
cellulose, lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium 
stearate. The film coating contains lactose monohydrate, hypromellose, triacetin and titanium 
dioxide.


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5.2.1.5.
Placebo to match TDF Tablets
Placebo tablets to match TDF 300 mg are light blue, almond-shaped, plain-faced, film-coated 
tablets. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose 
(hydroxypropyl methylcellulose), triacetin, titanium dioxide, and indigo carmine aluminum lake. 
5.2.1.6.
Placebo to Match TDF Tablets to be Used in Developing Markets
Placebo tablets to match TDF 300 mg for developing markets are white, almond-shaped, 
film-coated tablets, debossed with “GILEAD” and “4331” on one side and plain-faced on the 
other side. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose, 
triacetin, and titanium dioxide.
5.2.2.
Packaging and Labeling
TAF, TDF, and their matched placebo tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant and polyester coil. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap fitted 
with an induction-sealed, aluminum-faced liner. 
To ensure stability of the tablets and proper product identification, the drug should not be stored 
in a container other than the container in which it is supplied.
All labels for study drug bottles to be distributed to centers in the US, EU and the rest of the 
countries will meet all applicable requirements of the US Food and Drug Administration (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
TAF, TDF, and their matched placebo 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), inclusive. 
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures.
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos
Subjects will be randomly assigned (2:1) to receive one of the following treatments in a blinded 
fashion:
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD


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For China, approximately 150 additional subjects will be randomized 2:1 to receive either 
Treatment A (n = 100) or Treatment B (n = 50) for 144 weeks.
After 144 weeks of blinded randomized treatment (96 weeks under Amendment 2.1), each 
subject will switch to open-label TAF 25 mg QD for up to an additional 240 weeks
(Week 144 through Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED. 
It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
All study drugs should be taken at approximately the same time each day with food.
Observed in-clinic study drug dosing is required at Weeks 4 and 12 visits. Subjects who elect to 
dose in evening are not required to have in-clinic dosing and the single PK blood sample 
collection at the Week 4 and 12 visits.
Study drug should be administered after assessing adverse events and concomitant medication(s).
5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
Concomitant use of some medications including herbal/natural products/therapies and over the 
counter medications with TAF may result in PK interactions.
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
including herbal/natural products/therapies, and over the counter medications, the 
Gilead Sciences 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.
The following medications are excluded while subjects are participating in the study. These 
medications are prohibited during the screening period and for a minimum of 30 days prior 
to the Baseline/Day 1 visit through the end of treatment:

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir (e.g., 
cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)


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
Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or 
immunomodulating agents

Bisphosphonates

Investigational agents (unless approved by Gilead Sciences)

Medications excluded due to the potential for drug-drug interaction with TAF (Table 5-1)
Treatment-experienced subjects (defined as subjects meeting all entry criteria 
[including HBV DNA and serum ALT criteria] and with ≥12 weeks of previous treatment with 
any nucleoside or nucleotide analogue) receiving oral antiviral treatment at Screening must 
continue their treatment regimen until the time of randomization/Baseline/Day 1, when it will be 
discontinued.
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution 
Due to the Potential for Drug-Drug Interaction with Study 
Medication
Medication Class
Prohibited Medications
Medications to be used with caution
Analeptic
Modafinil
Antiarrhythmics
Amiodarone, Quinidine: may increase 
concentration of TAF and/or TFV
Antibacterials
Clarithromycin: may increase concentration of 
TAF and/or TFV
Anticonvulsants
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Voriconazole
Itraconazole, Ketoconazole: may increase 
concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, 
Rifampin
Calcium channel blockers
Diltiazem, Felodipine, Verapamil: may 
increase concentration of TAF and/or TFV
Digoxin
Digoxin: concomitant use may result in an 
increased or decreased level; use with caution 
and with appropriate monitoring of serum 
digoxin levels. Digoxin therapy should be 
initiated at the lowest dose, and the dose 
should be titrated to clinical response.
Herbal/Natural Supplements
St. John’s Wort, Echinacea, 
Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)


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5.5.
Accountability for Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product (IMP) kits and/or bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP kits and/or bottles dispensed to subjects must be returned to the site.
Investigational product accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits and/or bottles returned, along with the 
initials of the person recording the information
5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. A copy of the site’s 
SOP will be obtained for central files. Where possible, study drug will be destroyed at the site. 
Upon study completion, a copy of the Investigational Drug Accountability records must be filed 
at the site. Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the 
investigator must maintain accurate records for all study drug kits and/or bottles destroyed. 
Records must show the identification and quantity of each unit destroyed, the method of 
destruction, and person who disposed of the drug. All study drug records must be maintained at 
the site and copies must be submitted to Gilead Sciences at the end of the study. 


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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 described in the text that follows.
Any deviation from protocol procedures should be documented and the sponsor or the contract 
research organization (CRO) should be notified.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment. Once consent has been obtained, all screening tests and procedures 
have been completed, and study eligibility has been confirmed, subjects will be randomized
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 5.1. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principal Investigator’s opinion, the retest value will be within accepted parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample); or due to an extenuating circumstance.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 45 days before Baseline to determine eligibility for participation 
in the study. The following will be performed and documented during the screening period:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history, including HBV history

Review concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Complete physical examination including vital signs (blood pressure, pulse, respiration rate 
and temperature), body weight, and height


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
ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (at sites in China with capability only). DXA scan will be 
performed at any time during the Screening period and should be completed at least 14 days 
prior to the first dose of the study drug, in order to ensure an acceptable pre-dose DXA scan

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (
 only at select sites - separate consent required) 
– to be performed at any time during the Screening period and prior to the first dose of the 
study drug 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HIV-1, HDV, HCV, serum pregnancy test (for females of child-bearing potential), 
α-fetoprotein (AFP) and INR. An AFP > 50 ng/mL at Screening must have an appropriate 
evaluation (e.g. CT scan) in order to rule out HCC prior to being permitted to enter the study

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days for randomization into the study. If the subject is deemed ineligible for this 
study by HBV serology (i.e. HBeAg-positive CHB), this information may be used to determine 
eligibility for GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg positive, CHB 
subjects; this study must also be IRB/EC approved at the participating center).
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the adverse events case report form (CRF/eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history are to 
be captured on the medical history CRF/eCRF. See Section 7, Adverse Events and Toxicity 
Management for additional details.
6.2.2.
Baseline Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug. Subjects screened within 45 days before Baseline will be eligible to participate in the 
study. Initiation of treatment with study drug should take place on the day of the Baseline visit. 
The following will be performed at the Baseline visit:

Review of inclusion/exclusion criteria and confirm medical history

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight
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Tenofovir Alafenamide (T AF) 
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• 
Review concomitant medications 
• 
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Final 
Amendment 3 .4 
• 
Assess future risk of bone fracture using the Fracture Risk Assessment tool (FRAX®; at sites 
in China with DXA capability only) 
• 
Randomization 
• 
Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 
• 
Fasting urine sample for renal biomarkers 
• 
Dispense blinded study drugs 
• 
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HBV genotyping (A-H), virology (resistance surveillance), serum and plasma for storage, 
IL28B genotype, and vitamin D assessment 
• 
Cystatin C testing for estimated glomerular filtration rate (eGFR) by CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration) 
• 
Estimated creatinine clearance (using the Cockcroft-Gault method) 
• 
Blood sample for Fibrotest® 
• 
Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage 
• 
6.3. 
6.3.1. 
Treatment Assessments 
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144) 
Study visits Weeks 4 - 44 and Week 56 - 88 should be completed ± 3 days of the protocol 
specified visit date, based on the Baseline Visit. 
Study visit Week 48 should be completed 14 days of the protocol specified visit date, based on 
the Baseline Visit. 
Study visits Weeks 96, 108, 120, and 132, and 144 should be completed ± 14 days of the 
protocol specified visit date, based on the Baseline Visit. 
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6.3.1.1. 
Week4 
• 
Symptom directed physical exam 
• 
Body weight 
• 
Vital signs: blood pressure, pulse, respiration rate, and temperature 
• 
Review concomitant medications 
• 
Review adverse events 
• 
Perfonn study drug accountability 
• 
Fasting blood sample for bone biomarkers 
• 
Fasting urine sample for renal biomarkers 
• 
• 
Dispense blinded study drugs 
Final 
Amendment 3 .4 
• 
Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose (subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample) 
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Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 
• 
Estimated creatinine clearance (using the Cockcroft-Gault method) 
• 
Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage 
6.3.1.2. 
Week8 
• 
Symptom directed physical exam 
• 
Body weight 
• 
Vital signs: blood pressure, pulse, respiration rate, temperature 
• 
Review concomitant medications 
• 
Review adverse events 
• 
Perfonn study drug accountability 
• 
• 
Dispense blinded study drugs 
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Amendment 3 .4 
• 
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 
• 
Estimated creatinine clearance (using the Cockcroft-Gault method) 
• 
Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and storage 
6.3.1.3. 
Week 12 
• 
Symptom directed physical exam 
• 
Body weight 
• 
Vital signs: blood pressure, pulse, respiration rate, and temperature 
• 
Review concomitant medications 
• 
Review adverse events 
• 
Perfonn study drug accountability 
• 
Fasting blood sample for bone biomarkers 
• 
Fasting urine sample for renal biomarkers 
• 
I 
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I 
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I 
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
Dispense blinded study drugs

Dose in clinic and collect single plasma PK sample between 15 minutes to 4 hours post-dose
(subjects who elect to dose in the evening the previous day are not required to have in-clinic 
dosing and provide the single PK sample)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.4.
Weeks 16, 20, 28, 32, 40, and 44

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.5.
Week 24

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications


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Amendment 3.4
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
Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.6.
Week 36

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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Amendment 3.4
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6.3.1.7.
Week 48

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (within 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.8.
Weeks 56 and 88

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature


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Amendment 3.4
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
Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.9.
Weeks 64, 80, 108, and 132

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF at all 
subsequent visits)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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6.3.1.10.
Week 72

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (
6.3.1.11.
Weeks 96 and 120

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording) [Week 96 only]

Hepatic ultrasound for surveillance of hepatocellular carcinoma

DXA scan of spine and hip to be performed (within ± 14 days of the expected visit date; at 
sites in China with capability only)
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Amendment 3.4
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
Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (For Week 120, subjects already assigned to open-label TAF 
25 mg QD at Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF)

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest® [Week 96 only]

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) 
[Week 96 only]
6.3.1.12.
Week 144

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ± 14 days of the expected Week 144 visit 
date; at sites in China with capability only)

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Review concomitant medications

Review adverse events 
CCI


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Amendment 3.4
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
Retrieve study drug and perform study drug accountability

Dispense open label TAF 

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) 
At ED visit, ophthalmologic assessment should be performed only if not done within the 
last 12 weeks
6.3.2.
Open Label Visits
Study visits Weeks 168 through 384/ED should be completed ± 28 days of the protocol specified 
visit date, based on the Baseline Visit.
6.3.2.1.
Weeks 168, 216, 264, 312, and 360

Symptom directed physical exam

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events
CCI


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
Perform open-label study drug accountability

Dispense open-label TAF

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage.  For China only, the serum and 
plasma samples for storage are not being collected.

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage.  For China only, 
the urine sample for storage is not being collected.
6.3.2.2.
Weeks 192, 240, 288, 336, and 384/ED
The ED Visit should be performed within 72 hours (i.e., visit window is within 3 days) of 
the last study drug dose.

Symptom directed physical exam (At Week 240 and 384/ED, a complete physical exam 
should be performed) 

Hepatic ultrasound for surveillance of hepatocellular carcinoma
At ED visit, Hepatic ultrasound should be performed only if not done within the prior 
24 weeks

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ±28 days of the expected visit date; at 
sites in China with DXA capability only)
At ED visit, DXA scan should be performed only if not done within the prior 24 weeks

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability 


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Amendment 3.4
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
Dispense Open Label TAF (no study drug will be dispensed at Week 384/ ED visit)

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAb and reflex HBsAg), and virology 
(resistance surveillance), and serum and plasma for storage.  For China only, the serum and 
plasma samples for storage are not being collected.

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage. For China only, 
the urine sample for storage is not being collected.

For ED visit prior to Week 144 only, if not performed within the prior 24 weeks:
Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.4.
Post-treatment Assessments
6.4.1.
HBsAg Loss and Seroconversion Subjects
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to 
anti-HBs on or after the Week 48 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the study visit schedule through Week 384/ED (excluding drug 
dispensation and accountability).
6.4.2.
All other subjects who discontinue study drug
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be 
followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.4.3.
Follow up visit assessments (all subjects)
Treatment-free Follow Up Visits should be completed ±7 days from the protocol-specified visit 
date, determined by the date the subject discontinued the study drug.

Symptom directed physical exam


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Amendment 3.4
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
Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature 

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
serum for storage, HBV serology (HBsAg and reflex HBsAb at Follow Up visits 
Weeks 12 and 24), and serum HBsAg (quantitative). For China only, the serum sample for 
storage is not being collected.

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis
6.5.
Early Discontinuation (ED) from Study
If a subject discontinues study medication dosing for reasons other than HBsAg loss with 
confirmed seroconversion to anti-HBs (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related visits 
and procedures. If this is not possible or acceptable to the subject or investigator, the subject may 
be withdrawn from the study. Early Discontinuation Assessments are described in 
Section 6.3.2.2.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in 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

Subjects with confirmed creatinine clearance of < 30 mL/min at any time during the study 
will have their study drug permanently discontinued

Lack of efficacy (virologic failure)

HBsAg loss with seroconversion to anti-HBs. These subjects should discontinue study drug 
within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion before Week 48 are not permitted to discontinue 
study drug prior to the Week 48 visit


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• 
Discontinuation of study drug for subjects experiencing HBsAg loss with confirmed 
seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, should be 
considered on a case by case basis 
• 
Subject request to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study; refer to Appendix 6 
• 
Discontinuation of the study at the request of Gilead Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC) 
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6.9. 
Resistance Surveillance 
Final 
Amendment 3 .4 
Genotypic sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for 
resistance mutations will be conducted at Baseline for all subjects, and attempted for all viremic 
subjects (HBV DNA~ 69 IU/mL) at Week 48 and every 48 weeks m1til Week 384/ED visit. 
At Baseline, resistance surveillance will be conducted by INNO-LiPA Multi-DR v3 
(Innogenetics), which will detennine the presence of HBV pol/RT mutations known to confer 
resistance to lamivudine, adefovir, entecavir, clevudine and/or telbivudine. 
Every 48 weeks post Baseline (if viremic ), resistance surveillance will be conducted by 
population sequencing of the HBV pol/RT. 
As it may not be known at the time of the visit whether a patient is viremic or if it will be their 
last study visit, a separate virology sample for potential resistance surveillance will be collected 
at each study visit. 
6.10. 
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance 
Subjects will undergo hepatic ultrasound assessments for HCC surveillance, beginning at 
Week 96, at 24 week intervals. Subjects who have completed the Week 96 visit 
(under Amendment 2.1) should begin ultrasound assessments at the next visit at which an 
ultrasound assessment is included (see Appendix 2 and Section 6 of the Protocol). 
6.11. 
End of Study 
The end of this study will be the last subject's last observation ( or visit). 
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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

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.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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, and urinalysis) that require medical or 
surgical intervention or lead to IMP interruption, modification, 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 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigators is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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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 procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
Severity of adverse events is to be determined based on GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). 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: 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 7.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all serious adverse events (SAEs) and 
adverse events related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4-weeks after last administration of study IMP. AEs must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead 
Sciences may request that certain AEs be followed beyond the protocol defined follow up period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. Any SAEs and deaths, regardless of causality, that occur during the post 
treatment follow-up period or within 30 days of the last dose of study drug, when subject 
transitions to alternative, commercially available HBV therapy, should also be reported.


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30-day 
period. However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and report the event to Gilead PVE.

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 may be reported using a paper serious adverse event 
reporting form, but sites will transition to an electronic SAE (eSAE) system. Gilead will 
notify sites in writing and provide training and account information prior to implementing an 
eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead PVE or to the designated CRO.
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 within 24 hours of the investigator’s knowledge of 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 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.


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Safety: 
Medical Monitor: 
CONFIDENTIAL 
North America - PRA 
Email: CH0 safety@praintl.com, 
Final 
Amendment 3 .4 
Fax: 1-888-772-6919 
Europe (including Russian Federation), Asia Pacific - PRA 
Email: MHGSafety@PRAintl.com, 
Fax: +49-621-878-
2181 
Email: safetyreporting@klinera.com, 
Fax: +91-22-25004588 
China. Vietnam - IQVIA 
Email: Ph V _ Gilead@quintiles.com 
Fax: +65 6722 5011 
Japan- CMIC 
Email: GPV _ GileadHB@cmic.co.jp 
Fax: +81-3-3493-5523 
North America - PRA 
Tel: 1.866.326.5053(toll-free) 
Tel: 1.434.951.4082 (direct) 
Fax: 1.800.280.7035 (toll-free) 
Fax: 1.913.307.5751 (direct) 
Email: Gilead320-08@prahs.com 
Europe (including Russian Federation). Asia Pacific - PRA 
Phone: +44 179 252 5608 
Fax: +49 621 878 2181 
Email: MedicEU@PRAintl.com 
PPD 
Phone: PPD 
Fax: PPD 
Email: PPD 
-------
China, Vietnam - I VIA 
PPD 
Phone: PPD 
Mobile: PPD 
Fax: !PPD 
Ema11:i 
PD 
Ja an - CMIC 
PPD 
Phone~PPD 
Email:PPD 
----------
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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy. 
7.5.
Toxicity Management

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 4.

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 5).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.


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
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.

Administration of study drug may be discontinued due to a clinical or laboratory event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.5.2.
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.
7.5.3.
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 non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.


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7.5.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in 
bone mineral density for chronic HBV- infected patients, Gilead recommends that any subject 
who has a DXA scan that demonstrates a decrease from baseline of > 5% in bone mineral density 
of the spine region or the hip region be followed per local medical practice at the discretion of 
the investigator.
7.5.5.
Management of Potential Nephrotoxicity
Creatinine clearance (CLCr), estimated according to the Cockcroft-Gault formula, will be 
followed post-baseline during the study. All subjects with estimated CLCr < 50 mL/min must 
have serum creatinine measured again within 3 calendar days of receipt of results. At the time of 
this repeat serum creatinine assessment, Cystatin C will also be measured and the estimated 
glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be calculated and compared with 
the baseline measurement of this parameter. During the double-blind period, any subject, who 
has a confirmed CLCr estimated by the Cockroft-Gault formula < 50 mL/min and also 
experiences a > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline, will be 
managed as described below:
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499× max (Scys/0.8, 1)−1.328 ×
0.996Age [× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of
Scys/0.8 or 1, and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
Subjects meeting the above eGFR criteria (i.e. confirmed CLCr < 50 mL/min by Cockcroft-Gault 
equation and > 20% reduction from baseline in eGFR by CKD-EPI equation) will be managed as 
follows:

If the CLCr is confirmed to be ≥ 30 mL/min and < 50 mL/min, the subject will be required to 
undergo dose modification to every other day dosing of study drug during the double blind 
period only.

If the CLCr is confirmed ≥ 30 mL/min to < 50 mL/min and the subject has undergone dose 
modification to every other day dosing of study drug and subsequently develops a confirmed 
CLCr ≥50 mL/min, the subject may revert to once daily dosing of study drug after discussion 
with the Gilead Medical Monitor.

If the CLCr is confirmed to be < 30 mL/min at any time during the study, the subject will be 
required to permanently discontinue study drug.


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
All subjects with a change from baseline serum creatinine of ≥0.4 mg/dL must have serum 
creatinine repeated, with a concurrent urinalysis and urine chemistry, within two weeks of 
receipt of results. The following management will be required dependent upon the 
corresponding creatinine clearance value:
If creatinine clearance is < 50 ml/min, or the subject has other clinical and/or laboratory 
evidence of acute renal failure, the subject will be managed according to the guidance 
described above.
If creatinine clearance is ≥ 50 ml/min and the repeat testing of serum creatinine confirms 
a Grade 1 or Grade 2 serum creatinine elevation, it is recommended that subject be 
monitored weekly until the serum creatinine level returns to a value within the normal 
laboratory range.

All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis must have a urinalysis repeated, with a concurrent urinalysis and urine chemistry, 
within two weeks of receipt of results. Upon confirmation of new proteinuria, subjects will 
be asked to return to the clinic for a scheduled or unscheduled follow up visit for evaluation. 
It is recommended that the investigator contact the Gilead Medical Monitor to discuss if 
further consultation with a nephrologist is clinically warranted.
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × baseline 
value and >10 × ULN, with or without associated symptoms
7.5.6.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT > 2 × baseline and > 10 × ULN, the following is 
recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after 
initial laboratory results were drawn). During the visit, a clinical assessment of the subject
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
serum albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV, and 
HEV.


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Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable relative to baseline Liver Function Tests
If ALT levels are elevated (i.e., > 2 × baseline and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to baseline, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or baseline level. 
During monitoring, if the ALT values remain persistently elevated, the investigator should 
discuss with the Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × baseline and > 10 × ULN), and total bilirubin is confirmed 
to be 2 × baseline value, and INR is 0.5 above baseline, provided both are > ULN, the 
investigator should consider discontinuing study medication (upon discussion with the 
Gilead Medical Monitor, unless the safety of the subject is of immediate concern). 
The subject should be monitored weekly as long as ALT, total bilirubin, and INR values remain 
elevated or above baseline values.
During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
7.5.6.2.
Management of Exacerbation of Hepatitis in Subjects who have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation > 2 × baseline and > 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function 
(total bilirubin 2 × baseline, INR 0.5 above baseline, provided both are > ULN) and the subject is 
on no post-study therapy for HBV, the following is recommended:


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
Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV and 
HEV. If Plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy.

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or baseline up to a maximum of 6 months after the initial occurrence of the event. 
7.5.7.
Management of Potential Posterior Uveitis Cases
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/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 administered is lower than that given in the dog study, nor 
have there been reports of posterior uveitis in human clinical studies thus far. Nonetheless, if any 
subject develops 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).
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.


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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject 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).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead PVE using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. Refer to Section 7.3 and the CRF/eCRF completion guidelines for full 
instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion 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 AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Safety Dept. using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead PVE. Gilead PVE contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.


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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Special situations involving non-Gilead concomitant medications does 
not need to be reported on the special situations report form, however, for special situations that 
result in AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
form. Any inappropriate use of concomitant medications prohibited by this protocol should not 
be reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96, and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144


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
To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in 
a subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in a subset of subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and incidence of drug resistance 
mutations of TAF 25 mg QD from Week 144 through Week 384 in subjects initially 
randomized to TAF 25 mg QD and in subjects sequentially treated with TDF 300 mg QD and 
then switched to open-label TAF
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Week 48.
8.1.3.
Secondary Endpoints
The key secondary safety endpoints are:

The percent change from baseline at Week 48 in hip BMD

The percent change from baseline at Week 48 in spine BMD

The change from baseline at Week 48 in serum creatinine 
8.1.4.
Other Endpoints of Interest

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Weeks 96 and 144

The proportion of subjects with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

The proportion of subjects with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 48, 96, and 144

The proportion of subjects with HBsAg loss at Weeks 48, 96, 144, 240, and 384


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• 
The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 48, 96, 144, 
240, and 384 
• 
The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96, 144, 240 
and 384 
• 
The incidence of drug resistant mutations at Weeks 48, 96, 144, 240, and 384 
• 
The change from baseline in ophthalmologic findings by fundoscopic examination at 
Weeks 24, 48, 72, 96, and 144 in a subset of subjects 
• 
The proportion of subjects with treatment-emergent proteinuria (by dipstick) at 
Weeks 48, 96, 144, 240, and 384 
8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
The primary analysis set for efficacy analysis the Full Analysis Set (FAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment. 
8.2.1.2. 
Safety 
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the treatment actually received. 
All data collected during treatment will be included in the safety smmnaries. Data collected 
during treatment free follow up will be smmnarized or listed separately. 
8.2.1.3. 
Phannacokinetics 
The PK analysis set will include all subjects who are randomized and have received at least 
one dose of study medication and for whom concentration data of any analytes of interest 
( eg, T AF and TFV) are available. The PK analysis set will be used for analyses of general 
phannacokinetics. 
8.2.1.4. 
Biomarkers 
The Biomarker analysis set will include all subjects who have evaluable biomarkers data. 
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8.2.2.
Data Handling Conventions
For the primary endpoint missing data will be handled using a missing = failure approach, unless 
otherwise specified.
For key secondary safety endpoints, missing data will be handled via a Last Observation Carried 
Forward (LOCF) method.
For other categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach. For the drug resistant mutations endpoint, a missing = excluded
approach will be employed.
Sensitivity analyses will be performed as warranted.
8.3.
Multiplicity Adjustments
The primary hypothesis of non-inferiority between TAF 25 mg QD and TDF 300 mg QD with 
respect to the proportion of subjects with HBV DNA < 29 IU/mL will be tested first. If 
non-inferiority is established, then multiplicity adjustments will be performed for the secondary 
endpoints with a fallback procedure using the following weights:
a) Hip BMD (weight = 0.4)
b) Spine BMD (weight = 0.2)
c) Serum creatinine (weight = 0.4)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic summaries will include sex, race/ethnicity, geographical region, randomization 
stratification group, and age.
Baseline data will include a summary of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when approximately 390 randomized subjects
complete 48 weeks of the double-blind treatment period or discontinue prematurely. A two-sided 
95% confidence interval, based on the large sample theory adjusted for the randomization 
stratification factors (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) 
in the proportion of subjects who achieved HBV DNA < 29 IU/mL will be used to compare the 
treatment groups. A non-inferiority will be declared if the lower bound of this confidence 
interval exceeds a non-inferiority margin of –0.10. If non-inferiority is established, the lower 
bound of the 95% CI will be compared to 0; if the lower bound of the 95% CI is greater than 0, 
then superiority of TAF over TDF will be established using the same confidence interval. Details 
will be provided in the statistical analysis plan.
8.5.1.1.
Justification of the non-inferiority margin
At Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA < 29 IU/mL 
in the TDF arm was 91.2%. At Week 48 in study GS-98-438, the proportion of subjects with 
HBV DNA < 29 IU/mL in the placebo was 0%. The non-inferiority margin of 10% would 
preserve more than 88% of the lower bound of the 95% confidence interval of the difference 
between TDF and placebo.
NTDF
NPBO
Response rate 
in TDF
Response rate 
in PBO
Difference
95% confidence interval 
lower bound
250
61
91.2%
0%
91.2%
87.7%
Preserve at least 
88% of lower bound
10%
Furthermore, at Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA 
< 29 IU/mL in the TDF arm was 91.2% and the proportion of subjects with HBV DNA 
< 29 IU/mL in adefovir (ADV) arm was 56.0%. The non-inferiority margin of 10% would 
preserve more than 60% of the lower bound of the 95% confidence interval of the difference 
between TDF and adefovir (ADV).


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NTDF
NADV
Response rate 
in TDF
Response rate 
in ADV
Difference
95% confidence interval 
lower bound
Study 174-0102
250
125
91.2%
56.0%
35.2%
25.8%
Preserve at least 
60% of lower 
bound
10%
8.5.2.
Analyses of Other Endpoints of Interest
Continuous secondary endpoints will be summarized using conventional descriptive statistics 
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group and 
overall. A Wilcoxon rank sum test will be used to compare the treatment groups, in an 
exploratory manner.
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint. A two-sided Mantel-Haenszel test, controlling for the randomization strata,
will be used to compare the treatment groups, in an exploratory manner. Missing data will be 
handled by the missing = failure approach.
For the incidence of drug resistant mutations, the missing = excluded approach will be employed.
An analysis of the China subpopulation will also be conducted when approximately 
150 randomized and treated China subjects complete 48 weeks of double-blind treatment or 
discontinue prematurely to examine the consistency of the responses between the China 
subpopulation and the overall population.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose will be summarized by treatment group (according to the drug received). Data for the 
pretreatment and treatment-free follow-up periods will be included in data listings. 
8.6.1.
Key Secondary Safety Analyses
The percent change from baseline in hip and spine BMD at Week 48 will be analyzed using an
ANOVA model. The model will include treatment group as fixed effect. The details are provided 
in the Statistical Analysis Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be analyzed using an ANCOVA 
model with baseline serum creatinine as a covariate, and treatment group as a fixed effect. The 
details are provided in the SAP.


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8.6.2.
Extent of Exposure
A subject’s extent of exposure to drug data will be generated from the drug administration data. 
Exposure data will be summarized by treatment group. 
8.6.3.
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.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
treatment up to the date of last dose of treatment. Continuing adverse events diagnosed prior to 
the start of treatment and worsening in severity grade, or non-serious adverse events at baseline 
which become serious, or adverse events resulting in treatment discontinuation after the start of 
treatment will also be considered treatment-emergent.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group:

Treatment-emergent adverse events

Treatment-emergent study drug-related adverse events

Grade 3 or 4 treatment-emergent adverse event

Grade 3 or 4 treatment-emergent study drug-related adverse event

Grade 2, 3, or 4 treatment-emergent adverse event

Grade 2, 3, or 4 treatment-emergent study drug-related adverse event

AE that caused permanent discontinuation from study drug

AE that caused change in dose or temporary interruption of study drug

Treatment-emergent serious adverse event

Treatment-emergent study drug-related serious adverse event
8.6.4.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.


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Graded laboratory abnonnalities will be defined using the grading scheme in Appendix 5. 
Incidence of treatment-emergent laboratory abnonnalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of treatment, will be summarized by treatment group. If baseline data are missing, then any 
graded abnonnality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratory abnonnalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing. 
8.7. 
Pharmacokinetic Analysis 
Phannacokinetic parameters will be listed and summarized for T AF and TFV using descriptive 
statistics ( eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear fonnats as mean ± standard deviation. 
8.7.1. 
Biomarker Analysis 
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1 
N-tenninal propeptide (P 1 NP), and selected renal biomarkers, including urine retinol binding 
protein, and urine beta-2-microglobulin, will be smmnarized by treatment group and visit using 
descriptive statistics. The difference in change from baseline in these biomarkers between two 
treatment anns will be tested using Wilcoxon rank sum test. 
8.8. 
Sample Size 
With respect to the primary efficacy endpoint, a sample size of 130 for the TDF 300 mg group 
and 260 for the T AF 25 mg group will have 90% power to rule out the non-inferiority margin of 
10% at a one-sided significance level of 0.025. This assumes a rate of 91 % in the TDF 300 mg 
group and 91 % in the TAF 25 mg group in the proportion of subjects with HBV DNA 
< 29 IU/mL. A similar response rate in the TDF group was observed in GS-US-174-0102 
{Marcellin 2007, Marcellin 2008}. 
This sample size (n=260 for the TAF 25 mg ann, n=130 for the TDF 300 mg ann) also provides 
at least 90% power to detect a 1 % difference in the percentage change from baseline in hip BMD 
at Week 48 (assuming a 1.17% change from baseline in TDF 300 mg ann and 0.17% change 
from baseline in the TAF 25 mg ann, with a co1mnon standard deviation of 2.20% and a 
two-sided a = 0.025); a 77% power to detect a 1 % difference in the percentage change from 
baseline in spine BMD at Week 48 (assmning a 1.69% change from baseline in the TDF 
300 mg ann and 0.69% change in the TAF 25 mg ann, with a co1mnon standard deviation of 
3.08% and a two-sided a = 0.025); a 52% power to detect a 0.03 mg/dL difference in the change 
from baseline in serum creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in 
the TDF 300 mg arm and 0.01 mg/dL change from baseline in the TAF 25 mg ann, with a 
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common standard deviation of 0.12). These assumptions were derived from studies GS-98-437, 
GS-98-438, GS-US-174-0102, GS-US-174-0103, and GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD, and 50 subjects TDF 300 mg QD and matched placebo of TAF 
25 mg QD) will be enrolled.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study treatment warrant the 
early termination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications. The DMC may also 
provide recommendations as needed regarding study design
The DMC will convene approximately every 24 weeks following the time of randomization of 
the first subject during the blinded portion of the protocol and approximately every 48 weeks 
during the open-label period.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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, 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. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any sub-investigator’s) participation in the study. The investigator and 
sub-investigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, 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) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
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 


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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the 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 
or IEC and governmental 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 sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 


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audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site 
may destroy used (empty kits and/or bottles) and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, 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.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 113
25 September 2019
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. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
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 in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead 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. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s 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.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF 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 CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 114
25 September 2019
9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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 and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 115
25 September 2019
10.
REFERENCES
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective Lymphoid Cell 
and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-
7340. Mol Pharm 2013;10 (2):459-66.
Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, et al. Hepatitis B virus 
quasispecies susceptibility to entecavir confirms the relationship between 
genotypic resistance and patient virologic response. J Hepatol 2008;48 (6):895-
902.
Bam RA, Birkus G, Babusis D, Yant SR, Cihlar T. Minimal Donor Variation in Cathepsin A 
Expression and Antiviral Activity of GS-7340 in Primary Human CD4+ T Cells 
and Macrophages [Poster Number TUPE016]. XIX International AIDS 
Conference; 2012 July 22-27; Washington, D.C. . 
Birkus G, Bam R, Frey C, Tsai L, Stray K, Yant S, et al. Intracellular activation pathways for 
GS-7340 and the effect of antiviral protease inhibitors  [Poster #577]. Presented 
at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 2012 
March 5-8; Seattle, WA. 
Centers for Disease Control and Prevention (CDC). Hepatitis B Fact Sheet.  Available at:  
http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm. Accessed August 6, 
2003, 
Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Positive Chronic Hepatitis B (CHB): Study GS-US-
174-0103 [AASLD Abstracts]. Hepatology 2007;46 (4 Supp1):861A.
Marcellin P, Buti M, Kraslev Z, Germanidis G, Kaita K, Kotzev I, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Negative Chronic Hepatitis B (CHB): Study GS-US-
174-0102 [AASLD Abstracts]. Hepatology 2007;46 (4 Suppl 1):290A-1A.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis 
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-
year open-label follow-up study. Lancet 2013;381 (9865):468-75.
Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil 
for chronic hepatitis B. N Engl J Med 2008;359 (23):2442-55.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 116
25 September 2019
Marcellin PE, Heathcote EJ, Corsa A, et al. No detectable resistance to tenofovir disoproxil 
fumarate (TDF) following up to 240 weeks of treatment in patients with 
HBEAG+ and HBEAG- chronic hepatitis B virus infection [Abstract 238]. 
Hepatology 2011;54 (4 Suppl.):480A.
Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert-Bismut F, Thabut D, et al. A prospective 
analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic 
hepatitis C. Clin Chem 2006;52 (10):1887-96.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. 1–239. Available at  
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 
August 22.  2012.
Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of 
FibroTest diagnostic value in chronic liver disease. BMC gastroenterology 
2007;7:40.
Poynard T, Zoulim F, Ratziu V, Degos F, Imbert-Bismut F, Deny P, et al. Longitudinal 
assessment of histology surrogate markers (FibroTest-ActiTest) during 
lamivudine therapy in patients with chronic hepatitis B infection. Am J 
Gastroenterol 2005;100 (9):1970-80.
Robbins BL, Greenhaw JJ, Connelly MC, Fridland A. Metabolic pathways for activation of the 
antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. 
Antimicrob Agents Chemother 1995;39 (10):2304-8.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
World Health Organization (WHO). Fact Sheet WHO/204.  October, 2000.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
Gilead Sciences, lnc. 
11. 
Appendix I. --
Appendix 4. 
APPENDICES 
Investigator Signature Page 
Stud Procedures Table 
Management o 
mica an La oratoty Adverse Events 
Final 
Amendment 3 .4 
Appendix 5. 
Appendix 6. 
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnotmalities 
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations 
CONFIDENTIAL 
Page 117 
25 September 2019 


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0 I 08 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 3 .4 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 
Tenofovir Alafenamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 300 mg 
QD for the Treatment of HBeAg-Negative, Chronic Hepatitis B 
GS-US-320-0108, Amendment 3.4, 25 September 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
PPD 
PPD 
INVESTIGATOR ST A TEMENT 
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 118 
25 September 2019 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 119
25 September 2019
Appendix 2.
Study Procedures Table
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Informed Consent 
X
Review of Inclusion/ Exclusion 
Criteria 
X
X
Medical History, including HBV 
history
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination 
including vital signs, and weight 
X
X
X
X
X
X
X
X
Height
X
Symptom-directed Physical 
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXAd (spine & hip ) 
X
X
X
X
X
X
X
Fracture Risk Assessmentq
X
Study Drug Accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing in-clinicf
X
X


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 120
25 September 2019
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Serum Chemistry and Liver 
Function Testsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Estimated Creatinine Clearance 
(by Cockcroft-Gault Method)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin C (for estimated eGFR)
X
Plasma HBV DNA Levels 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
X
HBV Genotyping (A-H) 
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
Fibrotest®
X
X
X
X
IL28B Genotype
X
Vitamin D
X
Plasma PK 
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood for Bone 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Urine for Renal 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
X
X
Serum Pregnancy Testk
X


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
Final 
Gilead Sciences, Inc. 
Amendment 3 .4 
Week 
Screening 
108 
(45 days) 
BL 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48· 
56 
64 
72 
80 
88 
96 ... 
132' 
120 
144' 
Visit 
-14 
Window 
±3 days 
days 
±3 days 
± 14 days 
Urine Pregnancy Testk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONFIDENTIAL 
Page 121 
25 September 2019 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 122
25 September 2019
Visit windows
Week
168
192
216
240
264
288
312
336
360
384/EDo
FUp
±28 days
±7 days
Review Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination including vital signs, and weight 
X
X
Symptom-directed Physical Exam
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
DXA (spine & hip)d
X
X
X
X
X
Study Drug Accountability  
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
Xe
Serum Chemistry and Liver Function Testsg
X
X
X
X
X
X
X
X
X
X
X
Est Creatinine Clearance (Cockcroft-Gault) 
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
Plasma HBV DNA Levels 
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
Fibrotest®
X
X
X
X
X
Fasting Blood for Bone Biomarkersi
X
X
X
X
X
Fasting Urine for Renal Biomarkersi
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
Urine Pregnancy Testk
X
X
X
X
X
X
X
X
X
X


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
Final 
Gilead Sciences, Inc. 
Amendment 3 .4 
Week 
168 
192 
216 
240 
264 
288 
312 
336 
360 
384/ED0 
FUP 
Visit windows 
±28 days 
±7 days 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Semm and plasma for storage' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (semm only) 
Hepatic Ultrasound' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
The visit window for Week 48 visit is 14 days. The visit window for Week 96 is ± 14 days. 
b 
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording 
c 
Vital signs include blood pressure, pulse, respiration rate, and temperature 
d 
DXA scans will be perfomied only at sites in China with capability. The initial (baseline) DXA will be perfomied during Screening and should be completed at least 14 days 
prior to the first dose of study dmg. The Week 48 DXA window is 14 days only. DXA is re.quired for Early Discontinuation (ED) visit if not done within the last 24 weeks. 
e 
Subjects already assigned to open-label T AF 25 mg QD per Amend 2. 1 continue on open-label T AF 25 mg QD. Otherwise, blinded study drug will be dispensed until 
Week 144 visit. Open label TAF will be dispensed from Week 144 through Week 360. At Week 384/ED, study dmg will not be dispensed 
f 
It is preferred that subjects take their study dmg according to a morning dosing schedule; subjects who elect to dose in the evening the previous day are not re.quired to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 12 visits. 
g 
Semm chemistry and Liver Function Tests: alkaline phosphatase, AST, ALT, GGT, total bilimbin, direct and indirect bilimbin, total protein, albumin, LOH, CPK, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphoms, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is perfomied in subjects 
with total amylase > 1.5 >< ULN), and PTJ-1. PTH analyzed at all visits except for Screening through Week 96, and then at Weeks 120, 144, and then every 48 weeks through 
Week 384/ED. At Baseline, Weeks 24, 48, 72, 96, 120, 144, 192, 240, 288, 336 and 384/ED, subject will be fasting for semm and glucose and metabolic panel. Coagulation 
panel will be done at Screening and then as a reflex only test for ALT flares. 
h 
1-IBeAg and 1-IBeAb will be done at Screening and Baseline visits. HBsAg and reflex 1-IBsAb will be done at Screening and Baseline visits, and every 12 to 16 weeks until 
week 144, every 24 weeks untile Week 384/ED and at Follow Up visits Weeks 12 and 24. 
Blood for selected bone biomarkers and urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected >24 weeks 
prior 
j 
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 
k 
For female sub·ects of childbearing otential. In the event ofa ositive urine test a semm 
I 
111 
CONFI DENTIAL 
Page 123 
25 September 2019 


Tenofovir Alafenamide (T AF) 
Protocol GS-US-320-0108 
Gilead Sciences, Inc. 
n 
o 
The Early D1scontmuatton (ED) v1s1t should be perfom1ed within 72 hours of the last study drng dose(+ 3 days) 
Final 
Amendment 3 .4 
p 
Subjects who discontinue study drng for reasons other than 1-lBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks or up to 
initiation of alternative, commercially available HBV therapy, whichever occurs first. Subjects who lose 1-lBsAg with confim1ed seroconversion to anti-1-lBs should 
discontinue study drng within 3-6 months following confim1ation of 1-lBsAg loss and seroconversion to anti-HBs or after Week 48, if seroconversion occurs prior to this visit. 
These subjects will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule through Week 384/ED. 
q 
Complete the Fracture Risk Assessment specific eCRF at sites in China with DXA capability only. 
r 
I-le atic ultrasound for I-ICC surveillance 
s 
CONFIDENTIAL 
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25 September 2019 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 125
25 September 2019
CCI


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-0 I 08 
Gilead Sciences, Inc. 
Final 
Amendment 3.4 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
I 
G,ad,2 
I I 
G,ad,3 
I I 
G,ad, 4 
I 
i 
i 
! 
May continue 
Repeat lab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
• 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
1. 
Withhold investigational medicinal products until~ Grade 2 
2. 
Restart all investigational medicinal products at full dose 
! 
Repeat lab to 
confirm toxicity 
grade 
1 
1 
I 
inv 
dos 
dis 
onfirmed and unrelated to 
estigational medicinal products, 
ng may continue at the 
retion of the investigator 
If confirmed and 
possibly or probably 
l 
-.1 related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, discontinue 
all investigational medicinal products dosing permanently 
CONFIDENT IAL 
Page 126 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 
25 September 20 I 9 


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Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
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
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/ μL
200 to 300/mm3
200 to 300/ μL
100 to 200/mm3
100 to 200/ μL
100/mm3
100/ μL
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
100.0 to 125.0 GI/L
50,000 to 100,000/mm3
50.0 to 100.0 GI/L
25,000 to 50,000/mm3
25.0 to 50.0 GI/L
25,000/mm3
25.0 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.0 GI/L to 2.5 GI/L
1.5 to 2.0 GI/L
1.0 to 1.5 GI/L
1.0 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Fibrin Split Product 
20 to 40 μg /mL
40 to 50 μg /mL
50 to 60 μg /mL
60 μg /mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
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% 


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 mEq/L to LLN
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 mmol/L to LLN
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146 to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146 to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
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
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4 mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 mg/dL to LLN
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63 mmol/L to LLN 
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
ULN to 597 μmol /L
597 to 716 μmol /L
716 to 895 μmol /L
895 μmol /L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol /L to LLN
57 to 87 μmol /L
27 to 57 μmol /L
27 μmol /L
Creatinine 
1.50 to 2.0 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol /L
177 to 265 μmol /L
265 to 530 μmol /L
530 μmol /L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
* Calcium should be corrected for albumin if albumin is < 4.0 g/dL
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
2.0 to 3.0 g/dL
2.0 g/dL
NA
30 g/L to LLN
20 to 30 g/L
20 g/L


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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
Note: 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)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening 
hypotension OR Transfusion 
of 2 units packed RBCs 
indicated (for children 
10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 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 
(e.g., 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 
(e.g., malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated
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
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., Torsade 
de pointes or other 
associated serious 
ventricular dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade 
de pointes or other 
associated serious 
ventricular dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event 
(e.g., 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


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RESPIRATION
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 Respiration
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 
Respiration failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiration 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%
Respiration 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)


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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, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited number 
of bullae OR Superficial 
ulcerations of mucous 
membrane limited to one 
site
Extensive or generalized 
bullous lesions OR Stevens-
Johnson syndrome OR 
Ulceration of mucous 
membrane involving two or 
more distinct mucosal sites 
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


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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 [e.g., tube feeding 
or total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., 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 (e.g., sepsis or 
perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (e.g., 
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 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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 
(e.g., 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 
(e.g., IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences 
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in 
Personality-Behavior or in 
Mood (e.g., 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 
(e.g., 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 
Respiration 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 
(e.g., status epilepticus), or 
difficult to control 
(e.g., refractory epilepsy)


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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 (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or 
difficult to control (e.g., 
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
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater 
than minimal interference 
with usual social & 
functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling 
causing greater than minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score
–2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening 
consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening 
consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater 
than minimal interference 
with usual social & 
functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND 
No operative intervention 
indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings 
causing inability to perform 
basic self-care functions


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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 [e.g., 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 
(e.g., upper arm/thigh)
Erythema OR Induration OR 
Edema involving 50% 
surface area of the extremity 
segment (e.g., 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 (e.g., 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 
(e.g., 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 
(e.g., 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
(e.g., myxedema coma)
Lipoatrophy (e.g., 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 (IMB)
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic exam
Intermenstrual bleeding not 
greater in duration or 
amount than usual menstrual 
cycle
Intermenstrual bleeding 
greater in duration or 
amount than usual menstrual 
cycle
Hemorrhage with 
life-threatening hypotension 
OR Operative intervention 
indicated
Urinary Tract obstruction 
(e.g., stone)
NA
Signs or symptoms of 
urinary tract obstruction 
without hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening 
consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other than 
HIV infection)
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual 
social & functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Operative intervention 
(other than simple incision 
and drainage) indicated
Life-threatening 
consequences 
(e.g., septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations
1. Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential
The risks of treatment with study drug have not been evaluated. If females are using hormonal 
agents for contraception, the safety and/or efficacy may be affected by possible drug-drug 
interaction. However, it is recommended that the hormonal agent be continued and that a 
non-hormonal method(s) be used concurrently. If females utilize hormonal agents as one of their 
contraceptive methods, it is required that the same hormonal method be used for at least 
3 months before study dosing. Please refer to the latest version of the Investigator’s Brochure for 
GS-7340 for additional information
2. Definition of Female of Childbearing Potential

For the purposes of this study, a female subject of childbearing potential is a nonmenopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure. This definition includes a pubertal female who has not yet started 
menstruating. A woman who has had a tubal sterilization is considered to be of childbearing 
potential.

A female subject ≤54 years in age, with the absence of normal menses is considered to be of 
childbearing potential. Exceptions must be discussed with the medical monitor.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (ie, surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

Age > 54 years, with the cessation (for > 12 months) of previously occurring menses due to 
ovarian failure, will not be considered to be childbearing potential. 
3. Contraceptive Requirements for Female Subjects
Female subjects of childbearing potential who engage in intercourse must agree to utilize 
protocol specified methods of contraception from the screening visit throughout the study period 
and for 30 days following the last dose of study drug. Female study subjects who are not 
heterosexually active must provide periodic confirmation of continued abstinence from 
heterosexual intercourse and regular pregnancy testing while participating in the study. The 
investigator will counsel subjects on the protocol specified method(s) for avoiding pregnancy in 
case the subject chooses to engage in heterosexual intercourse.
Protocol specified contraceptive methods are as follows: (1) a combination of one hormonal 
method and one barrier method; (2) two barrier methods where one method is the male condom; 
or (3) use of an intrauterine device (IUD) or tubal sterilization; see Appendix Table 1 below; or 
(4) complete abstinence from intercourse. Periodic abstinence from intercourse (e.g. calendar, 
ovulation, sumptothermal, post-ovulation methods) is not permitted.


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Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
Page 150
25 September 2019
Acceptable hormonal methods include injectable progesterone, progesterone implants, 
combination oral contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable 
barrier methods include diaphragm with spermicide, cervical cap with spermicide, and the male 
condom. The use of spermicide is not recommended if the subject or subject’s partner is infected 
with HIV. Female subjects must use either a hormonal method or a barrier method if the partner 
has a vasectomy. If a subject has undergone tubal sterilization or has had a Copper T 380A IUD 
or LNg 20 IUD inserted, no other contraception is needed.
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least 
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of study 
drug. Lactating females must discontinue nursing before IMP administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with 
a barrier method)
Barrier Methods
(use both OR choose one and use 
with a hormone method)
Intrauterine Devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicide
OR

Cervical cap with spermicide

Male condom (with or without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
The investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.
4. Contraceptive Requirements for Male Subjects
Male subjects must agree to use protocol specified method of contraception during heterosexual 
intercourse and avoid sperm donation from the time of the first dose of study drug and 
throughout the study period, and for at least 30 days after administration of the last dose of study 
medication 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.4
CONFIDENTIAL
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25 September 2019
Use of condoms, except for lambskin, has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.
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. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.6.2.1.

Prot_001.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
ClinicalT rials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director: 
Gilead Sciences 
Medical Monitor: 
Protocol Version/Date: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy ofTenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment ofHBeAg-Negative, Chronic Hepatitis B 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
115, 561 
2013-000626-63 
NCT01940341 
HBeAg-negative Chronic Hepatitis B 
GS-US-320-0108 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Name: 
Telephone: 
Fax (paper): 
Mobile: 
Email: 
Amendment 3.1: 
John Flaherty, Phatm D 
PPD 
PPD 
PPD 
PPD 
Benedetta Massetto, MD, PhD 
[PPD 
PPD 
PPD 
PPD 
I 
23 Febmmy 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the propetiy 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 Bom·d or Independent Ethics Committee. The inf01m ation is only to be used 
by you in connection with authorized clinical studies of the investigational dmg described in the 
protocol. You will not disclose any of the inf01m ation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessmy to obtain inf01m ed consent from those 
persons to whom the dmg may be administered. 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Background ............................................................................................................................................23
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................25
1.2.1.
General Information .............................................................................................................25
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................26
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................29
1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF).........................................................................................................................41
1.3.
Rationale for This Study ........................................................................................................................49
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B .................................49
1.3.2.
Rationale for the Current Study............................................................................................50
1.3.3.
Rationale for Dose Selection................................................................................................52
1.4.
Compliance ............................................................................................................................................53
2.
OBJECTIVES.....................................................................................................................................................54
3.
STUDY DESIGN................................................................................................................................................56
3.1.
Treatment Plan and Regimen .................................................................................................................56
3.2.
Biomarker Testing..................................................................................................................................57
3.2.1.
Biomarker Samples to Address the Study Objectives:.........................................................57
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................58
3.3.
Intensive PK Substudy (Optional)..........................................................................................................58
3.4.
Ophthalmologic Substudy (Optional) ....................................................................................................59
4.
SUBJECT POPULATION..................................................................................................................................60
4.1.
Number of Subjects and Subject Selection ............................................................................................60
4.2.
Inclusion Criteria....................................................................................................................................60
4.3.
Exclusion Criteria...................................................................................................................................61
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................63
5.1.
Randomization and Blinding..................................................................................................................63
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................63
5.2.
Description and Handling of Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate 
(TDF) and Matched Placebos.................................................................................................................64
5.2.1.
Formulation..........................................................................................................................64
5.2.2.
Packaging and Labeling .......................................................................................................65
5.2.3.
Storage and Handling...........................................................................................................65
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos ...................................................65
5.4.
Prior and Concomitant Medications.......................................................................................................66
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos...................................................................................................................................68
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................68
6.
STUDY PROCEDURES ....................................................................................................................................69


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Amendment 3.1
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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................69
6.2.
Pretreatment Assessments......................................................................................................................69
6.2.1.
Screening Visit .....................................................................................................................69
6.2.2.
Baseline Assessments...........................................................................................................70
6.3.
Treatment Assessments..........................................................................................................................71
6.3.1.
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144) ......................................................................................................71
6.3.2.
Open Label Visits.................................................................................................................81
6.4.
Post-treatment Assessments ...................................................................................................................83
6.4.1.
HBsAg Loss and Seroconversion Subjects ..........................................................................83
6.4.2.
All other subjects who discontinue study drug.....................................................................83
6.4.3.
Follow up visit assessments (all subjects)............................................................................83
6.5.
Early Discontinuation (ED) from Study.................................................................................................84
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................84
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................85
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................85
6.9.
Resistance Surveillance..........................................................................................................................86
6.10.
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance ...........................................................86
6.11.
End of Study...........................................................................................................................................86
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................87
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................87
7.1.1.
Adverse Events.....................................................................................................................87
7.1.2.
Serious Adverse Events........................................................................................................87
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................88
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................88
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................88
7.2.2.
Assessment of Severity ........................................................................................................89
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................89
7.4.
Gilead Reporting Requirements.............................................................................................................92
7.5.
Toxicity Management ............................................................................................................................92
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................93
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................93
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................93
7.5.4.
Management of Bone Evaluation.........................................................................................94
7.5.5.
Management of Potential Nephrotoxicity.............................................................................94
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................95
7.5.7.
Management of Potential Posterior Uveitis Cases................................................................97
7.6.
Special Situations Reports......................................................................................................................97
7.6.1.
Definitions of Special Situations..........................................................................................97
7.6.2.
Instructions for Reporting Special Situations.......................................................................98
8.
STATISTICAL CONSIDERATIONS..............................................................................................................100
8.1.
Analysis Objectives and Endpoints......................................................................................................100
8.1.1.
Analysis Objectives............................................................................................................100
8.1.2.
Primary Endpoint ...............................................................................................................101
8.1.3.
Secondary Endpoints..........................................................................................................101
8.1.4.
Other Endpoints of Interest ................................................................................................101
8.2.
Analysis Conventions...........................................................................................................................102
8.2.1.
Analysis Sets ......................................................................................................................102
8.2.2.
Data Handling Conventions ...............................................................................................103


Tenofovir Alafenamide (TAF)
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Amendment 3.1
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8.3.
Multiplicity Adjustments......................................................................................................................103
8.4.
Demographic Data and Baseline Characteristics .................................................................................104
8.5.
Efficacy Analysis .................................................................................................................................104
8.5.1.
Primary Analysis................................................................................................................104
8.5.2.
Analyses of Other Endpoints of Interest.............................................................................105
8.6.
Safety Analysis.....................................................................................................................................105
8.6.1.
Key Secondary Safety Analyses.........................................................................................105
8.6.2.
Extent of Exposure.............................................................................................................105
8.6.3.
Adverse Events...................................................................................................................106
8.6.4.
Laboratory Evaluations ......................................................................................................106
8.7.
Pharmacokinetic Analysis....................................................................................................................107
8.7.1.
Biomarker Analysis............................................................................................................107
8.8.
Sample Size..........................................................................................................................................107
8.9.
Data Monitoring Committee ................................................................................................................108
9.
RESPONSIBILITIES........................................................................................................................................109
9.1.
Investigator Responsibilities ................................................................................................................109
9.1.1.
Good Clinical Practice........................................................................................................109
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................109
9.1.3.
Informed Consent...............................................................................................................109
9.1.4.
Confidentiality....................................................................................................................110
9.1.5.
Study Files and Retention of Records ................................................................................110
9.1.6.
Case Report Forms.............................................................................................................111
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................112
9.1.8.
Inspections..........................................................................................................................112
9.1.9.
Protocol Compliance..........................................................................................................112
9.2.
Sponsor Responsibilities ......................................................................................................................113
9.2.1.
Protocol Modifications.......................................................................................................113
9.2.2.
Study Report and Publications ...........................................................................................113
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................113
9.3.1.
Access to Information for Monitoring................................................................................113
9.3.2.
Access to Information for Auditing or Inspections ............................................................114
9.3.3.
Study Discontinuation........................................................................................................114
10.
REFERENCES .................................................................................................................................................115
11.
APPENDICES ..................................................................................................................................................117
Appendix 1.
Investigator Signature Page..................................................................................................118
Appendix 2.
Study Procedures Table........................................................................................................119
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])............................................................................125
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................126
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............127
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations.........................................................................................149


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Amendment 3.1
CONFIDENTIAL
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LIST OF IN-TEXT TABLES
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection......................................30
Table 1-2.
GS-US-320-0101: Baseline Demographics and Disease Characteristics ...............................33
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and Laboratory 
Abnormalities: Overall Summary, Safety Analysis Set..........................................................34
Table 1-4.
GS-US-320-0101: HBV DNA Results: Median Change from Baseline at Day 15 
and Day 29 by Treatment Group ............................................................................................37
Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on Day 1 ........................39
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on Day 1 ........................40
Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: Overall Summary, Safety 
Analysis Set............................................................................................................................44
Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities, 
Safety Analysis Set.................................................................................................................45
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine and Hip Bone 
Mineral Density at Week 24, DXA Analysis Set ...................................................................47
Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by Gradation at Week 
24, DXA Analysis Set ............................................................................................................48
Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover Markers, 
Safety Analysis Set.................................................................................................................49
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution Due to the 
Potential for Drug-Drug Interaction with Study Medication..................................................67
LIST OF IN-TEXT FIGURES
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance (Cockcroft-Gault 
Method) in GS-US-320-0101.................................................................................................35
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV DNA (Log10
IU/mL) by Treatment Group ..................................................................................................36
Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: TAF (GS-
7340), Linear Scale.................................................................................................................38
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: 
Tenofovir, Linear Scale..........................................................................................................39
Figure 1-5.
GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
Cockcroft-Gault by Visit, Safety Analysis Set.......................................................................46
Figure 3-1.
Study Schema.........................................................................................................................57


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 6
23 February 2016
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Title of Study:
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety 
and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD versus 
Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg-Negative, Chronic Hepatitis B
IND Number:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
115,561
2013-000626-63
NCT01940341
Study Centers Planned:
Approximately 160 centers worldwide
Objectives:
The primary objectives of this study are as follows:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg 
QD versus tenofovir disoproxil fumarate (TDF) 300 mg QD for 
the treatment of HBeAg-negative, chronic hepatitis B at 
Week 48 in treatment-naïve and treatment-experienced subjects. 
The primary efficacy parameter is the proportion of subjects 
with plasma HBV DNA levels below 29 IU/mL. 

To compare the safety and tolerability of TAF 25 mg QD versus 
TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows:

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the percent change from baseline in hip 
and spine bone mineral density (BMD) at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the change from baseline in serum 
creatinine at Week 48


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 7
23 February 2016
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA 
levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg 
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA 
levels below 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with 
seroconversion to anti-HBs) of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest® of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48, 96, and 144

To compare the incidence of drug resistant mutations of TAF 
25 mg QD versus TDF 300 mg QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic 
findings by fundoscopic examination of TAF 25 mg QD versus 
TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in a subset 
of subjects 

To characterize the pharmacokinetics of TAF and tenofovir 
(TFV) and determine intracellular concentrations of tenofovir 
diphosphate (TFV-DP) within peripheral blood mononuclear 
cells (PBMCs) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy , safety, and 
incidence of drug resistance mutations of TAF 25 mg QD in 
subjects initially randomized to TAF 25 mg QD and in subjects 
sequentially treated with TDF 300 mg QD and then switched to 
open-label TAF 25 mg QD


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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Study Design:
This is a randomized, double-blind, non-inferiority study to 
compare the antiviral activity of TAF 25 mg QD versus TDF 
300 mg QD. Approximately 390 subjects will be randomized in 
a 2:1 ratio (A:B) to the treatment arms and will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
> 7 log10 IU/mL −< 8 log10 IU/mL, > 8 log10 IU/mL) and oral 
antiviral treatment status (treatment-naïve vs. 
treatment-experienced).
Treatment Arm A: 260 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD
For China, approximately 150 additional subjects 
(100 in Treatment Arm A and 50 in Treatment Arm B) will be 
enrolled for local registration purposes.
The duration of double-blind treatment is 144 weeks (96 weeks 
under Amendment 2.1). All subjects who complete the double-blind 
period of treatment are eligible for participation in the open label 
TAF 25 mg QD extension period for an additional 240 weeks 
(through Week 384/ED). Subjects already assigned to open-label
TAF 25 mg QD at Week 96 per Amendment 2.1 will continue on 
open-label TAF 25 mg QD through Week 384/ED. For the entire 
duration of the study, subjects and investigators will remain blinded 
to the initial treatment regimen to which they were randomized.  
Subjects with a confirmed creatinine clearance (CLCr) 
< 50 mL/min, and > 20 % decline in eGFR by CKD-EPI 
(cystatin C), at any time during the double blind period of the study 
will be required to undergo dose modification to every other day 
dosing of study drug. Subjects with confirmed creatinine clearance 
< 30 mL/min at any time during the study will have the study drug 
permanently discontinued.
The primary analysis will occur at Week 48 with the primary 
efficacy endpoint being the proportion of subjects with complete 
viral suppression, i.e., plasma HBV DNA level below 29 IU/mL.
Subjects who permanently discontinue study drug 
(either prematurely or at the end of study [Week 384]) for reasons 
other than HBsAg loss with confirmed seroconversion to anti-HBs 
will be followed every 4 weeks for 24 weeks off treatment or until 
initiation of alternative, commercially available, HBV therapy, 
whichever occurs first. Use of commercial therapy is strongly 
encouraged.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
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Amendment 3.1
CONFIDENTIAL
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Subjects with HBsAg loss with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of seroconversion to anti-HBs. Subjects 
with HBsAg loss with confirmed seroconversion to anti-HBs prior 
to Week 48 are not permitted to discontinue study drug prior to the 
Week 48 visit. Subjects who discontinue study drug for confirmed 
seroconversion to anti-HBs will be followed off treatment every 
4 weeks for 12 weeks and then per the study visit schedule 
(Appendix 2) through Week 384/ED. Discontinuation of study drug 
for subjects experiencing HBsAg loss with confirmed 
seroconversion, who have known bridging fibrosis or cirrhosis, 
should be considered on a case by case basis.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will review the progress and safety of this study 
approximately every 24 weeks following the time of randomization 
of the first subject during the double blind period of the study. 
During the open-label duration of the study (Weeks 144 to 384), the 
DMC will convene approximately every 48 weeks. At each 
meeting, the DMC will review routine safety and dual energy X-ray 
absorptiometry (DXA) data and will make recommendations 
regarding modification of the study treatment.
Number of Subjects 
Planned:
390 subjects (260 subjects TAF 25 mg QD and matched placebo of 
TDF 300 mg QD, and 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD)
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of 
TAF 25 mg QD) will be enrolled.
Target Population:
Subjects, who are 18 years of age and older, with HBeAg-negative, 
chronic hepatitis B
Duration of Treatment:
The duration of the double-blind treatment is 144 weeks (96 weeks 
under Amendment 2.1). After completing the double-blind period 
of treatment, all subjects remaining on treatment will be eligible to 
receive open label TAF 25 mg QD for up to an additional 
240 weeks (Week 144 through Week 384). Subjects already 
assigned to open-label TAF 25 mg QD at Week 96 per Amendment 
2.1 will continue on open-label TAF through Week 384/ED. 
Subjects who lose HBsAg with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of seroconversion to anti-HBs, or after 
Week 48, if seroconversion occurs prior to this visit. 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 10
23 February 2016
Diagnosis and Main 
Eligibility Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible to participate in the study.
1) Must have the ability to understand and sign a written informed 
consent form, which must be obtained prior to initiation of 
study procedures.
2) Male and non-pregnant, non-lactating female subjects, 18 years 
of age and older, based on the date of the screening visit. 
A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in 
Appendix 6).
3) Documented evidence of chronic HBV infection 
(e.g. HBsAg positive for more than 6 months)
4) HBeAg-negative, chronic hepatitis B with all of the following:

HBeAg-negative and HBeAb positive at Screening (if the 
subject is deemed ineligible for this study by HBV serology 
[i.e. HBeAg positive CHB], this information may be used to 
determine eligibility for GS-US-320-0110 
[another Gilead Sciences Phase 3 study in HBeAg-positive, 
CHB subjects; this study must also be IRB/EC approved at 
the participating center])

Screening HBV DNA ≥ 2 × 104 IU/mL 

Screening serum ALT level > 60 U/L (males) or > 38 U/L 
(females) and ≤10 × ULN (by central laboratory range)
5) Treatment-naïve subjects (defined as < 12 weeks of oral 
antiviral treatment with any nucleoside or nucleotide analogue), 
OR treatment-experienced subjects (defined as subjects meeting 
all entry criteria [including HBV DNA and serum ALT criteria] 
and with ≥12 weeks of previous treatment with any nucleoside 
or nucleotide analogue) will be eligible for enrollment. 
Treatment-experienced subjects receiving oral antiviral 
treatment at Screening must continue their treatment regimen 
until the time of randomization, when it will be discontinued.
6) Any previous treatment with interferon (pegylated or 
non-pegylated) must have ended at least 6 months prior to the 
baseline visit.


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7) Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the 
Cockcroft-Gault method) based on serum creatinine and actual 
body weight as measured at the Screening evaluation, as 
follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8) Normal ECG (or if abnormal, determined by the investigator
not to be clinically significant)
9) Must be willing and able to comply with all study requirements.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in the study.
1) Pregnant women, women who are breastfeeding or who believe 
they may wish to become pregnant during the course of the 
study.
2) Males and females of reproductive potential who are unwilling 
to use an “effective”, protocol-specified method(s) of 
contraception during the study. For a list of protocol-specified 
contraceptive methods, refer to Appendix 6.
3) Co-infection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by 
recent imaging)
5) Any history of, or current evidence of, clinical hepatic 
decompensation (e.g., ascites, encephalopathy or 
variceal hemorrhage).
6) Abnormal hematological and biochemical parameters, 
including:

Hemoglobin < 10 g/dL 

Absolute neutrophil count < 750/mm3

Platelets ≤50,000/mm3

AST or ALT > 10 × ULN

Total bilirubin > 2.5 × ULN

Albumin < 3.0 g/dL

INR > 1.5 × ULN (unless stable on anticoagulant regimen)


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7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator
9) Significant bone disease (eg, osteomalacia, chronic 
osteomyelitis, osteogenesis imperfecta, osteochrondroses), or 
multiple bone fractures
10) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible
11) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), investigational agents, nephrotoxic agents, 
or agents capable of modifying renal excretion
12) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
13) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
14) Any other clinical condition or prior therapy that, in the opinion 
of the investigator, would make the subject unsuitable for the 
study or unable to comply with dosing requirements.
15) Subjects on prohibited concomitant medications 
(See Table 5-1). Subjects on prohibited medications, otherwise 
eligible, will need a wash out period of at least 30 days.
Study Procedures/
Frequency:
Laboratory analyses (serum chemistry, liver tests, hematology, 
urinalysis, plasma HBV DNA levels, pregnancy testing [for females 
of childbearing potential]), vital signs, adverse events and 
concomitant medications will be performed at Screening, Baseline, 
and every 4 weeks thereafter through Week 48, every 8 weeks 
through Week 96, every 12 weeks through Week 144, and every 
24 weeks through Week 384/Early Discontinuation (ED) visit. 
HBV serology (HBeAg and HBeAb, HBsAg and reflex HBsAb 
[anti-HBs]) will be performed at Screening and Baseline, HBsAg 
and reflex HBsAb will be performed every 12-16 weeks until 
Week 144, every 24 weeks until Week 384/ED and at Follow Up
Weeks 12 and 24. Quantitative serum HBsAg will be assessed at 
Screening, Baseline, and every 12-16 weeks until Week 144, every 
24 weeks until Week 384/ED, and at Follow Up visits. Bone and 
renal biomarker testing will be performed at Baseline and then at 
defined intervals (see Schedule of Assessments, Appendix 2)
throughout the study. IL28B polymorphism genotype, HBV 
genotyping and vitamin D level will be performed at Baseline only. 
Fibrotest® will be performed at Baseline and every 48 weeks until 


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Week 384/ED. Fasting metabolic assessments (fasting glucose and 
lipid panel) will be conducted at Baseline, every 24 weeks until 
Week 240, and every 48 weeks until Week 384/ED visit.
Complete physical examinations will be performed at Screening, 
Baseline, and Weeks 24, 48, 72, 96, 144, 240 and Week 384/ED. 
Height assessment will be conducted at Screening only. Symptom 
directed physical exams with body weight assessment will be 
conducted at all other visits. ECG will be performed at Screening 
and every 48 weeks thereafter. At sites in China with the capability 
only, DXA scans of the hip and spine will be conducted during the 
screening period, and should be conducted at least 14 days prior to 
the first dose of study drug, and will be subsequently conducted at 
Weeks 24, 48, 72, 120, 96, 144, every 48 weeks until Week 384, 
and the ED visit, if not done within the last 24 weeks. Hepatic 
ultrasound for surveillance of hepatocellular carcinoma will be 
performed starting at Week 96 and then every 24 weeks until 
Week 384/ED.  
Genotypic analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance will be performed at Baseline 
for all subjects and attempted for all viremic subjects (HBV DNA 
≥69 IU/mL) at Weeks 48, 96, 144 and every 48 weeks until 
Week 384/ED. As it may not be known at the time of the visit 
whether a patient is viremic or if it will be their last study visit, a 
separate virology sample for potential resistance surveillance will 
be collected at each study visit. Plasma, serum, and urine will be 
collected at Baseline and at every visit thereafter for storage. 
A single pharmacokinetic (PK) blood sample will be collected at all 
study visits from Weeks 4 through 48 for all subjects. At the 
Week 4 and 12 visits, dosing will occur in-clinic and a single PK 
blood sample will be collected between 15 minutes and 4 hours 
post-dose. It is preferred that subjects take their study drug 
according to a morning dosing schedule; however, evening dosing 
is allowable. Subjects who elect to dose in evening are not required 
to have in-clinic dosing and the single PK blood sample collection 
performed at the Week 4 and 12 visits.
Pharmacokinetic Substudy
For subjects who provide a separate informed consent (n=16 and up 
to n=32), an intensive PK substudy will be conducted once at either 
of the Week 4, 8 or 12 visits at select sites. Blood (plasma) samples 
will be collected at 0 (≤30 minutes pre-dose), at 5, 15 , 30, 
45 minutes, and at 1, 1.5, 2, 3, 4, 5, 8, 12, and 24 hours post dose. 
Subjects will be dosed in-clinic and should be in a fasted state 
(no food or drinks 8 hours prior except water up to 1 hr) prior to the


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intensive PK visit. The subjects will then be provided a 
standardized meal 4 hours post dose. Subjects participating in the 
PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the time of the intensive 
PK substudy. Please refer to the PK manual for specific restrictions 
on food and water intake.
Ophthalmologic Substudy
For subjects who provide a separate informed consent (n = 30, at 
select sites), a substudy will be conducted to assess ophthalmologic 
findings, including fundoscopic examination with slit lamp and 
retinal photographs (both eyes), anytime during the screening 
period, but must be completed prior to the first dose of study drug, 
and at Weeks 24, 48, 72, 96, and 144. An exam should be 
performed at the ED visit, if prior to Week 144 and not done within 
the last 24 weeks of this visit.
Pharmacogenomic Substudy
An optional blood sample may be obtained for exploratory 
biomarker and pharmacogenomic discovery research. This sample 
may only be collected following approval of the national and local 
regulatory bodies and Ethical Committees. This sample should be
collected at Baseline, prior to the first dose of study drug, but may 
be collected at any time during the study or at a separate 
unscheduled study visit, if necessary. Subjects who agree to have 
blood drawn for these purposes will sign a separate informed
consent form prior to obtaining this sample.
Subjects who receive at least one dose of study drug and 
permanently discontinue study drug for reasons other than HBsAg 
loss and seroconversion to anti-HBs, either prematurely or at the 
end of the study (Week 384), will be followed every 4 weeks for 
24 weeks post-treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. The 
following evaluations will occur every 4 weeks: vital signs, 
hematology, serum chemistry, liver function tests, and plasma HBV 
DNA. Plasma, serum, and urine will be collected for storage. 
HBsAg and reflex HBsAb will be evaluated at Follow up 
Weeks 12 and 24. 
Subjects who lose HBsAg with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of HBsAg loss and seroconversion to 
anti-HBs or after Week 48, if seroconversion occurs prior to this 
visit. These subjects will be followed off treatment every 4 weeks 
for 12 weeks and then per the study visit schedule (Appendix 2) 
through Week 384/ED.


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Test Product, Dose, and 
Mode of Administration:
Double-Blind Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 
and matched placebo of Tenofovir DF (TDF) 300 mg QD, 
oral administration
Open-Label Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 
Reference Therapy, 
Dose, and Mode of 
Administration:
Double-blind Treatment: 

Tenofovir DF 300 mg QD, oral administration and matched 
placebo of Tenofovir alafenamide (TAF) 25 mg QD, 
oral administration
Open-label Treatment: NA
Criteria for Evaluation:
Safety:
Key secondary safety endpoints include the percent change from 
baseline at Week 48 in hip and spine BMD, and change from 
baseline at Week 48 in serum creatinine.
If a subject has confirmed creatinine clearance (CLCr) < 50 mL/min, 
and > 20% decline in eGFR by CKD-EPI (cystatin C), at any time 
during the double-blind period of the study, the subject will be 
required to undergo dose modification to every other day dosing of 
study drug. Subjects with confirmed creatinine clearance 
< 30 mL/min at any time during the study will have the study drug 
permanently discontinued.
The proportion of subjects in each treatment arm with tolerability 
failure (defined as an adverse event [AE] leading to permanent 
discontinuation of study drug) at Weeks 48, 96, 144, 240, and 384
will be summarized. Change from baseline in serum creatinine will 
be assessed at every visit and summarized through Week 384/ED. 
Change from baseline in BMD by DXA of the spine and hip will be 
assessed at Weeks 24, 48, 72, 96, 120, and 144, and every 48 weeks 
until Week 384/ED. Fracture Risk Assessment will be evaluated at 
Baseline.
Ophthalmologic changes from baseline by fundoscopic examination 
at Weeks 24, 48, 72, 96, and 144 (or ED if prior to Week 144 and 
more than 24 weeks since the last exam) will be summarized for a 
subset of subjects (n = 30). In addition, for any subject who 
develops signs or symptoms of posterior uveitis, the investigator 
should contact the Gilead Medical Monitor to discuss the need for 
additional ophthalmologic evaluation including dilated fundoscopy 
and optical coherence tomography (OCT).


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Adverse events and clinical laboratory tests will be collected at
every visit and summarized through Week144. Additionally, 
summaries of AEs, discontinuations due to AEs, and laboratory 
data including BMD measurements (via DXA scans, serum 
creatinine and creatinine clearance by Cockcroft-Gault) by original 
treatment arms (TAF versus TDF) will continue through Week 384. 
Fracture risk assessment will be evaluated at Baseline. In China, 
this fracture risk assessment will be evaluated at sites with DXA 
capability only.
Efficacy:
The primary efficacy endpoint is the proportion of subjects with 
plasma HBV DNA levels below 29 IU/mL at Week 48. 
Other secondary efficacy endpoints are:

The proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Weeks 96, 144, 240, and 384

The proportion of subjects with plasma HBV DNA < 29 IU/mL
(target not detected) at Weeks 48, 96, 144, 240, and 384

The proportion of subjects with ALT normalization (by central 
laboratory and American Association for the Study of Liver 
Diseases [AASLD] criteria) at Weeks 48, 96, 144, 240, and 384

The proportion of subjects with HBsAg loss at 
Weeks 48, 96, 144, 240, and 384

The proportion of subjects with HBsAg seroconversion to 
anti-HBs at Weeks 48, 96, 144, 240, and 384

The change from baseline in fibrosis as assessed by FibroTest®
at Weeks 48, 96, 144, 240, and 384

The incidence of drug resistant mutations at 
Weeks 48, 96, 144, 240, and 384
Pharmacokinetics:
The following TAF and TFV plasma pharmacokinetic parameters 
will be calculated for the substudy population (n = 30): 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½
Single PK plasma samples collected at Weeks 4-48 may be used for 
estimation of population pharmacokinetics of TAF and TFV.
Single PBMC samples at selected PK substudy sites collected at the 
intensive PK substudy visit will be used for TFV-DP concentration 
determination


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Statistical Methods:
The primary analysis will be performed when approximately 
390 subjects complete 48 weeks of the double-blind treatment 
period or discontinue prematurely. The analysis will compare the 
TAF arm to the TDF arm.
Analysis Methods:
A two-sided 95% confidence interval, based on large sample 
theory, adjusted for the randomization stratification factors, for the 
difference (TAF-TDF) between treatments will be evaluated to 
compare treatment groups with respect to the primary efficacy 
endpoint. A missing equals failure approach will be employed for 
the primary analysis. Non-inferiority will be declared if the lower 
bound of this confidence interval exceeds −0.10 (i.e., 10% 
non-inferiority margin). If non-inferiority is established, the lower 
bound of the 95% confidence interval (CI) will be compared to 0; if 
the lower bound of the 95% CI is greater than 0, then superiority of 
TAF over TDF will be established using the same CI.
The percent change from baseline in hip and spine BMD at 
Week 48 will be analyzed using an analysis of variance (ANOVA)
model. The model will include treatment group as a fixed effect. 
The details are provided in the Statistical Analysis Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be 
analyzed using an analysis of covariance (ANCOVA) model with 
baseline serum creatinine as a covariate, and treatment group as a 
fixed effect. The details are provided in the SAP.
All secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum). All categorical secondary endpoints will 
be summarized by number and percentage of subjects who meet the 
endpoint.
Sample Size:
With respect to the primary efficacy endpoint of proportion of 
subjects with plasma HBV DNA levels below 29 IU/mL at 
Week 48, when the sample sizes are 260 (TAF 25 mg arm) and 
130 (TDF 300 mg arm), a two-group, large-sample normal 
approximation test of proportions with a one-sided 0.025 
significance level will have 90% power to reject the null 
hypothesis, that the TAF 25 mg arm is inferior to the TDF 300 mg 
arm (the difference in proportions [TAF-TDF] having a lower 
bound of the one-sided 97.5% confidence interval of less than 
−0.10, i.e., 10%) in favor of the alternative hypothesis that the TAF 
25 mg arm is not inferior to the TDF 300 mg arm. This assumes the 
expected difference (TAF-TDF) in proportion of subjects with 
HBV DNA < 29 IU/mL is 0 and the proportion of subjects with 
HBV DNA < 29 IU/mL in the TDF 300 mg arm is 0.91. 


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The TDF virologic rate of 0.91 was calculated using the observed 
rate in Study GS-US-174-0102. 
This sample size also provides 90% power to detect a 1% difference 
in the percentage change from baseline in hip BMD at Week 48 
(assuming a −1.17% change from baseline in TDF 300 mg arm and 
−0.17% change in TAF 25 mg arm, with a common standard 
deviation of 2.20% and a two-sided α = 0.025); a 77% power to 
detect a 1% difference in the percentage change from baseline in 
spine BMD at Week 48 (assuming a −1.69% change from baseline 
in the TDF 300 mg arm and −0.69% change in the TAF 25 mg arm, 
with a common standard deviation of 3.08% and a two-sided 
α = 0.025); a 52% power to detect a 0.03 mg/dL difference in the 
change from baseline in serum creatinine at Week 48 (assuming a 
0.04 mg/dL change from baseline in the TDF 300 mg arm and 
0.01 mg/dL change from baseline in the TAF 25 mg arm, with a 
common standard deviation of 0.12). These assumptions were 
derived from studies GS-98-437, GS-98-438, GS-US-174-0102, 
GS-US-174-0103, and GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of TAF 25 mg 
QD) will be enrolled.
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
AASLD
American Association for the Study of Liver Diseases
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AR
Adverse reaction
AST
Aspartate aminotransferase (SGOT)
AUCinf
Area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUC0last + (Clast/z)
AUCtau
Area under the plasma concentration versus time curve over the dosing interval (tau)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKF-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI / C
Cobicistat
CRF/eCRF
Case report form(s)/electronic case report form(s)
CRO
Contract (or clinical) research organization
CTX
C-type collagen sequence
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry


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E2
Estradiol
EC
Ethics committee
EudraCT
European clinical trials database
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX®
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)


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IRB
Institutional review board
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure


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STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
Tenofovir Alafenamide, GS-7340
TAF Fumarate
Tenofovir Alafenamide Fumarate, GS-7340-03
TDF
Tenofovir Disoproxil Fumarate
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TLOVR
Time to loss of virologic response
Tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
T3
Triiodothyronine
TSH
Thyroid stimulating hormone
UACR
Urine albumin-to-creatinine ratio
UGT1A1
Uridine glucuronosyltransferase 1 family, polypeptide A1 
ULN
Upper limit of the normal range
UPCR
Urine protein-to-creatinine ratio
US
United States
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a serious global health care problem and one of the principal causes 
of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Of the estimated 
2 billion people worldwide who have been acutely infected with the hepatitis B virus (HBV), 
approximately 400 million have developed CHB, and approximately 1 million people die 
annually from complications of CHB {World Health Organization (WHO) 2000}. Despite the 
availability of HBV vaccine programs in many countries, new HBV infections are still common 
even in areas of low endemicity. For example, approximately 80,000 people in the United States 
(US) become acutely infected each year, according to an estimate from the Centers for Disease 
Control and Prevention {Centers for Disease Control and Prevention (CDC) 2003}. Following 
acute HBV infection, approximately 5% to 10% of adults and up to 90% of children fail to 
produce an immune response adequate to clear the infection; these individuals become chronic 
carriers of the virus {Zuckerman 1996}.
Chronic hepatitis B has a broad clinical spectrum, ranging from asymptomatic, slowly 
progressive illness to severe, and more rapidly progressive liver disease. Chronic hepatitis B may 
remain quiescent for many years and represent a risk factor for progression to cirrhosis, liver 
failure, and death within a few years. Approximately 25% of subjects with CHB will ultimately 
develop serious liver disease such as hepatic decompensation, cirrhosis, or HCC 
{Zuckerman 1996}. The development of nucleos(t)ide analogues has been a major breakthrough 
for the treatment of CHB, providing effective suppression of viral replication and reducing the 
risk of long term complications. However, if viral replication resumes as a result of resistance 
mutation development, the clinical benefit is lost. The rate of resistance development in 
treatment-naive subjects varies depending on the treatment: up to 70% after 4 years with 
lamivudine (LAM), up to 29% after 5 years with adefovir dipivoxil (ADV), 25%/11% in 
hepatitis B e antigen positive/negative (hepatitis B e antigen [HBeAg]+/) subjects after 2 years 
with telbivudine (LdT), and 1.2% after 5 years with entecavir (ETV). To date, resistance to TDF 
has not been documented {Marcellin et al 2011}.
Tenofovir DF (Viread®) 300 mg once daily was first approved for the treatment of CHB in 
Turkey on 28 March 2008, and is currently approved in 101 countries, including the US, Canada, 
and Europe. Approval of TDF for CHB was based primarily on 48 week data from 375 adult 
subjects with HBeAg− CHB and 266 subjects with HBeAg+ CHB who enrolled in the similarly 
designed pivotal studies GS-US-174-0102 (HBeAg− subjects) and GS-US-174-0103 
(HBeAg+ subjects). In study GS-US-174-0102, TDF 300 mg once daily was shown to be 
superior to ADV 10 mg once daily for the treatment of HBeAg/antibody to hepatitis B e antigen 
(anti-HBe)-positive (presumed precore mutant) chronic HBV infection. At 48 weeks, 
70.8% of subjects in the TDF group (n = 250) had a complete response (plasma HBV 
deoxyribonucleic acid [DNA] < 69 IU/mL [400 copies/mL] and histologic improvement 
characterized by ≥2 point reduction in the Knodell necroinflammatory score and no worsening 
of Knodell fibrosis), compared to 48.8% of subjects in the ADV group (n = 125; p < 0.001) 
{Marcellin et al 2007}. In study GS-US-174-0103 (HBeAg+ subjects), at 48 weeks, 


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66.5% of subjects in the TDF group (n = 176) had a complete response, compared to 12.2% in 
the ADV group (n = 90; p < 0.001) {Heathcote et al 2007}. Subjects in both studies who 
completed the 48-week double-blind treatment period (including the end-of-blinded-treatment 
biopsy) were eligible to continue in an open-label (OL) extension phase consisting of treatment 
with TDF up to Week 480 (Year 10). 
In both Phase 3 studies, for viremic subjects originally randomized to ADV who rolled over to 
open-label TDF at Week 48, HBV DNA values decreased sharply during the first 16 weeks of 
TDF therapy. At Week 96, the percentages of subjects with plasma HBV DNA < 400 copies/mL 
were not significantly different between treatment groups in both studies. Viral suppression was 
maintained through Week 240 of these 2 pivotal studies in those subjects receiving continued 
treatment with TDF for 240 weeks (TDFTDF group), and in those subjects who received 
192 weeks of TDF treatment following an initial 48 weeks of treatment with ADV 
(ADVTDF group). Based on results from a pooled histology analysis at Year 5 for these 
2 studies, 96.2% of subjects on open-label TDF experienced either improvement or no change in 
fibrosis (by Ishak fibrosis scoring). Further, of the 96 subjects with cirrhosis at baseline 
(Ishak fibrosis score 5-6), 25% experienced no change in Ishak fibrosis score while 73% 
experienced reversal of cirrhosis by Week 240 with a reduction in Ishak fibrosis score of at least 
2 points (missing = excluded [M = E], data after addition of emtricitabine [FTC] included) 
{Marcellin et al 2013}. Importantly, viral suppression (HBV DNA < 69 IU/mL or 
< 400 copies/mL was documented in 330/334 (99%) of subjects with available histology who 
were maintained on therapy with an available HBV DNA measurement at Week 240. No 
mutations associated with TDF resistance developed in subjects treated with TDF for up to 
5 years in the pivotal studies {Marcellin et al 2013}. No phenotypic resistance to TDF has been 
observed among subjects with virologic breakthrough or who developed conserved-site changes 
in the HBV polymerase (pol)/reverse transcriptase (RT) during TDF treatment for up to 5 years. 
Continued treatment with TDF for 5 years revealed no new adverse reactions inconsistent with 
the known safety profile of TDF. Importantly, these results demonstrate that achievement and 
maintenance of long term viral suppression with TDF translates into a histological benefit 
(i.e. fibrosis regression) in the majority of subjects.
While liver biopsy provides important information regarding severity of necroinflammatory 
activity and fibrosis in diseases such as CHB, it is no longer considered routine in clinical 
practice for ongoing disease monitoring, and the procedure itself is challenging to perform within 
the context of clinical trials. Additionally, liver biopsy is costly and limited by sampling error as 
well as patient reluctance to undergo this invasive procedure. With the availability of 
non-invasive tests, including FibroTest® (also known as FibroSURE in the U.S.) and Fibroscan®, 
which have been shown to correlate with histology in liver diseases such hepatitis B 
{Poynard et al 2005}, hepatitis C {Ngo et al 2006}, and non-alcoholic fatty liver disease 
{Poynard et al 2007}, the need for liver biopsy has been largely replaced, particularly for 
ongoing monitoring of changes in fibrosis.
Tenofovir DF is also approved worldwide in many markets for administration in combination 
with other antiretroviral agents for treatment of human immunodeficiency virus (HIV)-1 
infection (first approval in 2001). Tenofovir DF is also a component of Truvada®
(FTC 200 mg/TDF 300 mg), a marketed fixed-dose combination product for treatment of HIV-1 


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infection in combination with other antiretroviral agents. More recently, TDF has been included 
in single tablet regimens (STRs) for treatment of HIV infection. Three STRs are currently 
approved for once-daily administration in the treatment of HIV-1 infection, efavirenz 
(EFV)/FTC/TDF (Atripla®), FTC/rilpivirine (RPV)/TDF (Complera®/Eviplera), and more 
recently, elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TDF (Stribild™). The newly approved 
Stribild™STR tablet, which contains a fixed-dose combination of E/C/F/TDF 
(150/150/200/300 mg), has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HIV-1 infection in treatment-naïve adults. E/C/F/TDF 
is the first approved STR that combines an integrase strand transfer inhibitor (elvitegravir) with a
nucleoside reverse transcriptase inhibitor (NRTI) backbone into a once-daily tablet. Since 
Viread® was first marketed on 31 October 2001, the overall exposure to TDF up to 31 May 2013 
from branded Viread®, Truvada®, Atripla®, Complera® and Stribild®, combined up to 
31 May 2013, is estimated to be in excess of 6 million patient years
TDF is a preferred oral N(t)RTIs for treatment of CHB infection by all current treatment 
guidelines. For the majority of CHB subjects, life-long treatment is required as only a small 
percentage (< 10%) of subjects experience sustained loss of hepatitis B surface antigen (HBsAg), 
and as a consequence, achieve an effective cure of the disease. Though highly effective, long 
term use of TDF is associated with nephrotoxicity and reduced bone mineral density in some 
subjects {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. Thus, alternative 
therapies with high antiviral potency, a high genetic barrier to resistance development, and 
improved long term safety and tolerability are needed in order to further advance treatment of 
chronic HBV infection worldwide.
Tenofovir alafenamide (TAF), a novel “intracellular” prodrug of tenofovir (TFV), has the 
potential to advance treatment of chronic HBV infection. In contrast to TDF, an oral prodrug that 
is rapidly cleaved by esterases in the intestines and plasma to TFV, TAF has been specifically 
synthesized to be more stable in resisting early enzymatic cleavage following oral administration 
and remain mostly intact until penetrating target cells. By virtue of this key distinguishing 
property, TAF when administered at a lower dose than TDF, is capable of efficiently delivering 
active drug (e.g. tenofovir diphosphate [TFV-DP]) to the cells where it is needed 
(e.g. HBV-infected hepatocytes, HIV-infected lymphoid cells) while systemic exposures of TFV 
are greatly reduced in comparison to oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication and an 
improved tolerability and safety profile.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is a next generation oral 
prodrug of TFV, a nucleotide analog that inhibits reverse transcription in HIV-1 and HBV. TFV
is metabolized intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) and HBV pol/RT that terminates the 
elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance 


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have been used in various studies: GS-7340, synonym for GS-7340 as the free base; 
GS-7340-02, synonym for TAF monofumarate (1:1); and GS-7340-03 as the hemifumarate (2:1). 
GS-7340-03, also known as TAF fumarate, the form being used in GS-US-292-0102 
(Phase 2 study in HIV subjects) and GS-US-320-0101 (Phase 1b study in HBV subjects), is 
considered comparable to GS-7340-02 based on physical/chemical properties of GS-7340-02, the 
form that has been used in previous studies and a number of currently ongoing studies. 
Importantly, both GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in 
blood and biological fluids.
For further information on TAF (GS-7340), please refer to the latest Investigator’s Brochure for 
GS-7340.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
TAF is converted intracellularly by cathepsin A (CatA) and carboxylesterase-1 (Ces1) to form 
TFV (i.e, a nucleoside monophosphate analog) which is not dependent on an intracellular 
nucleoside kinase activity for the first step in the conversion to the active metabolite, and is 
subsequently converted to TFV-DP by cellular kinases. The cellular enzymes responsible for 
TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{Robbins et al 1995} and nucleotide diphosphate kinase, which are highly active and ubiquitous. 
AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most 
efficiently by AK2. Analysis of primary cells showed that CatA activity varied minimally in both 
human cluster of differentiation 4 (CD4+) T-lymphocytes and macrophages. CatA activity was 
equivalent in resting and activated CD4s and approximately 2-fold higher in macrophages.
Intracellular metabolites of TAF were similar among individual donors in both CD4+ T-cells and 
macrophages. Carboxylesterease-1 (Ces1) which is highly expressed in liver, contributes to TAF 
conversion to TFV, particularly in hepatocytes {Bam et al 2012, Birkus et al 2012}.
The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T-cells, NK cells, B-cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite 
TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations. 
Additionally, a 24-hour continuous incubation of TAF in primary human hepatocytes in vitro 
resulted in approximately 120- or 5-fold higher levels of TFV-DP compared to incubation of 
TFV or TDF, respectively (AD-120-2017).
1.2.2.2.
Safety Pharmacology
TAF monofumarate (GS-7340-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006) and 
gastrointestinal systems (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). GS-7340-02 (at 1000 mg/kg) reduced 
distal transit and increased stomach weights starting 2 hours post dosing with reversibility 


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beginning by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. The 
IC50 for the inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current was 
estimated to be greater than 10 μM.
1.2.2.3.
Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate (GS-7340-02), and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of GS-7340-02 is equivalent to 80 mg of the GS-7340 free 
base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with 
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted), and 8.1 to
12.5 hours in rhesus monkeys. 
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the 
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug based on 
IV studies of TFV. Following oral administration of GS-7340-02, approximately 15% of a 
radiolabeled dose is recovered in dog urine in 24 hrs. TFV was the major species present in the 
urine (90%), with about 3.4% of TAF also present. Biliary excretion of TFV in dogs and fecal 
elimination of TFV in rats and dogs are negligible.
Tenofovir was the only species found in the intestinal contents and feces. In human systems, 
TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed 
oxidation (AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4, inhibition
or induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has 
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1 
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or 
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma 
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by 
clinically relevant drug-drug interactions is very low.
The hepatic extraction of TAF was estimated to be 70% suggesting that TAF was rapidly cleaved 
by hepatic hydrolases including Ces1 and CatA {Babusis et al 2013}. An in vitro study to 
evaluate effects of inhibitors of CatA or Ces1 on TAF metabolism in primary human hepatocytes 
is ongoing. Single and repeat dose dog liver pharmacokinetic studies are planned.


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1.2.2.4.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months and was negative in genetic toxicology studies.
In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. GS-7340-02 also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above. In chronic 
studies in dogs after 9 months of treatment with GS-7340-02, the primary target organs were 
kidney and bone.  
GS-7340-02 had no discernible electrocardiograph (ECG/EKG) effect at the low dose of 
2 mg/kg/day and slightly prolonged PR intervals at 6 and 18/12 mg/kg/day (started at 
18 mg/kg/day, then reduced to 12 mg/kg/day at Weeks 7-8). Additionally, at Week 39, 
GS-7340-02 appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but was 
reversible at the 3 month recovery period. Minor hematological and biochemistry parameters 
changes were observed but remained within normal historical ranges with the following 
exceptions: AST (~ 100% increase) and total bilirubin (~ 40% increase). There were no clear 
treatment-related effects observed in monkeys following 28 days of treatment, including no 
changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day 
(tenofovir AUC = 3758 ng•h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day 
(tenofovir AUC = 1180 ng•h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (tenofovir AUC = 5870 ng•h/mL). In conjunction with the nonclinical data with 
TDF and the clinical experience with TDF and TAF, these toxicology studies support studies in 
humans of doses up to 150 mg/day (equivalent to 120 mg free base, the highest anticipated 
human dose) for chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable TFV exposures 
less than previously tested in chronic and carcinogenicity studies with TDF, carcinogenicity 
studies in mice and rats with TAF are currently not required per agreement with FDA and EMA.
Also, TAF does not need to be evaluated in perinatal-postnatal reproductive toxicology studies
per agreement with FDA and EMA. Reproductive tissues were examined in repeat-dose 
toxicology studies in the rat, dog, and monkey. There were no clearly treatment-related 
histologic alterations or changes in organ weights in the rat and the dog following chronic daily 
dosing, or in the monkey. 
The TAF fumarate (GS-7340-03) oral rat fertility study is ongoing (Report No. TX-120-2012;
report in progress). 


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1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
To date, a total of 8 Phase 1 and Phase 1/2, or Phase 2, clinical trials of tenofovir alafenamide 
(TAF) have been conducted or are ongoing in 528 subjects. This includes seven HIV studies 
(total of 477 subjects; 2 completed Phase 1/2 studies [68 subjects], 3 completed Phase 1 studies 
[83 subjects], and 2 ongoing Phase 2 studies [326 subjects]), and 1 Phase 1b HBV study 
(completed enrollment; 51 subjects). TAF is presently in Phase 3 for treatment of HIV-1 
infection in combination with E, C and F, and a Phase 1b study has completed enrollment and 
dosing for treatment of chronic HBV. 
Clinical trials entailing the use of TAF (dose[s] studied) for HIV-1 infection and other Phase 1 
studies include:

GS-120-1101, a Phase 1/2 study of the pharmacokinetics and antiviral activity of TAF 
(GS-7340 [50 mg and 150 mg]) in HIV infected subjects (completed)

GS-US-120-0104, a Phase 1b study of the pharmacokinetics and antiviral activity of 
GS-7340 (8 mg, 25 mg, 40 mg) in HIV infected subjects (completed)

GS-US-120-0107, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-7340 (25 mg and 150 mg) on the QT/QTc interval in 
healthy subjects (completed)

GS-US-120-0108, A Phase 1, Open-Label, Parallel-Design Study to Evaluate the 
Pharmacokinetics of GS-7340 (25 mg) in Subjects with Severe Renal Impairment 
(completed)

GS-US-120-0109, A Phase 1 Study to Evaluate the Pharmacokinetics, Metabolism and 
Excretion of GS-7340 (25 mg [completed])
Further details regarding these studies are provided in the table below (Table 1-1). In Phase 1/2 
studies in HIV-infected subjects (Studies 120-1101 and 120-0104), the short-term 
safety/tolerability, PK, and antiviral activity of TAF when given as a stand alone agent (SA) 
were evaluated over a range of doses. In Study 120-0104, at TAF doses of 25 mg or higher, 
near-maximal HIV RNA suppression was observed at Day 10, and importantly, single dose PK 
assessments of TAF (8 mg, 25 mg, or 40 mg) and TDF (300 mg) demonstrated that the 
TAF-generated TFV systemic exposures (AUCinf) were markedly lower (approximately 90% 
lower at TAF 25 mg) than the TFV exposure generated with TDF 300 mg. For HIV Phase 2 
(and Phase 3) studies, however, a 10 mg dose of TAF was selected for inclusion as a component 
of the elvitegravir (E)/ cobicistat (COBI, or “C”)/emtricitabine(F)/TAF single tablet regimen 
(STR) in comparison to the E/C/F/TDF STR control arm. A reduction in dose from 25 mg to
10 mg of TAF in the E/C/F/TAF STR is required based on a drug-drug interaction between TAF 
and COBI resulting in increased exposures of both TAF and TFV which is likely a consequence 
of Pgp-mediated inhibition of TAF and TFV efflux within the gut by COBI. Importantly, the 
resultant TFV exposures when TAF is dosed at 10 mg with COBI in the E/C/F/TAF STR 
formulation are similar to TFV exposures generated with TAF 25 mg given as a SA. Given that 
TAF exposures with E/C/F/TAF 


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10 mg are comparable to those with TAF given alone, safety results in HIV trials using this 
formulation are being assessed at a TAF dose that is considered therapeutically equivalent to 
TAF 25 mg. Thus, HIV studies conducted at TAF exposures similar to those expected in HBV 
provide the basis for supporting safety data for the TAF HBV development program.
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection
Study #
Population
Design
Dosing/Duration
Rationale
HIV Studies (Phase 1/2)
120-1101
N = 30
Treatment naïve
Dose escalation
3 treatment cohorts
TAF 50 mg, 150 mg, TDF 
300 mg; multiple dosing 
for 14 days
Short-term proof of 
concept study;
safety, PK, and antiviral 
efficacy
120-0104
N = 38
Treatment naïve
(no ARV within 
90 days of screening)
Randomized 
(2:2:2:1:2) 
partially blinded
TAF 8 mg, 25 mg, 40 mg, 
TDF 300 mg, or placebo 
(PBO) for 10 days; off 
treatment follow up to 
Day 21
Confirmatory study for 
Study 1101 using a TAF 
reformulation; more 
rigorous design, evaluate 
lower TAF doses
Ongoing Supportive Phase 1 Studies
120-0107
N = 48
Males/females, 
age 18-45
Thorough QT 
(TQT)
TAF 25 mg, 125 mg;
each subject dosed 3 times 
for 37 days (with 10 day 
wash-out period)
Regulatory requirement
120-0108
N = 27 
(14 with severe renal 
impairment [CrCL 
15-29 mL/min] and 
13 matched controls 
[CrCL ≥90 mL/min])
PK in Renal 
impairment
TAF 25 mg single dose 
with 14 days of follow up
Characterizing TAF and 
TFV PK in severe renal 
impairment 
(to demonstrate no need 
for TAF dose adjustment)
120-0109
N = 8
healthy volunteer, 
male subjects
Mass Balance
Single radio-labeled TAF 
25 mg dose with 21 days 
of follow up
Regulatory requirement
Clinical trials entailing the use of TAF for the treatment of CHB virus:

GS-US-320-0101 A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess 
the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naïve Adults 
with Chronic Hepatitis B (CHB) Infection (enrollment and dosing completed)
The two proof-of concept studies, GS-120-1101 and GS-US-120-0104, as well as 
GS-US-292-0101, a STR bioequivalence study, were performed using TAF monofumarate
(GS-7340-02). All subsequent studies discussed herein were performed using TAF fumarate 
(GS-7340-03). 
GS-120-1101 was a Phase 1/2 randomized double-blind, active-controlled, dose escalation study 
of the safety, tolerance, pharmacokinetics, and antiviral activity of TAF in antiretroviral-naïve 
subjects who are chronically infected with HIV-1. The subjects were randomized to receive 


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14 days of monotherapy, fasting, with GS-7340-02 50 mg (40 mg GS-7340 [free base]
equivalent) QD, 150 mg (120 mg GS-7340 [free base] equivalent) QD, or tenofovir DF 300 mg 
QD (n = 10 per group). TAF was rapidly absorbed into the systemic circulation, and 
subsequently following attainment of Cmax, was eliminated rapidly with a short plasma half-life 
(20-40 minutes). Compared with TDF, GS-7340-02 50 mg provided a ~16-fold lower TFV Cmax
(207 ng/mL vs 13 ng/mL), about 2-fold longer elimination half-life (26 hours vs 48 hours) and 
lower overall systemic tenofovir exposure (AUCinf: 1814 ng.h/mL vs 383 ng.h/ml). TAF 
monofumarate 150 mg provided lower Cmax (42 ng/mL), but comparable AUCinf: (1740 ng.h/mL) 
as TDF. In PBMCs, TFV was detected earlier, more frequently, and in higher concentrations 
following dosing of TAF monofumarate as compared to TDF. The intracellular delivery of TFV
is approximately 30-fold greater for GS-7340-02 versus TDF. The decrease from Baseline to 
Day 14 in plasma HIV-RNA levels was greater for groups treated with GS-7340-02 50 mg 
(p = 0.02757) or 150 mg (p = 0.0010) than the group that received TDF 300 mg. The median 
changes from baseline in plasma HIV-1 RNA after 14 days of monotherapy were 
−0.96 log10 copies/mL for TDF 300 mg, −1.65 log10 copies/mL for GS-7340-02 50 mg, and 
−1.68 for GS-7340-02 150 mg. 
A second proof-of-concept study, GS-US-120-0104, evaluated monotherapy, fasting, with three 
lower doses of TAF compared with TDF 300 mg, or placebo, administered for 10 days. Potent 
antiviral activity was achieved with TAF in treatment-naïve HIV-1 infected subjects; mean viral 
load declines for both the 25 mg and 40 mg doses were statistically better than the 8 mg dose. 
TAF exposure (AUC) was best associated with antiviral activity despite its short plasma half-life 
(~ 30 min). TFV AUC values were 97%, 87%, and 80% lower at 8 mg, 25 mg, and 40 mg TAF
respectively, compared to TDF administration. When compared to 40 mg and historical 120 mg 
data, 25 mg TAF provides near maximal anti-HIV-1 activity. From this PK-PD analysis, a target 
exposure of a dose of 25 mg TAF monotherapy is expected to provide near maximal antiviral 
activity and ~ 90% reduction in circulating TFV. 
Study GS-US-120-0107 is a Phase 1, partially-blinded, randomized, placebo- and 
positive-controlled study to evaluate the effect of TAF on the QT/QTc interval in healthy 
subjects. This was a negative thorough-QTc study. No effect of TAF was observed on the QTcF 
interval (ie, no QTc interval prolongation > 10 msec at any time point post-dose and assay 
sensitivity was confirmed via the positive control [moxifloxacin]). As such, these findings satisfy 
the guidelines set forth in the International Conference on Harmonization (ICH) E14 guidance 
and support the conclusion that there is no significant effect of TAF on the QT/QTc interval.
Study GS-US-120-0108 is a Phase 1, open-label, parallel-design study to evaluate the PK of TAF 
in subjects with severe renal impairment. TAF was well tolerated in the study. Subjects with 
severe renal impairment had < 2-fold higher TAF and 5-6 fold higher TFV systemic exposures as 
assessed by AUC relative to subjects with normal renal function. TFV exposures in subjects with 
severe renal impairment are comparable to those with normal renal function receiving 300 mg 
TDF QD. Given the extensive safety data available for TDF at a dose of 300 mg, TFV exposures 
in severely renally impaired subjects similar to those associated with TDF 300 mg are deemed 
appropriate for further study of TAF in HIV-infected subjects without TAF dose modification.


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Preliminary results from Study GS-US-120-0109, a Phase 1 PK, metabolism and excretion study 
demonstrated that TAF is eliminated in both feces and urine. TAF and its metabolites are 
eliminated in both feces and urine. The predominant species detected in feces and urine is TFV, 
accounting for 31.4% ± 10.4% and 22.2% ± 4.47% respectively of the total radioactive dose.
These human data are consistent with the established preclinical profile of TAF. Following
administration of TAF, plasma [14C] radioactivity showed a time dependent profile with TAF as 
the most abundant species in the initial few hours and uric acid, a byproduct of TAF metabolism, 
in the remaining period. The whole blood-to-plasma concentration ratio of [14C] radioactivity 
increased from 0.511 at 0.25 hours post dose to 2.32 at 216 hours post dose, suggesting a 
relatively slower clearance of [14C] radioactivity from blood cells relative to the plasma 
[14C] radioactivity time-course. In addition to TFV and uric acid, additional low quantities of 
metabolites were formed, including xanthine, hypoxanthine, and adenine. They are identical to 
the endogenous products of purine metabolism and therefore should not cause any safety risk. 
TAF 25 mg tablets administered together with tracer dose of [14C] radiolabeled TAF as a single 
oral tablet, were well tolerated.
HBV Study – GS-US-320-0101
In HBV subjects, a 28 day Phase 1b study (GS-US-320-0101), was conducted to evaluate 
safety/tolerability, pharmacokinetics, and antiviral activity of TAF at doses of 8 mg, 25 mg, 
40 mg, and 120 mg compared to TDF 300 mg control in 50 subjects (10/cohort). As of 
April 2, 2013, enrollment was completed (n = 51) and all subjects have completed study drug 
dosing through Day 29.
Preliminary data suggest that all treatment groups were generally well matched (Table 1-2) and 
representative of the chronic HBV population. Overall, the majority of subjects were male 
(66.7%), and of Asian descent (56.9%). Of the 51 randomized subjects, 27 (53%) and 24 (47%) 
were HBeAg-negative and HBeAg-positive, respectively. Median age ranged among groups 
from 34 years in the 8 mg and 25 mg TAF groups to 40 and 42 years in the 40 mg and 120 mg 
TAF groups, respectively; median age in the TDF group was 34 years. The most common HBV 
genotype at enrollment was genotype C (16/51; 31%), the proportions of other genotypes were: 
A (7/51; 14%), B (10/51; 20%), D (9/51; 18%), and E (9/51; 18%). The distribution of HBV 
genotypes was similar within groups, with the exception of a higher proportion (5 of 11 [45.5%]) 
of subjects in the 40 mg TAF group having genotype B.




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2 subjects in the TAF 120 mg group (1 subject each with elevated transaminases [both AST and 
ALT occurring during treatment follow-up], and amylase elevation), and in 1 subject in the TDF 
arm (amylase elevation). The subject with Grade 3 glycosuria in the TAF 40 mg group, 
experienced this abnormality at Day 29 which was associated with a corresponding serum 
glucose elevation (212 mg/dL); the subject also had a history of diabetes mellitus.
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and 
Laboratory Abnormalities: Overall Summary, Safety Analysis Set
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(N = 10)
TDF 300 mg
(N = 10)
Subjects Experiencing Any 
Treatment-Emergent Adverse Event
7 (70%)
6 (60%)
6 (55%)
8 (80%)
5 (50%)
Subjects Experiencing Any 
Treatment-Emergent 
Study Drug-Related Adverse Event
2 (20%)
4 (40%)
3 (27%)
4 (40%)
5 (50%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Adverse Event
1 (10%)
1 (10%)
0
4 (40%)
2 (20%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Study Drug-Related Adverse Event
0
0
0
3 (30%)
1 (10%)
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Laboratory Abnormality
0
0
3 (27%)
2 (20%)
1 (10%)
Subjects Experiencing Any 
Treatment-Emergent 
Serious Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Treatment-Emergent Adverse Event 
Leading to Premature Study Drug 
Discontinuation
0
0
0
0
0
Given the significantly smaller declines in creatinine clearance (CLCr) observed at Week 24 with 
TAF relative to TDF in the HIV Phase 2 study (GS-US-209-0102; Section 1.2.4), changes in 
CLCr were also assessed in HBV subjects participating in GS-US-320-0101. After 4 weeks of 
dosing, numerically smaller changes in CLCr at Day 29 were seen in HBV subjects receiving 
TAF compared with TDF (Figure 1-1). At Day 29, median (range) change from baseline in CLCr
was −2.0 (−13.2, 9.6) mL/min for the TAF 25 mg group compared with a change of 
−10.4 (−35.7, 13.0) mL/min in the TDF group. Further, there were no notable differences in CLCr
change among the two lowest dose groups (TAF 8 mg and TAF 25 mg), and the highest dose 


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group (120 mg). An early decline in CLCr, similar to that observed in the TDF group was noted 
in the TAF 40 mg group; however, by Day 29 the change in CLCr was similar to the other TAF 
groups. These results are consistent with findings in HIV subjects receiving the E/C/F/TAF 
10 mg STR and provide additional evidence to support the concept that lower TFV exposures 
with TAF relative to TFV exposures with TDF are associated with notable differences in renal 
function as determined by estimated CLCr.
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance 
(Cockcroft-Gault Method) in GS-US-320-0101
Baseline is defined as Day 1.
Over 28 days of study drug treatment, similar median declines in HBV DNA levels were 
observed among treatment groups (Figure 1-2). Overall, viral decay results among subjects who 
received treatment with TAF demonstrated the absence of a dose effect. In addition, the HBV 
DNA declines with TAF (n = 41) over 28 days of dosing were similar to HBV DNA declines 
observed in the TDF 300 mg group (n = 10). A summary of change from baseline in HBV DNA 
results at Day 15 and Day 29 is provided in the table below (Table 1-4) below. Among TAF 
groups, median change from baseline in HBV DNA at Day 29 ranged from −1.98 log10 IU/mL
for the TAF 40 mg group to −2.76 log10 IU/mL for the TAF 8 mg group. For TAF 25 mg, the 
change from baseline in HBV DNA at Day 29 was −2.67 log10 IU/mL. Consistently smaller 
declines in HBV DNA over time, and slightly lower median change from baseline in HBV DNA
were observed in the TAF 40 mg group at Day 29. The reason for this is unclear and possibly 


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related to a lower median HBV DNA value at Baseline (Table 1-4). In this group, 
5/11 (45.5%) subjects had a baseline HBV DNA value below 5.0 log10 IU/mL. In comparison to 
TAF groups, the change from baseline in HBV DNA at Day 29 was −2.60 log10 IU/mL with 
TDF 300 mg. 
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV 
DNA (Log10 IU/mL) by Treatment Group
Baseline is defined as Day 1/pre-dose.




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Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: TAF (GS-7340), Linear Scale
TAF plasma pharmacokinetic parameters are summarized in Table 1-5. Day 1 pharmacokinetic 
results in CHB subjects participating in GS-US-320-0101 are consistent with previously reported 
results in the HIV Phase 1/2 study GS-US-120-0104, which evaluated TAF single-dose 
pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 40 mg (n=8), versus TDF 
300 mg (n=6). In GS-US-120-0104, mean (%CV) AUC0-last was 38.4 (80.6) ng∙h/mL, 
139.7 (57.8) ng∙h/mL, and 322.1 (42.0) ng∙h/mL after single doses of TAF 8 mg, 25 mg, and 
40 mg, respectively. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to the results generated in GS-US-120-0104.
Similar findings to the present study were also observed when TAF pharmacokinetic parameters 
were assessed after multiple doses at steady-state in the ongoing Phase 2 study, 
GS-US-292-0102, which compares STRs of E/C/F/TAF 10 mg to E/C/F/TDF 300 mg in HIV-1 
infected, treatment-naive subjects. Mean (%CV) AUClast, and Cmax values for TAF at the 10 mg 
dose in combination with COBI were 230.4 (47.3) ng∙h/mL and 232.8 (64.6) ng/mL, 
respectively. As TAF exposures at the 10 mg dose, when included as a component of the 
E/C/F/TAF STR, have been shown to be comparable to those with TAF 25 mg given as the 
stand-alone agent, these results indicate similar TAF exposures in both subjects infected with 
HIV and those infected with HBV.  


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Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on 
Day 1
TAF PK Parameter
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(N = 11)
TAF 120 mg
(N = 10)
AUC0-last (ngh/mL)
59.2 (54.1)
153.0 (41.1)
328.1 (58.4)
832.4 (39.1)
AUCinf (ngh/mL)
60.6 (52.8)
154.4 (41.0)
329.8 (58.1)
834.6 (38.9)
Cmax (ng/mL))
83.2 (46.3)
249.5 (45.9)
527.4 (50.6)
1128.7 (33.7)
Tmax (h) median
0.5
0.5
0.5
0.5
T1/2 (h)
0.36 (23.8)
0.51 (32.6)
0.59 (30.7)
0.76 (30.8)
All results expressed as mean (%CV) unless otherwise stated
TFV Pharmacokinetic Results
Mean (SD) plasma concentration versus time profiles for TFV following single dose 
administration of ascending doses of TAF and TDF 300 mg are shown in Figure 1-4. At each 
TAF dose evaluated, plasma TFV concentrations resulting from TAF administration were lower 
than plasma TFV concentrations following TDF administration. The TFV concentrations 
achieved from all TAF dose levels in HBV subjects in GS-US-320-0101 are comparable to TFV 
concentrations achieved after TAF administration in the HIV program.
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: Tenofovir, Linear Scale


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Tenofovir (TFV) plasma pharmacokinetic parameters are summarized in Table 1-6. As with 
TAF, Day 1 TFV pharmacokinetic results in CHB subjects participating in GS-US-320-0101 are 
consistent with those previously reported in the HIV Phase 1/2 study GS-US-120-0104, which 
evaluated TAF single-dose pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 
40 mg (n=8), versus TDF 300 mg (n=6). In GS-US-120-0104, mean (%CV) AUCinf for TFV 
were 49.4 (30.3) ng∙h/mL, 195.9 (27.2) ng∙h/mL, and 287.3 (33.7) ng∙h/mL after single doses of 
TAF 8 mg, 25 mg, and 40 mg, respectively. Mean (%CV) AUCinf for TFV following TDF 
300 mg was 1719.2 ng∙h/mL. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to results seen in HIV subjects in GS-US-120-0104. As stated 
earlier, When TAF is included as a component of the E/C/F/TAF STR, a reduced dose (10 mg) is
required due to a drug-drug interaction (inhibition of P-gp in the gut by cobicistat) that results in
increased exposures of both TAF and TFV (see Section 1.2.4).
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on 
Day 1
TFV PK Parameter
TAF 8 mg
(n=10)
TAF 25 mg
(n=10)
TAF 40 mg
(n=11)
TAF 120 mg
(n=10)
TDF 300 mg
(n=10)
AUC0-last (ngh/mL)
32.9 (35.0)
90.6 (25.8)
213.4 (40.2)
607.7 (35.4)
1682.1 (28.0)
AUCinf (ngh/mL),
74.0 (41.2)
171.4 (29.9)
444.6 (43.0)
1572.0 (47.2)
2309.8 (27.9)
Reduction in AUCinf, 
TAF/TDF (%)
97
93
81
32
N/A
Cmax (ng/mL),
3.0 (34.5)
8.3 (41.6)
20.3 (43.2)
61.0 (33.5)
306.8 (24.5)
Reduction in Cmax, 
TAF/TDF (%)
99
97
93
80
N/A
Tmax (h) median
1.25
1.0
1.0
1.0
1.0
t1/2 (h)
26.7 (23.4)
20.7 (39.6)
26.3 (33.8)
31.4 (38.6)
10.8 (17.4)
The following Section (1.2.4) provides a summary of experience with TAF in HIV-1 infection, 
including the final Week 24 analysis results for TAF when used as a component of the 
E/C/F/TAF STR in the HIV Phase 2 study GS-US-292-0102. Because TAF exposures in this 
ongoing trial are similar to those expected in the TAF HBV development program, these results 
provide important supporting safety data.


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1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)
Phase 1 and 2 clinical trials using TAF, coformulated into the E/C/F/TAF STR for the treatment 
of HIV-1 infection include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI when administered as E/C/F/TAF STR relative to E/C/F/TDF or 
TAF (completed)

GS-US-292-0103, a Phase 1 healthy volunteer study to evaluate the pharmacokinetics and 
relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
GS-7340 doses of 10 mg (STR) or 25 mg SA (completed)

GS-US-292-0102, a Phase 2 randomized, double-blinded study of the safety and efficacy of 
E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, antiretroviral treatment-naive 
adults (ongoing)
1.2.4.1.
Summary of Phase 1 Studies (Study GS-US-292-0102, GS-US-292-0103)
Study GS-US-292-0101 is a completed Phase 1 study of 40 subjects evaluating the relative 
bioavailability of two different formulations of E/C/F/TAF STR, each with TAF dose of 25 mg 
or 40 mg, versus E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, and FTC 
were comparable between E/C/F/TAF vs E/C/F/TDF regardless of formulation (monolayer or 
bi-layer). In contrast, TAF exposures were ~2.2-fold higher (and corresponding tenofovir 
exposures ~ 3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 25 mg for both 
formulations of the E/C/F/TAF. This is likely mediated by inhibition of Pgp-mediated intestinal 
secretion of TAF by COBI and consistent with data from Study GS-US-311-0101 described 
below. 
Study GS-US-292-0103 is a completed Phase 1 healthy volunteer study which evaluated the PK 
and relative bioavailability of the E/C/F/TAF STR relative to the individual components at TAF 
doses of 10 mg (as STR) or 25 mg SA. Results indicate that when dosed as the E/C/F/TAF 
10 mg STR, TAF and TFV exposures were comparable to those observed with TAF 25 mg dosed 
alone. Exposures of EVG, COBI, and FTC were also comparable between the STR and 
individually dosed formulations. 
1.2.4.2.
Week 24 Summary of Phase 2 Study (Study GS-US-292-0102)
GS-US-292-0102 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of E/C/F/TAF STR versus E/C/F/TDF in 
HIV-1 infected, antiretroviral treatment-naive adults with plasma HIV-1 RNA levels 
≥5,000 copies/mL at Screening. 


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Eligible subjects were randomized in a 2:1 ratio to 1 of the following 2 treatment arms and 
randomization was stratified by HIV-1 RNA level (≤ 100,000 copies/mL or > 100,000 copies/mL) 
at Screening:

Treatment Arm 1: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TAF 10 mg 
(E/C/F/TAF) + placebo-to-match STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TDF 300 mg (E/C/F/TDF) once daily (n = 100)

Treatment Arm 2: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TDF 300 mg 
(E/C/F/TDF) + placebo-to-match STR EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TAF 10 mg (E/C/F/TAF) once daily (n = 50)
The Independent Data Monitoring Committee (IDMC) reviewed the safety and study conduct at 
Week 12 and determined that no changes were required for study GS-US-292-0102. Interim data 
at Week 24 is presented below.
1.2.4.3.
Week 24 Subject Disposition and Demographics
A total of 170 subjects were randomized and treated in this study: 112 subjects in the E/C/F/TAF 
group and 58 subjects in the E/C/F/TDF group. The full analysis set (FAS) and safety analysis 
set (SAS) each included all randomized and treated subjects from each group. A total of 
24 subjects were included in the pharmacokinetic substudy analysis set. At the time of the 
Week 24 data analysis, 6 subjects (2.4%) had been discontinued from treatment and 4 subjects 
(2.4%) had been discontinued from study. 
Of the 170 subjects in the FAS and SAS, 165 (97.1%) were male; 115 (67.6%) were white and 
50 (29.49%) were black; and the mean age was 36 years (range: 18 to 71 years). Demographic 
and baseline disease characteristics were similar between the 2 treatment groups.
1.2.4.4.
Week 24 Efficacy Results
Proportion of Subjects with Plasma HIV-1 RNA < 50 copies/mL at Week 24
The proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at Week 24 was 86.6% in 
the E/C/F/TAF group and 89.7% in the E/C/F/TDF group, with a stratum-adjusted difference in 
the response rate between the 2 treatment groups of −4.9% (95% CI: −15.7% to 5.9%; p = 0.36).
Results of the secondary efficacy endpoint confirmed those of the primary analysis. The 
proportion of subjects with suppression of plasma HIV-1 RNA < 50 copies/mL at Week 24 
(time-to-loss of virologic-response [TLOVR] analysis) was 88.4% (99/112) in the E/C/F/TAF 
group and 84.5% (49/58) in the E/C/F/TDF group. The stratum-adjusted difference in the 
response rate between the 2 treatment groups was −0.1% (95% CI: −10.4% to 10.2%; p = 0.99).
The mean increase in CD4 cell count from baseline to Week 24 was 163 cells/μL in the 
E/C/F/TAF group and 177 cells/μL in the E/C/F/TDF group (-6 difference in LSM, 95% CI 
−44 to 33).


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1.2.4.5.
Week 24 Pharmacokinetic Results
Results from the intensive pharmacokinetic substudy demonstrated that, consistent with data in 
healthy subjects and HIV-infected subjects treated with TAF monotherapy, E/C/F/TAF (10 mg) 
produced substantially lower tenofovir systemic exposures than E/C/F/TDF (TDF 300 mg). TAF 
exhibited a short median (min-max) plasma half-life of 0.47 (0.37 to 0.87) hours with no 
detectable drug after 8 hours post-administration. Steady-state mean (CV%) AUCtau was 
230 ng•hr/mL (47%). PK results for the other components EVG, COBI and FTC were similar to 
historical data for these agents when administered as E/C/F/TDF (data not shown). In addition, 
TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) in subjects in the 
E/C/F/TAF group showed that TFV-DP was detectable within PBMCs at greater exposures 
(approximately 5-fold) after administration of E/C/F/TAF than with E/C/F/TDF.
1.2.4.6.
Week 24 Safety Results
1.2.4.6.1.
Overall Safety
At the time of the 24-week interim analysis, 112 subjects had been treated with E/C/F/TAF for a 
median duration of 21.1 weeks and 58 subjects had been treated with E/C/F/TDF for a median 
duration of 21.3 weeks. The overall subject incidence of treatment-emergent adverse events 
(AEs) was balanced between treatment groups (81.3% E/C/F/TAF, 81.0% E/C/F/TDF) 
(Table 1-7). The most frequent treatment-emergent AEs (> 10% in either treatment group) were 
(17.9% E/C/F/TAF, 12.1% E/C/F/TDF) nausea, diarrhea (11.6% E/C/F/TAF, 12.1%
E/C/F/TDF), fatigue (11.6% E/C/F/TAF, 8.6% E/C/F/TDF), upper respiratory tract infection 
(7.1% E/C/F/TAF, 12.1% E/C/F/TDF), and headache (9.8% E/C/F/TAF, 10.3% E/C/F/TDF), 
respectively.  
Most treatment-emergent AEs were assessed as Grade 1 or Grade 2 in severity. The incidence of 
Grade 3 or 4 AEs was higher in the E/C/F/TAF group (7.1%) compared to the E/C/F/TDF group 
(3.4%). No Grade 3 or 4 event occurred in > 1 subject; the system organ class (SOC) with the 
highest subject incidence of Grade 3 or 4 events was Nervous System Disorders 
(2.7% E/C/F/TAF, 0% E/C/F/TDF). The only Grade 3 or 4 event that was considered by the 
investigator to be related to investigational product was Grade 3 diarrhea in 1 subject (0.9%) in 
the E/C/F/TAF group; there were no treatment-related Grade 3 or 4 AEs in the E/C/F/TDF 
group. Based on these data, there do not appear to be any signature, higher grade AEs associated 
with the use of E/C/F/TAF through 24 weeks of treatment.
More subjects in the E/C/F/TAF group compared to the E/C/F/TDF group also had 
treatment-emergent serious AEs (SAEs) (5.4% vs 3.4%) or AEs leading to premature treatment 
discontinuation (3.6% vs 0). None of these events occurred in > 1 subject, and none of the SAEs 
were considered by the investigator to be related to treatment with investigational product. The 
system organ class (SOC) with the highest subject incidence of treatment-emergent SAEs was 
Infections and Infestations (4.5% E/C/F/TAF, 0% E/C/F/TDF). No deaths or pregnancies 
occurred.


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Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: 
Overall Summary, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Subjects Experiencing Any Treatment-Emergent Adverse Event
91 (81.3%)
47 (81.0%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Adverse Event
42 (37.5%)
17 (29.3%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Adverse Event
8 (7.1%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related Adverse Event
38 (33.9%)
15 (25.9%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Study-Drug-Related 
Adverse Event
6 (5.4%)
1 (1.7%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Study-Drug-Related 
Adverse Event
1 (0.9%)
0
Subjects Experiencing Any Treatment-Emergent Serious Adverse Event
6 (5.4%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related 
Serious Adverse Event
0
0
Subjects Experiencing Any Treatment-Emergent Adverse Event Leading to 
Premature Study Drug Discontinuation
4 (3.6%)
0
Subjects who had Treatment-Emergent Death
0
0
Treatment-emergent death refers to a death occurring between the first dose date and the last dose date plus 30 days (inclusive).
At least 1 treatment-emergent laboratory abnormality (ie, at least 1 grade level increase in graded 
abnormality) was reported for 103/111 subjects (92.8%) in the E/C/F/TAF group and 
46/58 subjects (79.3%) in the E/C/F/TDF group. The majority of laboratory abnormalities were 
Grade 1 or 2 in severity. Subject incidence of Grade 3 or 4 treatment-emergent laboratory 
abnormalities is summarized in Table 1-8.


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Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Maximum Post-Baseline Toxicity Grade 3 or 4
19 (17.1%)
8 (13.8%)
Neutrophils
5 (4.5%)
1 (1.7%)
WBC
1 (0.9%)
0
Amylase
2 (1.8%)
1 (1.7%)
Creatine Kinase (CK)
6 (5.4%)
2 (3.4%)
Lipase
0
1 (12.5%)
Serum Glucose (Hyperglycemia)
0
1 (1.7%)
Total Cholesterol (Fasting, Hypercholesterolemia)
1 (0.9%)
0
Triglycerides (Fasting)
1 (0.9%)
1 (1.7%)
LDL (Fasting)
7 (6.4%)
2 (3.4%)
Urine Protein (Proteinuria)
1 (0.9%)
0
Urine RBC (Hematuria, Quantitative)
1 (0.9%)
0
Denominator for percentage is the number of subjects in the SAS with at least 1 post-baseline laboratory value (for the test).
Subjects were counted once for the maximum postbaseline severity for each laboratory test.
Lipase test was only performed for subjects with serum amylase > 1.5 × upper limit of normal.
Urine RBC (hematuria, quantitative) was graded based on DAIDS grading scale (with the modification of urine RBC
> 75 cells/HPF as Grade 3).
For Urinalysis (i.e., urine glucose, urine protein, and urine RBC), the highest grade is up to Grade 3.
No clinically significant changes in mean thyroid function tests (TSH, free T3, free T4) or serum 
immunoglobulins (IgG and IgM) were observed.
1.2.4.6.2.
Renal Safety
On multiple objective laboratory tests of renal function, subjects receiving E/C/F/TAF had a 
lower magnitude of change than subjects receiving E/C/F/TDF through 24 weeks.  
The change from baseline in serum creatinine (sCr) was lower in the E/C/F/TAF group compared 
to the E/C/F/TDF group at most assessments through Week 24. At Week 24, median change 
from baseline in serum creatinine was 0.07 mg/dL (range through Week 24: 
0.05 mg/dL to 0.08 mg/dL) for the E/C/F/TAF group and 0.11 mg/dL (range through Week 24: 
0.08 mg/dL to 0.11 mg/dL) for the E/C/F/TDF group (Week 24 p = 0.016).
Accordingly, the decrease from baseline in estimated glomerular filtration rate (GFR) by 
Cockcroft-Gault formula for CLCr was lower in the E/C/F/TAF group compared to the 
E/C/F/TDF group at most assessments through Week 24 (Figure 1-5). At baseline, the mean 
(SD) estimated GFRC-G was similar between groups (120.1 [30.22] (mL/min) for subjects in the 
E/C/F/TAF group and 114.7 [21.68] (mL/min) for subjects in the E/C/F/TDF group. At Week 24, 


Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-0108 
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Amendment 3 .1 
median change from baseline estimated GFR.c-G was - 6.6 mL/min for the E/C/F/TAF group and 
-10.6 mL/min for the E/C/F/TDF group (p = 0.009). At Week 24, 3 (5.2%) subjects in the 
E/C/F/TDF group would be classified as new Stage 3 CKD (eGFR 30-59 mL/mi.n) vs. 
1 (1.0%) subjects in the E/C/F/TAF group, and 15 (14.4%) subjects in the E/C/F/TAF group 
would be classified as new Stage 2 CKD (eGFR 60-89 mL/min) vs. 20 (34.5%) subjects in the 
EICIFITDF group. 
Figure 1-5. 
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GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in 
Estimated GFR by Cockcroft-Gault by Visit, Safety Analysis Set 
Bl 
112 
109 
58 
54 
4 
109 
58 
8 
110 
58 
12 
107 
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At Week 24, a trend towards reduced proteinuria was observed in the E/C/F/TAF group. By 
urine dipstick, the frequency of maximmn post -baseline proteinuria (any grade) was 13.5% in 
E/C/F/TAF vs. 20.7% in E/C/F/TDF. The median change from baseline in urine albumin to 
creatinine ratio (UACR) was - 0.84 mg/g in E/C/F/TAF vs - 0.07 in E/C/F/TDF. The median 
change fi·om baseline in urine protein to creatinine ratio (UPCR) was - 5.6 mg/ g and 1.6 mg/g in 
the E/C/F IT AF and E/C/F /TDF groups, respectively. Explorat01y biomarkers of tubular 
proteinuria were also assessed, and demonstrated a statistically significant reduction in tubular 
proteinuria in the E/C/F/TAF group. At Week 24, median change fi·om baseline 
beta-2-microglobulin to creatinine ratio was - 35.9 f.!g/g for E/C/F/TAF vs - 1.1 f.!g/g for 
E/C/F/TDF (p = 0.004), and median change fi·om baseline in retinol binding protein to creatinine 
ratio was - 0.7 ~tg/g for E/C/F/TAF vs 11.9 ~tg/g for E/C/F/TDF (p = 0.006). 
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A treatment difference for other laboratory markers of kidney function were not observed, 
including median change from baseline for serum phosphate and fractional excretion of 
phosphate (fractional excretion of phosphate [FEPO4] using adjusted sCr).
1.2.4.6.3.
Bone Safety
DXA scans of the spine and hip were performed at the Baseline and Week 24 visits (and at the 
early study drug discontinuation visit, if applicable) to measure changes from baseline in BMD. 
The percent changes from baseline in BMD values in the lumbar spine and hip are summarized 
in Table 1-9. The median percentage decrease from baseline was significantly less for subjects in 
the E/C/F/TAF group compared with that for subjects in the E/C/F/TDF group for both spine 
(p = 0.002) and hip (p < 0.001) BMD. 
The categorical distribution of subjects in each treatment group with percentage changes in BMD 
from baseline within specified ranges at Week 24 is summarized for spine and hip in Table 1-10. 
At Week 24, a significantly higher proportion of subjects in the E/C/F/TAF group than in the 
E/C/F/TDF group had no decreases in BMD at the hip (40.6% vs 22.8%; p < 0.001) and spine 
(37.5% vs 12.1%; p = 0.003). Substantially fewer subjects in the E/C/F/TAF group had decreases 
in BMD of >3% at the hip than in the E/C/F/TDF group (3.0% vs 31.6%) at Week 24.
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine 
and Hip Bone Mineral Density at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Change at Week 24
Spine
N
104
58
0.002
Mean (SD)
-0.84 (3.411)
-2.48 (2.519)
Median (Q1, Q3)
-0.92 (-3.00, 0.99)
-2.34 (-3.65, -0.33)
Min, Max
-8.49, 17.12
-10.37, 2.43
Hip
N
101
57
< 0.001
Mean (SD)
-0.30 (1.774)
-2.103 (2.677)
Median (Q1, Q3)
-0.42 (-1.44, 0.71)
-2.08 (-3.60, -0.48)
Min, Max
-4.68, 7.84
-8.55, 4.86
P-values were from the Wilcoxon rank sum test.
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 E/C/F/TDF post baseline visit were 
included in the DXA substudy analysis set.


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Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by 
Gradation at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Percentage Change at Week 24
Spine
No Decrease
39/104 (37.5%)
7/58 (12.1%)
0.003
> 0 to < = 1% Decrease
14/104 (13.5%)
11/58 (19.0%)
> 1 to < = 3% Decrease
25/104 (24.0%)
17/58 (29.3%)
> 3 to < = 5% Decrease
18/104 (17.3%)
15/58 (25.9%)
> 5% Decrease
8/104 (7.7%)
8/58 (13.8%)
Hip
No Decrease
41/101 (40.6%)
13/57 (22.8%)
< 0.001
> 0 to < = 1% Decrease
23/101 (22.8%)
7/57 (12.3%)
> 1 to < = 3% Decrease
34/101 (33.7%)
19/57 (33.3%)
> 3 to < = 5% Decrease
3/101 (3.0%)
12/57 (21.1%)
> 5% Decrease
0/101
6/57 (10.5%)
P-value was from the CMH test for ordinal data (row mean scores differ statistic was used).
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 postbaseline visit were included in 
DXA substudy analysis set.
Clinical BMD status was assessed using BMD T-scores. Changes from baseline in BMD status 
at Week 24 were determined using T-scores. At Week 24, 6 of 99 subjects (6.1%) in the 
E/C/F/TAF group and 2 of 58 subjects (3.4%) in the E/C/F/TDF group showed a deterioration 
from baseline in spine BMD T-score category, and 1 of 99 subjects (1.1%) in the E/C/F/TAF 
group and 5 of 54 subjects (9.3%) in the E/C/F/TDF group showed a deterioration from baseline 
in hip BMD T-score category. In the E/C/F/TAF group at Week 24, 5 subjects had improvement 
in spine BMD T-score category and 1 subject had improvement in hip BMD T-score category. 
One subject in the E/C/F/TDF group showed improvement in the hip BMD T-score category. As 
a continuous variable, median decrease from baseline BMD T-score was significantly less for 
E/C/F/TAF vs E/C/F/TDF at both spine (-0.08 vs. −0.22, p = 0.005) and hip (−0.03 vs −0.14, 
p < 0.001).
Bone turnover markers, including one for bone resorption (C-type collagen sequence [CTX]) and 
three for formation (bone specific alkaline phosphatase [bsAP], osteocalcin [OC], and 
procollagen type 1 N-terminal propeptide [P1NP]), were assessed to support the BMD data. 
Comparisons of percent change from baseline for each bone turnover marker at Weeks 12 and 24 
demonstrated statistically significantly less change in the E/C/F/TAF arm, and provide evidence 
of less bone turnover at both timepoints in the E/C/F/TAF arm vs the E/C/F/TDF arm 
(Table 1-11). These results are consistent with the observations made in the BMD analyses.


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Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover 
Markers, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
E/C/F/TAF vs E/C/F/TDF
p-value
Week 12
CTx, % change in mean (SD)
37.9 (62.0)
103.7 (109.1)
<0.001
bsAP, % change in mean (SD)
-13.4 (16.0)
2.0 (16.3)
<0.001
OC, % change in mean (SD)
22.0 (32.5)
46.9 (49.1)
<0.001
P1NP, % change in mean (SD)
2.6 (32.2)
30.1 (36.1)
<0.001
Week 24
CTx, % change in mean (SD)
39.2 (79.2)
94.8 (107.9)
<0.001
bsAP, % change in mean (SD)
4.1 (17.2)
25.3 (24.9)
<0.001
OC, % change in mean (SD)
30.3 (43.5)
71.0 (74.3)
<0.001
P1NP, % change in mean (SD)
10.6 (38.7)
58.8 (61.4)
<0.001
P-values were from the Wilcoxon rank sum test; CTx = Type 1 collagen crosslinked C-telopeptide; 
bsAP = serum bone specific alkaline phosphatase; OC = osteocalcin; P1NP = procollagen Type 1 N-terminal propeptide.
1.2.4.6.4.
Week 24 Conclusions
Key conclusions from the Week 24 analysis of Study GS-US-292-0102 included the following:

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 24 was similar 
between treatment groups

Treatment was generally well tolerated as most AEs were mild and not associated with 
treatment discontinuation. No new or unexpected adverse events occurred.

The data shows that subjects taking E/C/F/TAF had more modest changes in creatinine and 
in bone mineral density than subjects taking E/C/F/TDF. The differences were statistically 
significant and may have important clinical relevance for individual subjects.
Other than renal lab abnormalities and biomarkers and bone biomarkers, the frequency and type 
of laboratory abnormalities was comparable between the two treatment arms.
1.3.
Rationale for This Study
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B
Approximately one-third of the world’s population has serological evidence of past or present 
HBV infection with over 350 million people globally who are chronic HBV surface antigen 
(HBsAg) carriers. The disease burden for HBV varies regionally, with greater than 50% of all 
subjects residing in Asian countries with the highest prevalence (e.g. China, India, Vietnam, 
Indonesia, South Korea, Taiwan, the Philippines, and Pakistan). The primary goal of treatment is 
to achieve and maintain virologic suppression, without resistance, which has been shown to 


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translate to improvement in liver disease outcomes. Current guidelines recommend treatment for 
subjects with evidence of ongoing viral replication along with liver injury based on elevated 
levels of serum ALT. 
TDF and ETV are highly potent first line therapies for CHB; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically 
lamivudine-experienced/resistant subjects {Baldick et al 2008, Tenney et al 2009}. The latter is a 
key limitation for ETV use as LAM remains one of the most commonly prescribed HBV 
treatments in most regions of the world. Thus, despite the availability of effective treatments 
there remains a clear need for newer oral HBV agents that are safe and well tolerated for long 
term use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development. 
Tenofovir alafenamide (TAF), a novel prodrug of TFV, has the potential to further advance the 
treatment of chronic HBV infection. In contrast to TDF, an agent that is rapidly and completely 
cleaved by intestinal and plasma esterases to TFV, TAF is a more stable prodrug that efficiently 
resists early enzymatic cleavage following oral administration and remains more fully intact until 
it is taken up by target cells. As a consequence, TAF, when given at a lower dose than TDF, is 
capable of efficiently delivering active drug (e.g. TFV-DP) to the virally-infected cells 
(e.g. HBV-infected hepatocytes and HIV-infected lymphoid cells) while systemic exposures of 
TFV are reduced compared with oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication, and an 
improved tolerability and safety profile.
Results from GS-US-320-0101, a Phase 1b study evaluating the short-term (28 day) safety, 
efficacy (HBV DNA suppression), and PK of TAF at 4 dose levels (8 mg, 25 mg, 40 mg, 
and 120 mg) compared to TDF 300 mg, has shown no dose effect in regard to viral suppression, 
and similar short-term safety and tolerability compared with TDF. Intensive PK results show 
93% or greater reductions in TFV exposures with doses of TAF 25 mg or lower compared to the 
TFV exposures generated with TDF 300 mg. These results, taken together with 24 weeks safety 
results from the HIV Phase 2 study GS-US-292-0102, which directly compares TAF to TDF 
(each included as a component of an STR), suggest that TAF is safe and well tolerated and may 
have a lower potential for renal- and bone-related AEs compared to TDF. Importantly, TFV 
exposures for E/C/F/TAF 10 mg are comparable to TFV exposures generated with TAF 25 mg 
given as a stand alone agent.
1.3.2.
Rationale for the Current Study
TDF and ETV are highly potent first line therapies for chronic HBV; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically lamivudine 
(LAM)-experienced/resistant subjects. Thus, despite the availability of effective treatments there 
remains a clear need for newer oral HBV agents that are safe and well tolerated for long term 
use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development. TAF has the potential to address each of these requirements. 


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The current study is designed to evaluate non-inferiority of TAF compared to TDF in regard to 
the proportion of subjects with HBV DNA levels below 29 IU/mL at Week 48. The durability of 
TAF compared to TDF in regard to the proportion of subjects with HBV DNA < 29 IU/mL at 
Weeks 96 and 144 will also be assessed in a double blind fashion. In addition to treatment naïve 
subjects, treatment experienced CHB subjects who are viremic and with elevated ALT levels at 
screening are included. This is based on given results from GS-US-174-0106 (ADV suboptimal 
responders) and GS-US-174-0121 (LAM-resistant subjects) which demonstrated in viremic 
patients comparable rates of HBV DNA suppression, as described below, in comparison to 
results in mostly treatment naïve subjects participating in pivotal studies GS-US-174-0102 
(HBeAg-negative subjects) and GS-US-174-0103 (HBeAg-positive subjects). Given the unique 
properties of TAF (efficient delivery of the active moiety, TFV-DP, to HBV-infected 
hepatocytes with reduced systemic TFV exposures), this study will also evaluate the potential 
safety differences (e.g. renal- and bone-related complications) of TAF relative to TDF at
Week 48 and long term comparative safety at Week 96 and 144, after which subjects will be 
further evaluated for longer-term safety and efficacy of TAF in an open-label TAF 25 mg QD 
extension phase through Week 384. The extension phase is important as it will enable the 
evaluation of subjects treated for the entire 384 week period with TAF as well as those who 
received 144 weeks of TDF initially in a double-blinded fashion followed by an additional 
240 weeks of open-label TAF. The latter group will allow an ongoing assessment, including 
possible resolution, of any potential bone- and/or renal-related (or other) complications during 
TAF treatment that might have arisen under initial treatment with TDF.
The primary endpoint of this study is the proportion of subjects with HBV DNA < 29 IU/mL at 
Week 48; the lowest limit of susceptibility of the polymerase chain reaction (PCR) assay to be 
employed (Roche COBAS® Taqman® HBV test for use with the High Pure System). A
histological component of treatment response is not included. Alternatively, non-invasive means 
(i.e. Fibrotest®) will be used to assess the degree of fibrosis at baseline and the change in fibrosis 
on an annual basis for all subjects participating in the trial. In support of this, 48 week results 
from studies, GS-US-174-0102 and GS-US-174-0103, which formed the basis for TDF approval 
for CHB, showed TDF to be superior to ADV based on a “complete response” to treatment 
(a composite endpoint of HBV DNA suppression and histologic improvement based on repeat 
liver biopsy). In GS-US-174-0102, conducted in HBeAg-negative (presumed pre-core mutant) 
subjects, 70.8% and 48.8% of subjects randomized to TDF and ADV, respectively, achieved a 
complete response at Week 48 (treatment difference: 23.5%; p < 0.001). Of the components, 
HBV DNA suppression (< 69 IU/mL) was achieved in 94.4% and 64.0% (treatment difference: 
30.3%; p < 0.001), while histologic improvement was achieved in 74.2% and 68.8% 
(treatment difference: 5.2%; p = 0.292) of TDF- and ADV-treated subjects, respectively. Thus, 
the greater potency of TDF relative to ADV resulting in a significantly higher rate of viral 
suppression was the primary element associated with the superior treatment response at 48 weeks
{Marcellin et al 2007, Marcellin et al 2008}. Similar findings were observed in HBeAg-positive 
subjects in GS-US-174-0103.
After 48 weeks, subjects in GS-US-174-0102 and GS-US-174-0103 were eligible to continue 
open-label treatment with TDF. At Year 5 (Week 240), 331/641 (52%) of subjects on TDF 
(without addition of FTC) underwent a repeat liver biopsy, and regression of fibrosis 


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(improvement in Ishak fibrosis score of ≥1 point) was seen in 52% (172/331) of subjects. 
Furthermore, in 94/331 (28%) subjects with cirrhosis (Ishak score ≥5) at baseline, 73% (69/94) 
were no longer cirrhotic at year 5 (≥1 unit decrease in Ishak score). These results confirm the 
benefits of long term viral suppression with TDF in terms of regression of fibrosis and reversal 
of cirrhosis in the majority of TDF-treated subjects {Marcellin et al 2013}.
The efficacy of TDF in viremic treatment experienced CHB populations has been shown to be 
similar to treatment naïve subjects. In a prospective, randomized (1:1), double-blind, Phase 3b 
study (GS-US-174-0121) which compared TDF alone to the combination of FTC/TDF in 
280 HBeAg-positive and HBeAg-negative subjects receiving treatment with LAM and having 
HBV DNA > 3 log10 IU/mL with documented LAM-resistance (rtM204I/V ± rtL180M 
mutation[s]), 89.4% of TDF-treated subjects vs. 86.3% treated with FTC/TDF had HBV DNA 
< 69 IU/mL at Week 96 (primary endpoint, missing equals failure analysis; p = 0.43). BMD was 
also assessed in GS-US-174-0121, and small declines in BMD (< 2%) of both hip and spine were 
seen with equal frequency in both groups which occurred by Week 24 (spine) and Week 72 
(hip). In another prospective, randomized, double-blind study of TDF vs. FTC/TDF in 
105 HBeAg-positive and HBeAg-negative subjects with a prior suboptimal response to ADV 
(GS-US-174-0106), no differences in HBV DNA suppression (proportion less than 69 IU/mL) 
were seen between treatment groups (82.4% TDF vs. 84.0% FTC/TDF; ITT, non-completer 
equals failure; p = 0.78). Taken together, these studies support the efficacy of TDF in treatment 
experienced subjects as being similar to results seen in treatment naïve subjects.
1.3.3.
Rationale for Dose Selection
In the Phase 1b study, GS-US-320-0101, which has completed enrollment, 4 doses 
(8, 25, 40, and 120 mg) of TAF monotherapy, and TDF 300 mg were evaluated in 
51 treatment naïve CHB subjects. To date, all subjects have completed the 28 day dosing period. 
Results demonstrate that TAF when given in doses over a range of 8 to 120 mg results in similar 
HBV DNA declines over 28 days. Furthermore, HBV DNA suppression with TAF is comparable 
to that of TDF 300 mg. In GS-US-320-0101, increased rates of viral suppression were not 
observed with higher TAF doses (40 mg, 120 mg) relative to lower TAF doses 
(8 mg and 25 mg), and similar safety profiles were observed among TAF treatment groups. PK 
results demonstrate a 93% reduction in TFV exposures relative to TDF 300 mg when TAF is 
dosed at 25 mg. These results in CHB subjects are consistent with data in healthy volunteers and 
HIV-infected subjects given TAF 25 mg as a stand alone agent. Importantly, as previously 
stated, the TFV exposures seen with TAF 25 mg in CHB subjects are therapeutically comparable 
to those in HIV patients receiving E/C/F/TAF 10 mg (due to an inhibitory drug-drug interaction 
between TAF and COBI when these agents are included in the E/C/F/TAF STR) which provide 
safety data (from Phase 2 study GS-US-292-0102) supporting the development of TAF for 
hepatitis B at the 25 mg dose level. Further, in CHB subjects participating in the Phase 1b study 
who were dosed at the lowest TAF dose (8 mg), a 97% reduction in TFV exposures relative to 
TDF 300 mg was observed, representing an incremental reduction in TFV exposure of only 
5% at this dose level relative to TAF 25 mg.


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Importantly, the TFV exposures at a 25 mg dose when given alone are consistent with TAF 
exposures generated with the E/C/F/TAF 10 mg STR currently in Phase 3 development for 
treatment of HIV infection. Thus, the efficacy and safety of TAF in HIV is also being evaluated 
at a dose level that is therapeutically equivalent to the dose selected for study GS-US-320-0108.
Final Week 24 results from GS-US-292-0102, a phase 2 study being conducted in HIV-1 
treatment naïve subjects, demonstrated similar safety and tolerability of TAF vs. TDF when each 
is included as a component of STRs containing elvitegravir, cobicistat, and emtricitabine. At 
Week 24, significant differences were noted between arms in regard to smaller declines in hip 
BMD, estimated CLCr (Cockcroft-Gault), and changes in various biomarkers of bone and renal 
function which are suggestive of differences in bone and renal tolerability of TAF vs. TDF. 
Similar assessments are included in the present trial in HBeAg-negative, chronic HBV subjects, 
and the study is sufficiently powered to demonstrate a potentially superior safety profile for TAF 
relative to TDF in regard to these bone and renal parameters.
In summary, a 25 mg dose was selected for TAF for use in this non-inferiority trial based upon 
the safety profile for TAF in treatment naïve HIV-1-infected subjects from GS-US-292-0102, 
which utilizes a therapeutically equivalent TAF dose (10 mg as a component of the E/C/F/TAF 
STR), the viral suppression results in chronic HBV subjects in GS-US-320-0101 showing 
comparable rates of HBV DNA decline for a TAF 25 mg dose compared to TDF 300 mg 
(the approved dose for treatment of HBV), and the reduced systemic TFV exposures (~93%) 
seen with TAF relative to TDF 300 mg, when dosed at this level.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative,
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL 

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and 
treatment experienced subjects
The key secondary safety objectives of the study are:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization by central laboratory and AASLD criteria) 
response of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144


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
To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72 , 96, and 144 
(or ED visit if prior to Week 144 and more than 24 weeks since prior exam) in a subset of 
subjects

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and the incidence of drug resistance 
mutations of TAF 25 mg QD in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD and then switched to open-label 
TAF 25 mg QD


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a randomized, double-blind, non-inferiority study to compare the antiviral activity of 
TAF 25 mg QD versus TDF 300 mg QD. Approximately three hundred ninety (390) subjects 
will be randomized in a 2:1 ratio (A:B) to the treatment arms for 144 weeks (96 weeks under 
Amendment 2.1), and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced).
For China, approximately 150 additional subjects will be randomized in a 2:1 ratio (A: B) to the 
treatment arms for 96 weeks, and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced). 
If the subject is deemed ineligible for this study by HBV serology (i.e. HBeAg positive CHB), 
this information may be used to determine eligibility for GS-US-320-0110 
(another Gilead Sciences Phase 3 study in HBeAg positive, CHB subjects; this study must also 
be IRB/EC approved at the participating center). 
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD
For China, approximately 150 additional subjects (100 in Treatment Arm A and 50 in 
Treatment Arm B) will be enrolled for local registration purposes.
Subjects with a history of or current diagnosis of compensated cirrhosis are eligible for 
enrollment. Acceptable diagnostic criteria for cirrhosis include a Metavir or Knodell fibrosis 
score ≥4 or Ishak fibrosis score ≥ 5 by liver biopsy, or previous Fibroscan result > 12kPa 
(in countries where locally approved). Available information regarding the presence or absence 
of cirrhosis by these criteria will be captured in the electronic case report forms at Baseline, and 
any other time during the trial should an investigator opt to undertake additional studies. 
Importantly, the change in fibrosis as assessed by Fibrotest® will be performed in all subjects 
participating in the trial at Baseline, and annually thereafter through Week 384/ED.
The duration of double-blind treatment is 144 weeks (96 weeks under Amendments 2.1). At 
Week 144, all subjects remaining on blinded treatment will be switched to the open-label TAF 
25 mg QD extension period for up to an additional 240 weeks (Week 144 through 
Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at Week 96 per 
Amendment 2.1 will continue on open-label TAF 25 mg QD through Week 384/ED. All subjects 
who complete the double-blind period of treatment are eligible for participation in the open label 
TAF 25 mg QD extension period. Subjects who permanently discontinue study drug 
(either prematurely [ED] or at the end of study [Week 384]) for reasons other than HBsAg loss 
with confirmed seroconversion to anti-HBs, will be followed every 4 weeks for 24 weeks off 
treatment or until initiation of alternative, commercially available HBV therapy, whichever 
occurs first. 


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Subjects with HBsAg loss with confirmed seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion to anti-HBs prior to Week 48 are not permitted to 
discontinue study drug prior to the Week 48 visit. After Week 48, these subjects who discontinue 
study drug will be followed off treatment every 4 weeks for 12 weeks and then per the study visit 
schedule (Appendix 2) through Week 384/ED. Discontinuation of study drug for subjects 
experiencing HBsAg loss with confirmed seroconversion to anti-HBs, who have known bridging 
fibrosis or cirrhosis, should be considered on a case by case basis.
Figure 3-1.
Study Schema
3.2.
Biomarker Testing
3.2.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected in this study and will be used to evaluate 
the association of exploratory systemic and/or tissue specific biomarkers with study drug 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the biomarkers and assays listed below. Because biomarker science is a rapidly evolving area 


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of investigation, and adverse events in particular are difficult to predict, it is not possible to 
specify prospectively all tests that will be done on the specimens provided. The testing outlined 
below is based upon the current state of scientific knowledge. It may be modified during or after 
the end of the study to remove tests no longer indicated and/or to add new tests based upon the 
growing state of art knowledge. 

Blood sample for bone biomarkers – including, but not limited to, C-type collagen sequence 
(CTX) and procollagen type 1 N-terminal propeptide (P1NP)

Urine sample for renal biomarkers −including, but not limited to, retinol binding protein and
beta-2-microglobulin
These specimens will be collected from all subjects in a fasted state.
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research
A separate, specific consent form will be required to document a subject’s agreement to provide 
additional samples for optional pharmacogenomic research. From subjects who agree to 
participate and provide their additional specific consent, a blood sample will be obtained. This
sample should be collected at the Baseline visit, prior to the first dose of study drug, but may be 
collected at any time during the study or at a separate unscheduled study visit, if necessary. The 
specimens collected for optional pharmacogenomic research will be used to identify or validate 
genetic markers that may increase our knowledge and understanding of the biology of the study 
disease and related diseases and to study the association of genetic markers with disease 
pathogenesis, progression and/or treatment outcomes, including efficacy, adverse events, and the 
processes of drug absorption and disposition. These specimens may be used also to develop 
biomarker or diagnostic assays and establish the performance characteristics of these assays. The 
collection and analysis of optional future research specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for subjects in the future.
3.3.
Intensive PK Substudy (Optional)
For subjects who provide a separate informed consent (n=16 and up to n=32), an intensive 
pharmacokinetic substudy will be performed once at either of the Week 4, 8 or 12 visits, at select 
sites to assess intensive PK profiling in plasma. 
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the intensive PK substudy visit. This will be used to 
evaluate PBMC concentrations of tenofovir diphosphate (TFV-DP), the active form of tenofovir 
(TFV).


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3.4.
Ophthalmologic Substudy (Optional)
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to 
assess ophthalmologic findings, including fundoscopic examination with retinal photographs 
(both eyes), anytime during the screening period, and must be completed prior to the first dose of 
study drug, and at Weeks 24, 48, 72, 96 and 144/ visits at select sites. An exam should be 
performed at the ED visit if prior to Week 144 and not done within the past 24 weeks.
An examination of the full retinal field should be conducted noting changes or abnormalities. 
Photographs of the retina must be taken at each exam and filed in the subject’s source medical 
records. A central vendor will be used to assess the retinal photographs.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 390 subjects, who are 18 years of age and older, with HBeAg-negative chronic 
hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 300 mg 
matched placebo (n = 260) or TDF 300 mg and TAF 25 mg matched placebo (n = 130) for 
144 weeks (96 weeks under Amendment 2.1).
For China, approximately 150 subjects, who are 18 years of age and older, with HBeAg-negative 
chronic hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 
300 mg matched placebo (n = 100) or TDF 300 mg and TAF 25 mg matched placebo (n = 50) 
for 96 weeks.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures.
2. Male and non-pregnant, non-lactating female subjects, 18 years of age and older, based on 
the date of the screening visit. A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in Appendix 6).
3. Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 
6 months).
4. HBeAg-negative, chronic hepatitis B with all of the following:

HBeAg-negative and HBeAb-positive at Screening (if the subject is deemed ineligible for 
this study by HBV serology [i.e. HBeAg-positive CHB], this information may be used to 
determine eligibility for GS-US-320-0110 [another Gilead Sciences Phase 3 study in 
HBeAg-positive, CHB subjects; this study must also be IRB/EC approved at the 
participating center])

Screening HBV DNA ≥ 2 × 104 IU/mL

Screening serum ALT level 60 U/L (males) or > 38 U/L (females) and ≤10 × ULN 
(by central laboratory range)


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5. Treatment-naïve subjects (defined as < 12 weeks of oral antiviral treatment with any 
nucleoside or nucleotide analogue), OR treatment-experienced subjects (defined as subjects 
meeting all entry criteria [including HBV DNA and serum ALT criteria] and with 
> 12 weeks of previous treatment with any nucleoside or nucleotide analogue) will be 
eligible for enrollment. Treatment-experienced subjects receiving oral antiviral treatment at 
Screening must continue their treatment regimen until the time of randomization, when it will 
be discontinued.
6. Any previous treatment with interferon (pegylated or non-pegylated) must have ended at 
least 6 months prior to the baseline visit. 
7. Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the Screening evaluation, 
as follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8. Normal ECG (or if abnormal, determined by the investigator not to be clinically significant)
9. Must be willing and able to comply with all study requirements.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study.
2. Males and females of reproductive potential who are unwilling to use an “effective”, 
protocol-specified method(s) of contraception during the study. For a list of 
protocol-specified contraceptive methods, refer to Appendix 6. 
3. Co-infection with HCV, HIV, or HDV.
4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5. Any history of, or current evidence of, clinical hepatic decompensation 
(e.g., ascites, encephalopathy or variceal hemorrhage).  
6. Abnormal hematological and biochemical parameters, including:

Hemoglobin < 10 g/dL

Absolute neutrophil count < 750/mm3


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
Platelets ≤50,000/mm3

AST or ALT > 10 × ULN

Total Bilirubin > 2.5 × ULN

Albumin < 3.0 g/dL

INR > 1.5 × ULN (unless stable on anticoagulant regimen)
7. Received solid organ or bone marrow transplant.
8. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator.
9. Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures.
10. Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
11. Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational 
agents, nephrotoxic agents, or agents capable of modifying renal excretion.
12. Known hypersensitivity to study drugs, metabolites, or formulation excipients.
13. Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance.
14. Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
15. Subjects on prohibited concomitant medications (See Table 5-1). Subjects on prohibited 
medications, otherwise eligible, will need a wash out period of at least 30 days.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
A centralized randomization procedure via an Interactive Voice/Web Response System 
(IVRS/IWRS) will be used for this study, whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. If the subject is deemed ineligible for this study by HBV serology 
(i.e. HBeAg-positive CHB), this information may be used to determine eligibility for 
GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg-positive, CHB subjects; this 
study must also be IRB/EC approved at the participating center). Eligible subjects will be 
randomized 2:1 to receive either blinded TAF 25 mg and TDF matched placebo or TDF 300 mg 
and TAF matched placebo for 144 weeks (96 weeks under Amendment 2.1). Subjects will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, ≥7 log10 IU/mL - < 8 log10 IU/mL, 
≥8 log10 IU/mL) and oral antiviral treatment status (treatment-naïve vs. treatment-experienced). 
At Week 144, all subjects will be switched to open label TAF 25 mg QD up to an additional
240 weeks (Week 144 through Week 384/ED). Subjects already assigned to open-label 
TAF 25 mg QD at Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED.
For the entire duration of the study, subjects and investigator will remain blinded to the initial 
treatment regimen to which the subjects were randomized.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IVRS/IWRS
for that subject. Gilead recommends, but does not require that the investigator contact the 
Gilead Medical Monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report form/ 
electronic case report form (CRF/eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead Medical Monitor promptly in 
case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (TAF). The tablets are yellow, round-shaped, and film-coated. 
The tablets are debossed with “GSI” on one side and “25” on the other side. In addition to the 
active ingredient, each film-coated tablet contains the following inactive ingredients: 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. 
5.2.1.2.
Placebo to match TAF Tablets
Placebo tablets to match TAF 25 mg are yellow, round-shaped, and film-coated. The tablets are 
debossed with “GSI” on one side and “25” on the other side. Each tablet contains the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
yellow iron oxide. 
5.2.1.3.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF)
TDF 300 mg tablets contain 300 mg of tenofovir disoproxil fumarate (TDF), which is equivalent 
to 245 mg of tenofovir disoproxil. The tablets are light blue, almond-shaped, plain-faced, and
film-coated. Each tablet contains the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose (hydroxypropyl methylcellulose), 
glycerol triacetate, titanium dioxide, and indigo carmine aluminum lake.
5.2.1.4.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF) to be Used in 
Developing Markets
TDF 300 mg tablets to be used in developing markets contain 300 mg of tenofovir disoproxil 
fumarate (TDF), which is equivalent to 245 mg of tenofovir disoproxil. The tablets are white, 
almond-shaped, film-coated, debossed with “GILEAD” and “4331” on one side and plain-faced 
on the other side. Each tablet contains the following inactive ingredients: microcrystalline 
cellulose, lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium 
stearate. The film coating contains lactose monohydrate, hypromellose, triacetin and titanium 
dioxide.


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5.2.1.5.
Placebo to match TDF Tablets
Placebo tablets to match TDF 300 mg are light blue, almond-shaped, plain-faced, film-coated 
tablets. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose 
(hydroxypropyl methylcellulose), triacetin, titanium dioxide, and indigo carmine aluminum lake. 
5.2.1.6.
Placebo to Match TDF Tablets to be Used in Developing Markets
Placebo tablets to match TDF 300 mg for developing markets are white, almond-shaped, 
film-coated tablets, debossed with “GILEAD” and “4331” on one side and plain-faced on the 
other side. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose, 
triacetin, and titanium dioxide.
5.2.2.
Packaging and Labeling
TAF, TDF, and their matched placebo tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant and polyester coil. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap fitted 
with an induction-sealed, aluminum-faced liner. 
To ensure stability of the tablets and proper product identification, the drug should not be stored 
in a container other than the container in which it is supplied.
All labels for study drug bottles to be distributed to centers in the US, EU and the rest of the 
countries will meet all applicable requirements of the US Food and Drug Administration (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
TAF, TDF, and their matched placebo 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), inclusive. 
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures.
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos
Subjects will be randomly assigned (2:1) to receive one of the following treatments in a blinded 
fashion:
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD


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For China, approximately 150 additional subjects will be randomized 2:1 to receive either 
Treatment A (n = 100) or Treatment B (n = 50) for 144 weeks.
After 144 weeks of blinded randomized treatment (96 weeks under Amendment 2.1), each 
subject will switch to open-label TAF 25 mg QD for up to an additional 240 weeks
(Week 144 through Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED. 
It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
All study drugs should be taken at approximately the same time each day with food.
Observed in-clinic study drug dosing is required at Weeks 4 and 12 visits. Subjects who elect to 
dose in evening are not required to have in-clinic dosing and the single PK blood sample 
collection at the Week 4 and 12 visits.
Study drug should be administered after assessing adverse events and concomitant medication(s).
5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
Concomitant use of some medications including herbal/natural products/therapies and over the 
counter medications with TAF may result in PK interactions.
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
including herbal/natural products/therapies, and over the counter medications, the 
Gilead Sciences 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.
The following medications are excluded while subjects are participating in the study. These 
medications are prohibited during the screening period and for a minimum of 30 days prior 
to the Baseline/Day 1 visit through the end of treatment:

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir (e.g., 
cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)


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
Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or 
immunomodulating agents

Bisphosphonates

Investigational agents (unless approved by Gilead Sciences)

Medications excluded due to the potential for drug-drug interaction with TAF (Table 5-1)
Treatment-experienced subjects (defined as subjects meeting all entry criteria 
[including HBV DNA and serum ALT criteria] and with ≥12 weeks of previous treatment with 
any nucleoside or nucleotide analogue) receiving oral antiviral treatment at Screening must 
continue their treatment regimen until the time of randomization/Baseline/Day 1, when it will be 
discontinued.
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution 
Due to the Potential for Drug-Drug Interaction with Study 
Medication
Medication Class
Prohibited Medications
Medications to be used with caution
Analeptic
Modafinil
Antiarrhythmics
Amiodarone, Quinidine: may increase 
concentration of TAF and/or TFV
Antibacterials
Clarithromycin: may increase concentration of 
TAF and/or TFV
Anticonvulsants
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Voriconazole
Itraconazole, Ketoconazole: may increase 
concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Calcium channel blockers
Diltiazem, Felodipine, Verapamil: may increase 
concentration of TAF and/or TFV
Digoxin
Digoxin: concomitant use may result in an 
increased or decreased level; use with caution 
and with appropriate monitoring of serum 
digoxin levels. Digoxin therapy should be 
initiated at the lowest dose, and the dose should 
be titrated to clinical response.
Herbal/Natural Supplements
St. John’s Wort, Echinacea, 
Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)


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5.5.
Accountability for Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product (IMP) kits and/or bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP kits and/or bottles dispensed to subjects must be returned to the site.
Investigational product accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits and/or bottles returned, along with the 
initials of the person recording the information
5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. A copy of the site’s 
SOP will be obtained for central files. Where possible, study drug will be destroyed at the site. 
Upon study completion, a copy of the Investigational Drug Accountability records must be filed 
at the site. Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the 
investigator must maintain accurate records for all study drug kits and/or bottles destroyed. 
Records must show the identification and quantity of each unit destroyed, the method of 
destruction, and person who disposed of the drug. All study drug records must be maintained at 
the site and copies must be submitted to Gilead Sciences at the end of the study. 


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Amendment 3.1
CONFIDENTIAL
Page 69
23 February 2016
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 described in the text that follows. 
Any deviation from protocol procedures should be documented and the sponsor or the contract 
research organization (CRO) should be notified.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment. Once consent has been obtained, all screening tests and procedures 
have been completed, and study eligibility has been confirmed, subjects will be randomized
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 5.1. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principal Investigator’s opinion, the retest value will be within accepted parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample); or due to an extenuating circumstance.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 45 days before Baseline to determine eligibility for participation 
in the study. The following will be performed and documented during the screening period:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history, including HBV history

Review concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Complete physical examination including vital signs (blood pressure, pulse, respiration rate 
and temperature), body weight, and height


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Amendment 3.1
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
ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (at sites in China with capability only). DXA scan will be 
performed at any time during the Screening period and should be completed at least 14 days 
prior to the first dose of the study drug, in order to ensure an acceptable pre-dose DXA scan

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required) 
– to be performed at any time during the Screening period and prior to the first dose of the 
study drug 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HIV-1, HDV, HCV, serum pregnancy test (for females of child-bearing potential), 
α-fetoprotein (AFP) and INR. An AFP > 50 ng/mL at Screening must have an appropriate 
evaluation (e.g. CT scan) in order to rule out HCC prior to being permitted to enter the study

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days for randomization into the study. If the subject is deemed ineligible for this 
study by HBV serology (i.e. HBeAg-positive CHB), this information may be used to determine 
eligibility for GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg positive, CHB 
subjects; this study must also be IRB/EC approved at the participating center).
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the adverse events case report form (CRF/eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history are to 
be captured on the medical history CRF/eCRF. See Section 7, Adverse Events and Toxicity 
Management for additional details.
6.2.2.
Baseline Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug. Subjects screened within 45 days before Baseline will be eligible to participate in the 
study. Initiation of treatment with study drug should take place on the day of the Baseline visit. 
The following will be performed at the Baseline visit:

Review of inclusion/exclusion criteria and confirm medical history

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
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
Review concomitant medications

Review adverse events 

Assess future risk of bone fracture using the Fracture Risk Assessment tool (FRAX®; at sites 
in China with DXA capability only)

Randomization

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HBV genotyping (A-H), virology (resistance surveillance), serum and plasma for storage, 
IL28B genotype, and vitamin D assessment

Cystatin C testing for estimated glomerular filtration rate (eGFR) by CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration)

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Optional blood sample for biomarker/pharmacogenomics (separate consent required prior to 
obtaining sample)
6.3.
Treatment Assessments
6.3.1.
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144)
Study visits Weeks 4 – 44 and Week 56 - 88 should be completed ± 3 days of the protocol 
specified visit date, based on the Baseline Visit.
Study visit Week 48 should be completed −14 days of the protocol specified visit date, based on 
the Baseline Visit.
Study visits Weeks 96, 108, 120, and 132, and 144 should be completed ± 14 days of the 
protocol specified visit date, based on the Baseline Visit.


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6.3.1.1.
Week 4

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – Can also be done at Weeks 8 or 12 
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours, except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose (subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample) 


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Amendment 3.1
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23 February 2016

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.2.
Week 8

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – If not done at Week 4; can also be done at Week 12
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 74
23 February 2016

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and storage
6.3.1.3.
Week 12

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – If not done at Weeks 4 or 8, must be completed by this visit.
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose


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Protocol GS-US-320-0108
Final
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Amendment 3.1
CONFIDENTIAL
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
Dispense blinded study drugs

Dose in clinic and collect single plasma PK sample between 15 minutes to 4 hours post-dose
(subjects who elect to dose in the evening the previous day are not required to have in-clinic 
dosing and provide the single PK sample)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.4.
Weeks 16, 20, 28, 32, 40, and 44

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.5.
Week 24

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.6.
Week 36

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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6.3.1.7.
Week 48

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (within −14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.8.
Weeks 56 and 88

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature


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Final
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Amendment 3.1
CONFIDENTIAL
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23 February 2016

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.9.
Weeks 64, 80, 108, and 132

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF at all 
subsequent visits)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
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6.3.1.10.
Week 72

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.11.
Weeks 96 and 120

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording) [Week 96 only]

Hepatic ultrasound for surveillance of hepatocellular carcinoma

DXA scan of spine and hip to be performed (within ± 14 days of the expected visit date; at 
sites in China with capability only)


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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
Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (For Week 120, subjects already assigned to open-label TAF 
25 mg QD at Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF)

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest® [Week 96 only]

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
[Week 96 only]
6.3.1.12.
Week 144

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ± 14 days of the expected Week 144 visit 
date; at sites in China with capability only)

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Review concomitant medications

Review adverse events 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016

Retrieve study drug and perform study drug accountability

Dispense open label TAF 

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
At ED visit, ophthalmologic assessment should be performed only if not done within the 
last 12 weeks
6.3.2.
Open Label Visits
Study visits Weeks 168 through 384/ED should be completed ± 28 days of the protocol specified 
visit date, based on the Baseline Visit.
6.3.2.1.
Weeks 168, 216, 264, 312, and 360

Symptom directed physical exam

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 


Tenofovir Alafenamide (TAF)
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Final
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Amendment 3.1
CONFIDENTIAL
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
Perform open-label study drug accountability

Dispense open-label TAF

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.2.2.
Weeks 192, 240, 288, 336, and 384/ED
The ED Visit should be performed within 72 hours (i.e., visit window is within 3 days) of 
the last study drug dose.

Symptom directed physical exam (At Week 240 and 384/ED, a complete physical exam 
should be performed) 

Hepatic ultrasound for surveillance of hepatocellular carcinoma
At ED visit, Hepatic ultrasound should be performed only if not done within the prior 
24 weeks

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ±28 days of the expected visit date; at 
sites in China with DXA capability only)
At ED visit, DXA scan should be performed only if not done within the prior 24 weeks

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability 

Dispense Open Label TAF (no study drug will be dispensed at Week 384/ ED visit)


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAb and reflex HBsAg), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

For ED visit prior to Week 144 only, if not performed within the prior 24 weeks:
Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.4.
Post-treatment Assessments
6.4.1.
HBsAg Loss and Seroconversion Subjects
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to 
anti-HBs on or after the Week 48 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the study visit schedule through Week 384/ED (excluding drug 
dispensation and accountability).
6.4.2.
All other subjects who discontinue study drug
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be 
followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.4.3.
Follow up visit assessments (all subjects)
Treatment-free Follow Up Visits should be completed ±7 days from the protocol-specified visit 
date, determined by the date the subject discontinued the study drug.

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature 


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
Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
serum for storage, HBV serology (HBsAg and reflex HBsAb at Follow Up visits 
Weeks 12 and 24), and serum HBsAg (quantitative) 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis
6.5.
Early Discontinuation (ED) from Study
If a subject discontinues study medication dosing for reasons other than HBsAg loss with 
confirmed seroconversion to anti-HBs (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related visits 
and procedures. If this is not possible or acceptable to the subject or investigator, the subject may 
be withdrawn from the study. Early Discontinuation Assessments are described in 
Section 6.3.2.2.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in 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

Subjects with confirmed creatinine clearance of < 30 mL/min at any time during the study 
will have their study drug permanently discontinued

Lack of efficacy (virologic failure)

HBsAg loss with seroconversion to anti-HBs. These subjects should discontinue study drug 
within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion before Week 48 are not permitted to discontinue 
study drug prior to the Week 48 visit

Discontinuation of study drug for subjects experiencing HBsAg loss with confirmed 
seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, should be 
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
Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.7.
Intensive Pharmacokinetic Substudy (Optional)
A PK substudy will be performed in a subset of subjects (n=16 and up to n=32) at selected study 
sites. Separate consent for the PK substudy is required. The substudy will include intensive PK 
profiling in plasma and will be conducted once at either of the Weeks 4, 8 or 12 visits. 
Blood samples will be collected at 0 (≤30 minutes pre-dose), 5 minutes, 15 minutes, 30 minutes, 
45 minutes, 1 hour, 1.5 hours, 2, 3, 4, 5, 8, 12 and 24 hours post-dose. 
Subjects participating in the PK substudy should not take their dose on the morning of the PK 
visit. Study medication will be administered in clinic on the morning of intensive PK. Subjects 
who have been routinely dosing in the evening will need to switch to a morning dosing regimen 
at least 10 days prior to the intensive PK visit. In addition, subjects should fast (no food or drinks 
for a minimum of 8 hours except water for up to 1 hour) prior to the scheduled intensive PK visit
After collection of the pre-dose sample, subjects will be provided a standardized, moderate fat 
meal (approximately 600 cal, 27% fat; Details can be found in the PK Manual). Within 
5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive 
PK sampling at the following time points will occur: 5, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 8, 12 
and 24 hours post-dose. Subjects will be restricted from further water intake until 2 hours after 
and food intake until 4 hours after dosing. The date and time of the subject’s previous dose will 
need to be collected in addition to the data at the PK substudy visit.
Details of pharmacokinetic blood sampling procedures and sample management will be 
documented in the Pharmacokinetic Sample Collection, Processing, Storage, and Shipment 
Manual.
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the time of the intensive PK substudy.
6.8.
Urine, Serum and Plasma for Storage
A portion of the blood samples collected at each visit starting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its research partners for HBV 
genotyping/phenotyping assays or their development, for retesting the amount of HBV in the 
blood, for measurement of antiviral drug levels in the blood, or for future testing to learn more 
about how the study drug has worked against HBV or clinical laboratory testing to provide 
additional safety data. No human genetic testing on this sample will be performed. 


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A portion of the urine samples collected at each visit starting at Baseline will be frozen and 
stored. These stored urine samples may be used by Sponsor for future renal and bone biomarker 
testing (in addition to the tests planned for the study).
At the conclusion of this study, these samples may be retained in storage by Gilead Sciences, 
Inc. for a period up to 15 years.
6.9.
Resistance Surveillance
Genotypic sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for 
resistance mutations will be conducted at Baseline for all subjects, and attempted for all viremic 
subjects (HBV DNA 69 IU/mL) at Week 48 and every 48 weeks until Week 384/ED visit. 
At Baseline, resistance surveillance will be conducted by INNO-LiPA Multi-DR v3 
(Innogenetics), which will determine the presence of HBV pol/RT mutations known to confer 
resistance to lamivudine, adefovir, entecavir, clevudine and/or telbivudine.  
Every 48 weeks post Baseline (if viremic), resistance surveillance will be conducted by 
population sequencing of the HBV pol/RT.
As it may not be known at the time of the visit whether a patient is viremic or if it will be their 
last study visit, a separate virology sample for potential resistance surveillance will be collected 
at each study visit. 
6.10.
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance
Subjects will undergo hepatic ultrasound assessments for HCC surveillance, beginning at 
Week 96, at 24 week intervals. Subjects who have completed the Week 96 visit 
(under Amendment 2.1) should begin ultrasound assessments at the next visit at which an 
ultrasound assessment is included (see Appendix 2 and Section 6 of the Protocol).
6.11.
End of Study
The end of this study will be the last subject’s last observation (or visit).


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

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.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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, and urinalysis) that require medical or 
surgical intervention or lead to IMP interruption, modification, 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 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigators is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified sub-investigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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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 procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
Severity of adverse events is to be determined based on GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). 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: 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 7.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all serious adverse events (SAEs) and 
adverse events related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4-weeks after last administration of study IMP. AEs must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead 
Sciences may request that certain AEs be followed beyond the protocol defined follow up period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. Any SAEs and deaths, regardless of causality, that occur during the post 
treatment follow-up period or within 30 days of the last dose of study drug, when subject 
transitions to alternative, commercially available HBV therapy, should also be reported.


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30-day 
period. However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document
and report the event to Gilead DSPH.

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 may be reported using a paper serious adverse event 
reporting form, but sites will transition to an electronic SAE (eSAE) system. Gilead will 
notify sites in writing and provide training and account information prior to implementing an 
eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH or to the designated CRO.
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 DSPH within 24 hours of the investigator’s knowledge of 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 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.


Tenofovir Alafenamide (TAF) 
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Safety: 
Medical Monitor: 
CONFIDENTIAL 
North America- PRA 
Email: CHOsafety@praintl.com, 
Final 
Amendment 3. 1 
Fax: 1-888-772-6919 
Europe (including Russian Federation), Asia Pacific - PRA 
Email: MHGSafety@PRAintl.com, 
Fax: +49-621-878-2181 
!wll! - KlinEra 
Email: safetyreporting@klinera.com, 
Fax: +91-22-25004588 
China, Vietnam - Quintiles 
Email: Ph V _ Gilead@quintiles.com 
Fax: 4001-206110 
Japan- CMIC 
Email: GPV _ GileadHB@cmic.co.jp 
Fax: +81-3-3493-5523 
North America- PRA 
Tel: 1.866.326.5053(toll-free) 
Tel: 1.434.951.4082 (direct) 
Fax: 1.800.280.7035 (toll-free) 
Fax: 1.913.307.5751 (direct) 
Email: Gilead320-08@prahs.com 
Europe (including Russian Federation), Asia Pacific- PRA 
Phone: +44 179 252 5608 
Fax: +49 621 878 2181 
Email: MedicEU@PRAintl.com 
India - KlinEra 
Vikram Vora, MD 
Phone: PPD 
Fax:IPPD 
Emml: PPD 
...._ _____ ..... 
China, Vietnam - Quintiles 
Ian Escudero 
Phone: '-P ... P"'D...----
Mobile: PPD 
Fax: PPD 
Email: PPD 
~--------~ 
Japan- CMIC 
Mistuhiro Omine 
Phone:PPD 
EmailP PD 
...._ ________ 
~ 
Page 91 
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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy. 
7.5.
Toxicity Management

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 4.

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 5).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.


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
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.

Administration of study drug may be discontinued due to a clinical or laboratory event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.5.2.
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.
7.5.3.
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 non-fasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product.


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7.5.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in 
bone mineral density for chronic HBV- infected patients, Gilead recommends that any subject 
who has a DXA scan that demonstrates a decrease from baseline of > 5% in bone mineral density 
of the spine region or the hip region be followed per local medical practice at the discretion of 
the investigator.
7.5.5.
Management of Potential Nephrotoxicity
Creatinine clearance (CLCr), estimated according to the Cockcroft-Gault formula, will be 
followed post-baseline during the study. All subjects with estimated CLCr < 50 mL/min must 
have serum creatinine measured again within 3 calendar days of receipt of results. At the time of 
this repeat serum creatinine assessment, Cystatin C will also be measured and the estimated 
glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be calculated and compared with 
the baseline measurement of this parameter. During the double-blind period, any subject, who 
has a confirmed CLCr estimated by the Cockroft-Gault formula < 50 mL/min and also 
experiences a > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline, will be 
managed as described below:
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499× max (Scys/0.8, 1)−1.328 ×
0.996Age [× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of
Scys/0.8 or 1, and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
Subjects meeting the above eGFR criteria (i.e. confirmed CLCr < 50 mL/min by Cockcroft-Gault 
equation and > 20% reduction from baseline in eGFR by CKD-EPI equation) will be managed as 
follows:

If the CLCr is confirmed to be ≥ 30 mL/min and < 50 mL/min, the subject will be required to 
undergo dose modification to every other day dosing of study drug during the double blind 
period only.

If the CLCr is confirmed ≥ 30 mL/min to < 50 mL/min and the subject has undergone dose 
modification to every other day dosing of study drug and subsequently develops a confirmed 
CLCr ≥50 mL/min, the subject may revert to once daily dosing of study drug after discussion 
with the Gilead Medical Monitor.

If the CLCr is confirmed to be < 30 mL/min at any time during the study, the subject will be 
required to permanently discontinue study drug.


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
All subjects with a change from baseline serum creatinine of ≥0.4 mg/dL must have serum 
creatinine repeated, with a concurrent urinalysis and urine chemistry, within two weeks of 
receipt of results. The following management will be required dependent upon the 
corresponding creatinine clearance value:
If creatinine clearance is < 50 ml/min, or the subject has other clinical and/or laboratory 
evidence of acute renal failure, the subject will be managed according to the guidance 
described above.
If creatinine clearance is ≥ 50 ml/min and the repeat testing of serum creatinine confirms 
a Grade 1 or Grade 2 serum creatinine elevation, it is recommended that subject be 
monitored weekly until the serum creatinine level returns to a value within the normal 
laboratory range.

All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis must have a urinalysis repeated, with a concurrent urinalysis and urine chemistry, 
within two weeks of receipt of results. Upon confirmation of new proteinuria, subjects will 
be asked to return to the clinic for a scheduled or unscheduled follow up visit for evaluation. 
It is recommended that the investigator contact the Gilead Medical Monitor to discuss if 
further consultation with a nephrologist is clinically warranted.
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × baseline 
value and >10 × ULN, with or without associated symptoms
7.5.6.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT > 2 × baseline and > 10 × ULN, the following is 
recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after 
initial laboratory results were drawn). During the visit, a clinical assessment of the subject
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
serum albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV, and 
HEV.


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Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable relative to baseline Liver Function Tests
If ALT levels are elevated (i.e., > 2 × baseline and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to baseline, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or baseline level. 
During monitoring, if the ALT values remain persistently elevated, the investigator should 
discuss with the Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × baseline and > 10 × ULN), and total bilirubin is confirmed 
to be 2 × baseline value, and INR is 0.5 above baseline, provided both are > ULN, the 
investigator should consider discontinuing study medication (upon discussion with the 
Gilead Medical Monitor, unless the safety of the subject is of immediate concern). 
The subject should be monitored weekly as long as ALT, total bilirubin, and INR values remain 
elevated or above baseline values.
During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
7.5.6.2.
Management of Exacerbation of Hepatitis in Subjects who have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation > 2 × baseline and > 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function 
(total bilirubin 2 × baseline, INR 0.5 above baseline, provided both are > ULN) and the subject is 
on no post-study therapy for HBV, the following is recommended:


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
Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV and 
HEV. If Plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy. 

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or baseline up to a maximum of 6 months after the initial occurrence of the event. 
7.5.7.
Management of Potential Posterior Uveitis Cases
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/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 administered is lower than that given in the dog study, nor 
have there been reports of posterior uveitis in human clinical studies thus far. Nonetheless, if any 
subject develops 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).
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.


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An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject 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).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. Refer to Section 7.3 and the CRF/eCRF completion guidelines for full 
instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion 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 AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Safety Dept. using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.


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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Special situations involving non-Gilead concomitant medications does 
not need to be reported on the special situations report form, however, for special situations that 
result in AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
form. Any inappropriate use of concomitant medications prohibited by this protocol should not 
be reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows: 

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96, and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144


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
To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in 
a subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in a subset of subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and incidence of drug resistance 
mutations of TAF 25 mg QD from Week 144 through Week 384 in subjects initially 
randomized to TAF 25 mg QD and in subjects sequentially treated with TDF 300 mg QD and 
then switched to open-label TAF
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Week 48.
8.1.3.
Secondary Endpoints
The key secondary safety endpoints are:

The percent change from baseline at Week 48 in hip BMD 

The percent change from baseline at Week 48 in spine BMD 

The change from baseline at Week 48 in serum creatinine 
8.1.4.
Other Endpoints of Interest

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Weeks 96 and 144

The proportion of subjects with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

The proportion of subjects with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 48, 96, and 144

The proportion of subjects with HBsAg loss at Weeks 48, 96, 144, 240, and 384


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
The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 48, 96, 144, 
240, and 384

The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96, 144, 240 
and 384

The incidence of drug resistant mutations at Weeks 48, 96, 144, 240, and 384

The change from baseline in ophthalmologic findings by fundoscopic examination at 
Weeks 24, 48, 72, 96, and 144 in a subset of subjects

The proportion of subjects with treatment-emergent proteinuria (by dipstick) at 
Weeks 48, 96, 144, 240, and 384
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis the Full Analysis Set (FAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the randomized treatment assignment.
8.2.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed 
according to the treatment actually received.
All data collected during treatment will be included in the safety summaries. Data collected 
during treatment free follow up will be summarized or listed separately.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are randomized and have received at least 
one dose of study medication and for whom concentration data of any analytes of interest 
(eg, TAF and TFV) are available. The PK analysis set will be used for analyses of general 
pharmacokinetics.
The PK substudy analysis set will include all subjects who are randomized and have received at 
least one dose of study medication and for whom steady-state PK parameters of analytes TAF 
and TFV are available. The PK substudy analysis set will be used for detailed pharmacokinetics 
analyses.
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.


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8.2.2.
Data Handling Conventions
For the primary endpoint missing data will be handled using a missing = failure approach, unless 
otherwise specified.
For key secondary safety endpoints, missing data will be handled via a Last Observation Carried 
Forward (LOCF) method.
For other categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach. For the drug resistant mutations endpoint, a missing = excluded
approach will be employed.
Sensitivity analyses will be performed as warranted.
8.3.
Multiplicity Adjustments
The primary hypothesis of non-inferiority between TAF 25 mg QD and TDF 300 mg QD with 
respect to the proportion of subjects with HBV DNA < 29 IU/mL will be tested first. If 
non-inferiority is established, then multiplicity adjustments will be performed for the secondary 
endpoints with a fallback procedure using the following weights:
a) Hip BMD (weight = 0.4)
b) Spine BMD (weight = 0.2)
c) Serum creatinine (weight = 0.4)


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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic summaries will include sex, race/ethnicity, geographical region, randomization 
stratification group, and age.
Baseline data will include a summary of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when approximately 390 randomized subjects
complete 48 weeks of the double-blind treatment period or discontinue prematurely. A two-sided 
95% confidence interval, based on the large sample theory adjusted for the randomization 
stratification factors (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) 
in the proportion of subjects who achieved HBV DNA < 29 IU/mL will be used to compare the 
treatment groups. A non-inferiority will be declared if the lower bound of this confidence 
interval exceeds a non-inferiority margin of –0.10. If non-inferiority is established, the lower 
bound of the 95% CI will be compared to 0; if the lower bound of the 95% CI is greater than 0, 
then superiority of TAF over TDF will be established using the same confidence interval. Details 
will be provided in the statistical analysis plan.
8.5.1.1.
Justification of the non-inferiority margin
At Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA < 29 IU/mL 
in the TDF arm was 91.2%. At Week 48 in study GS-98-438, the proportion of subjects with
HBV DNA < 29 IU/mL in the placebo was 0%. The non-inferiority margin of 10% would 
preserve more than 88% of the lower bound of the 95% confidence interval of the difference 
between TDF and placebo.
NTDF
NPBO
Response rate 
in TDF
Response rate 
in PBO
Difference
95% confidence interval 
lower bound
250
61
91.2%
0%
91.2%
87.7%
Preserve at least 88% 
of lower bound
10%
Furthermore, at Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA 
< 29 IU/mL in the TDF arm was 91.2% and the proportion of subjects with HBV DNA 
< 29 IU/mL in adefovir (ADV) arm was 56.0%. The non-inferiority margin of 10% would 
preserve more than 60% of the lower bound of the 95% confidence interval of the difference 
between TDF and adefovir (ADV).


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NTDF
NADV
Response rate 
in TDF
Response rate 
in ADV
Difference
95% confidence interval 
lower bound
Study 174-0102
250
125
91.2%
56.0%
35.2%
25.8%
Preserve at least 60% 
of lower bound
10%
8.5.2.
Analyses of Other Endpoints of Interest
Continuous secondary endpoints will be summarized using conventional descriptive statistics 
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group and 
overall. A Wilcoxon rank sum test will be used to compare the treatment groups, in an 
exploratory manner.
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint. A two-sided Mantel-Haenszel test, controlling for the randomization strata,
will be used to compare the treatment groups, in an exploratory manner. Missing data will be 
handled by the missing = failure approach.
For the incidence of drug resistant mutations, the missing = excluded approach will be employed.
An analysis of the China subpopulation will also be conducted when approximately 
150 randomized and treated China subjects complete 48 weeks of double-blind treatment or 
discontinue prematurely to examine the consistency of the responses between the China 
subpopulation and the overall population.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose will be summarized by treatment group (according to the drug received). Data for the 
pretreatment and treatment-free follow-up periods will be included in data listings. 
8.6.1.
Key Secondary Safety Analyses
The percent change from baseline in hip and spine BMD at Week 48 will be analyzed using an
ANOVA model. The model will include treatment group as fixed effect. The details are provided 
in the Statistical Analysis Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be analyzed using an ANCOVA 
model with baseline serum creatinine as a covariate, and treatment group as a fixed effect. The 
details are provided in the SAP.
8.6.2.
Extent of Exposure
A subject’s extent of exposure to drug data will be generated from the drug administration data. 
Exposure data will be summarized by treatment group. 


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8.6.3.
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.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
treatment up to the date of last dose of treatment. Continuing adverse events diagnosed prior to 
the start of treatment and worsening in severity grade, or non-serious adverse events at baseline 
which become serious, or adverse events resulting in treatment discontinuation after the start of 
treatment will also be considered treatment-emergent.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group:

Treatment-emergent adverse events

Treatment-emergent study drug-related adverse events

Grade 3 or 4 treatment-emergent adverse event

Grade 3 or 4 treatment-emergent study drug-related adverse event

Grade 2, 3, or 4 treatment-emergent adverse event

Grade 2, 3, or 4 treatment-emergent study drug-related adverse event

AE that caused permanent discontinuation from study drug

AE that caused change in dose or temporary interruption of study drug

Treatment-emergent serious adverse event

Treatment-emergent study drug-related serious adverse event
8.6.4.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 5.


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Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of treatment, will be summarized by treatment group. If baseline data are missing, then any 
graded abnormality (i.e., at least a Grade 1) will be considered treatment emergent. 
Laboratory abnormalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment will be included in a data listing.
8.7.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for TAF and TFV using descriptive 
statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear formats as mean ± standard deviation.
For the PK intensive substudy, the following pharmacokinetic parameters will be calculated: 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½.
8.7.1.
Biomarker Analysis
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1
N-terminal propeptide (P1NP), and selected renal biomarkers, including urine retinol binding
protein, and urine beta-2-microglobulin, will be summarized by treatment group and visit using
descriptive statistics. The difference in change from baseline in these biomarkers between two 
treatment arms will be tested using Wilcoxon rank sum test.
8.8.
Sample Size
With respect to the primary efficacy endpoint, a sample size of 130 for the TDF 300 mg group 
and 260 for the TAF 25 mg group will have 90% power to rule out the non-inferiority margin of 
10% at a one-sided significance level of 0.025. This assumes a rate of 91% in the TDF 300 mg 
group and 91% in the TAF 25 mg group in the proportion of subjects with HBV DNA 
< 29 IU/mL. A similar response rate in the TDF group was observed in GS-US-174-0102
{Marcellin et al 2007, Marcellin et al 2008}.
This sample size (n=260 for the TAF 25 mg arm, n=130 for the TDF 300 mg arm) also provides 
at least 90% power to detect a 1% difference in the percentage change from baseline in hip BMD 
at Week 48 (assuming a −1.17% change from baseline in TDF 300 mg arm and −0.17% change 
from baseline in the TAF 25 mg arm, with a common standard deviation of 2.20% and a 
two-sided α = 0.025); a 77% power to detect a 1% difference in the percentage change from 
baseline in spine BMD at Week 48 (assuming a −1.69% change from baseline in the TDF 
300 mg arm and −0.69% change in the TAF 25 mg arm, with a common standard deviation of 
3.08% and a two-sided α = 0.025); a 52% power to detect a 0.03 mg/dL difference in the change 
from baseline in serum creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in 
the TDF 300 mg arm and 0.01 mg/dL change from baseline in the TAF 25 mg arm, with a 
common standard deviation of 0.12). These assumptions were derived from studies GS-98-437, 
GS-98-438, GS-US-174-0102, GS-US-174-0103, and GS-US-174-0121.


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For China, approximately 150 additional subjects (100 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD, and 50 subjects TDF 300 mg QD and matched placebo of TAF 
25 mg QD) will be enrolled.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study treatment warrant the 
early termination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications. The DMC may also 
provide recommendations as needed regarding study design
The DMC will convene approximately every 24 weeks following the time of randomization of 
the first subject during the blinded portion of the protocol and approximately every 48 weeks 
during the open-label period.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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, 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. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any sub-investigator’s) participation in the study. The investigator and 
sub-investigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, 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) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
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 


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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the 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 
or IEC and governmental 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 sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 


Tenofovir Alafenamide (TAF)
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Amendment 3.1
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audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site 
may destroy used (empty kits and/or bottles) and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, 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.


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Amendment 3.1
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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. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
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 in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead 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. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s 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.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF 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 CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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 and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
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Gilead Sciences, Inc.
Amendment 3.1
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10.
REFERENCES
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective Lymphoid Cell 
and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-
7340. Mol Pharm 2013;10 (2):459-66.
Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, et al. Hepatitis B virus 
quasispecies susceptibility to entecavir confirms the relationship between 
genotypic resistance and patient virologic response. J Hepatol 2008;48 (6):895-
902.
Bam RA, Birkus G, Babusis D, Yant SR, Cihlar T. Minimal Donor Variation in Cathepsin A 
Expression and Antiviral Activity of GS-7340 in Primary Human CD4+ T Cells 
and Macrophages [Poster Number TUPE016]. XIX International AIDS 
Conference; 2012 July 22-27; Washington, D.C. . 
Birkus G, Bam R, Frey C, Tsai L, Stray K, Yant S, et al. Intracellular activation pathways for 
GS-7340 and the effect of antiviral protease inhibitors [Poster #577]. Presented 
at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 2012 
March 5-8; Seattle, WA. 
Centers for Disease Control and Prevention (CDC). Hepatitis B Fact Sheet.  Available at:  
http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm. Accessed August 6, 
2003, 
Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Positive Chronic Hepatitis B (CHB): Study GS-US-
174-0103 [AASLD Abstracts]. Hepatology 2007;46 (4 Supp1):861A.
Marcellin P, Buti M, Kraslev Z, Germanidis G, Kaita K, Kotzev I, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Negative Chronic Hepatitis B (CHB): Study GS-US-
174-0102 [AASLD Abstracts]. Hepatology 2007;46 (4 Suppl 1):290A-1A.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis 
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-
year open-label follow-up study. Lancet 2013;381 (9865):468-75.
Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil 
for chronic hepatitis B. N Engl J Med 2008;359 (23):2442-55.


Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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Marcellin PE, Heathcote EJ, Corsa A, et al. No detectable resistance to tenofovir disoproxil 
fumarate (TDF) following up to 240 weeks of treatment in patients with 
HBEAG+ and HBEAG- chronic hepatitis B virus infection [Abstract 238]. 
Hepatology 2011;54 (4 Suppl.):480A.
Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert-Bismut F, Thabut D, et al. A prospective 
analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic 
hepatitis C. Clin Chem 2006;52 (10):1887-96.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. 1–239. Available at  
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 
August 22.  2012.
Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of 
FibroTest diagnostic value in chronic liver disease. BMC gastroenterology 
2007;7:40.
Poynard T, Zoulim F, Ratziu V, Degos F, Imbert-Bismut F, Deny P, et al. Longitudinal 
assessment of histology surrogate markers (FibroTest-ActiTest) during 
lamivudine therapy in patients with chronic hepatitis B infection. Am J 
Gastroenterol 2005;100 (9):1970-80.
Robbins BL, Greenhaw JJ, Connelly MC, Fridland A. Metabolic pathways for activation of the 
antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. 
Antimicrob Agents Chemother 1995;39 (10):2304-8.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
World Health Organization (WHO). Fact Sheet WHO/204.  October, 2000.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations


Teoofovir Alafenamide (TAF) 
Protocol GS-US-320-0 I 08 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER OTY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 3.1 
A Phase 3, Randomjzed, Double-Blind Study to Evaluate the Safety and Efficacy of 
Tenofovir Alafcnamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 300 mg 
QD for the Treatment ofHBeAg-Negative, Chronic Hepatitis B 
GS-US-320-0108, Amendment 3.1, 23 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Jolm Flaherty, Pharm D 
Study Director 
Date 
PPD 
INVESTIGATOR STATEMENT 
J have read the protocol, including aU appendices; and I agree that it contains all necessary 
details for me and my stair to conduct this study as described. l 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 118 
23 February 2016 


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
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Appendix 2.
Study Procedures Table
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Informed Consent 
X
Review of Inclusion/ Exclusion 
Criteria 
X
X
Medical History, including HBV 
history
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination 
including vital signs, and weight 
X
X
X
X
X
X
X
X
Height
X
Symptom-directed Physical 
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXAd (spine & hip ) 
X
X
X
X
X
X
X
Fracture Risk Assessmentq
X
Study Drug Accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing in-clinicf
X
X


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 120
23 February 2016
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Serum Chemistry and Liver 
Function Testsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Estimated Creatinine Clearance 
(by Cockcroft-Gault Method)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin C (for estimated eGFR)
X
Plasma HBV DNA Levels 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
X
HBV Genotyping (A-H) 
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
Fibrotest®
X
X
X
X
IL28B Genotype
X
Vitamin D
X
Plasma PK 
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood for Bone 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Urine for Renal 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
X
X
Serum Pregnancy Testk
X


Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 121
23 February 2016
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Urine Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional Intensive PK substudyl
X
Optional PBMCm
X
Serum and plasma for storage 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for Storage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ophthalmologic substudyn –
fundoscopic examination with 
slit lamp
X
X
X
X
X
X
Hepatic Ultrasoundr
X
X
X
Optional Biomarker/ 
Pharmacogenomic Sample
For subjects who provide a separate informed consent, a blood sample should be collected at Baseline, prior to first dose of 
study drug, but may be collected at any time during the study.


Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 3.1
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Visit windows
Week
168
192
216
240
264
288
312
336
360
384/EDo
FUp
±28 days
±7 days
Review Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination including vital signs, and weight 
X
X
Symptom-directed Physical Exam
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
DXA (spine & hip)d
X
X
X
X
X
Study Drug Accountability  
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
Xe
Serum Chemistry and Liver Function Testsg
X
X
X
X
X
X
X
X
X
X
X
Est Creatinine Clearance (Cockcroft-Gault) 
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
Plasma HBV DNA Levels 
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
Fibrotest®
X
X
X
X
X
Fasting Blood for Bone Biomarkersi
X
X
X
X
X
Fasting Urine for Renal Biomarkersi
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
Urine Pregnancy Testk
X
X
X
X
X
X
X
X
X
X


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016
Visit windows
Week
168
192
216
240
264
288
312
336
360
384/EDo
FUp
±28 days
±7 days
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
Serum and plasma for storage 
X
X
X
X
X
X
X
X
X
X
X (serum only)
Urine for Storage
X
X
X
X
X
X
X
X
X
X
Ophthalmologic substudyn −fundoscopic examination with slit lamp
Xn
Hepatic Ultrasoundr
X
X
X
X
X
X
X
X
X
X
a
The visit window for Week 48 visit is −14 days. The visit window for Week 96 is ±14 days.
b
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording
c
Vital signs include blood pressure, pulse, respiration rate, and temperature 
d
DXA scans will be performed only at sites in China with capability. The initial (baseline) DXA will be performed during Screening and should be completed at least 14 days 
prior to the first dose of study drug. The Week 48 DXA window is −14 days only. DXA is required for Early Discontinuation (ED) visit if not done within the last 24 weeks.
e
Subjects already assigned to open-label TAF 25 mg QD per Amend 2.1 continue on open-label TAF 25 mg QD. Otherwise, blinded study drug will be dispensed until 
Week 144 visit. Open label TAF will be dispensed from Week 144 through Week 360. At Week 384/ED, study drug will not be dispensed
f
It is preferred that subjects take their study drug according to a morning dosing schedule; subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 12 visits.
g
Serum chemistry and Liver Function Tests : alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects 
with total amylase > 1.5 × ULN), and PTH. PTH analyzed at all visits except for Screening through Week 96, and then at Weeks 120, 144, and then every 48 weeks through 
Week 384/ED. At Baseline, Weeks 24, 48, 72, 96, 120, 144, 192, 240, 288, 336 and 384/ED, subject will be fasting for serum and glucose and metabolic panel. Coagulation 
panel will be done at Screening and then as a reflex only test for ALT flares.
h
HBeAg and HBeAb will be done at Screening and Baseline visits. HBsAg and reflex HBsAb will be done at Screening and Baseline visits, and every 12 to 16 weeks until 
week 144, every 24 weeks untile Week 384/ED and at Follow Up visits Weeks 12 and 24.  
i
Blood for selected bone biomarkers and urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample was collected >24 weeks
prior
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 
k
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done
l
The optional intensive PK substudy will be conducted once at either of the Weeks 4,8 or 12 visits in a subset (n=16 and up to n= 32) of subjects who provide a separate 
consent form, at select sites. Subjects should fast (no food or drinks for a minimum of 8 hours except water for up to 1 hour) prior to the scheduled intensive PK visit. Subjects 
participating in the PK substudy should not take their dose on the morning of the PK visit. Study medication will be administered in clinic on the morning of intensive PK. 
Subjects who have been routinely dosing in the evening will need to switch to a morning dosing regimen at least 10 days prior to the intensive PK visit. After collection of the 
pre-dose sample and the PBMC sample (at sites which can process PBMCs), subjects will be provided a standardized meal (approximately 600 kcal, 27% fat; details can be 
found in the PK Manual). Within 5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive PK sampling will then occur. Subjects will be 
restricted from further water intake for until 2 hours after and food intake until 4 hours after dosing. 
m
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a PBMC (pre-dose) sample at the intensive PK substudy visit to 
assess intracellular TFV-DP concentration in PBMCs


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 124
23 February 2016
n
For a subset of subjects (n = 30), who provide a separate consent form, a substudy will be conducted to assess ophthalmologic findings, including fundoscopic examination 
with retinal photographs (both eyes). The examination can be conducted anytime during the screening period, but must be completed prior to the first dose of the study drug,
and will be conducted at Weeks 24, 48, 72, 96, and 144 at select sites. Required for Early Discontinuation (ED) visit if prior to Week 144 and not done within the last 
24 weeks. An examination of the full retinal field should be conducted noting changes or abnormalities. Photographs of the retina must be taken at each exam and filed in the 
subject’s source medical records. A central vendor will be used to assess the retinal photographs.
o
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
p
Subjects who discontinue study drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks or up to 
initiation of alternative, commercially available HBV therapy, whichever occurs first. Subjects who lose HBsAg with confirmed seroconversion to anti-HBs should 
discontinue study drug within 3-6 months following confirmation of HBsAg loss and seroconversion to anti-HBs or after Week 48, if seroconversion occurs prior to this visit. 
These subjects will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule through Week 384/ED.
q
Complete the Fracture Risk Assessment specific eCRF at sites in China with DXA capability only.
r
Hepatic ultrasound for HCC surveillance


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 125
23 February 2016
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected 
sites in a subset of subjects [n=16 and up to n=32])
Time Point (Once at either of the Week 4, 8 or 12 visits)
0 (within 30 minutes of dose)*
5 minutes post dose
15 minutes post dose
30 minutes post dose
45 minutes post dose
1 hour post dose
1.5 hours post dose
2 hours post dose
3 hours post dose
4 hours post dose
5 hours post dose
8 hours post dose
12 hours post dose
24 hours post dose
*
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a PBMC 
(pre-dose) sample at the intensive PK substudy visit to assess intracellular TFV-DP concentration in PBMCs


Tenofovir Alafenamide (TAP) 
Protocol GS-US-320-0108 
Gilead Sciences, Inc. 
Final 
Amendment 3.1 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
L------G-ra_d_e_2----~~ 
Ll ------G-ra_d_e_3----~~ 
LI _________ G_r_ad_e_4--------~ 
May continue 
Repeat lab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
lf confirmed and possibly and/or probably related to 
investigational medicinal products: 
l. Withhold investigational medicinal products until~ Grade 2 
2. 
Restart all investigational medicinal products at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, discontinue 
all investigational medicinal products dosing permanently 
l 
If c 
Repeat lab to 
confirm toxicity 
grade 
l 
inve 
onfirmed and unrelated to 
stigational medicinal products, 
ng may continue at the 
dosi 
disc retion of the investigator 
If confirmed and 
possibly or probably 
-.. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at pe1iodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
Ir Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 
CONFIDENTIAL 
Page 126 
23 February 2016 


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 127
23 February 2016
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
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


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
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
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/ μL
200 to 300/mm3
200 to 300/ μL
100 to 200/mm3
100 to 200/ μL
100/mm3
100/ μL
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
100.0 to 125.0 GI/L
50,000 to 100,000/mm3
50.0 to 100.0 GI/L
25,000 to 50,000/mm3
25.0 to 50.0 GI/L
25,000/mm3
25.0 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.0 GI/L to 2.5 GI/L
1.5 to 2.0 GI/L
1.0 to 1.5 GI/L
1.0 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Fibrin Split Product 
20 to 40 μg /mL
40 to 50 μg /mL
50 to 60 μg /mL
60 μg /mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
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% 


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 mEq/L to LLN
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 mmol/L to LLN
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146 to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146 to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
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
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4 mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 mg/dL to LLN
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63 mmol/L to LLN 
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 132
23 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
ULN to 597 μmol /L
597 to 716 μmol /L
716 to 895 μmol /L
895 μmol /L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol /L to LLN
57 to 87 μmol /L
27 to 57 μmol /L
27 μmol /L
Creatinine 
1.50 to 2.0 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol /L
177 to 265 μmol /L
265 to 530 μmol /L
530 μmol /L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
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


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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23 February 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
* Calcium should be corrected for albumin if albumin is < 4.0 g/dL
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
2.0 to 3.0 g/dL
2.0 g/dL
NA
30 g/L to LLN
20 to 30 g/L
20 g/L


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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
Note: 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.


Tenofovir Alafenamide (TAF)
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-urgent 
medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) 
indicated
Hypertension (with repeat 
testing at same visit)
140–159 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 
(e.g., 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 
(e.g., 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


Tenofovir Alafenamide (TAF)
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pericardial Effusion
Asymptomatic, small
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated
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
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event 
(e.g., 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


Tenofovir Alafenamide (TAF)
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RESPIRATION
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 Respiration 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 
Respiration failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiration 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%
Respiration 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)


Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
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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, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited number of 
bullae OR Superficial 
ulcerations of mucous 
membrane limited to one site
Extensive or generalized 
bullous lesions OR Stevens-
Johnson syndrome OR 
Ulceration of mucous 
membrane involving two or 
more distinct mucosal sites 
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


Tenofovir Alafenamide (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 [e.g., tube feeding 
or total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., 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 (e.g., sepsis or 
perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (e.g., 
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 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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 
(e.g., 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 
(e.g., IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences 
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)


Tenofovir Alafenamide (TAF)
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in 
Personality-Behavior or in 
Mood (e.g., 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 
(e.g., 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


Tenofovir Alafenamide (TAF)
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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 
Respiration 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 
(e.g., status epilepticus), or 
difficult to control 
(e.g., refractory epilepsy)


Tenofovir Alafenamide (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 (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or 
difficult to control (e.g., 
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
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater 
than minimal interference 
with usual social & 
functional activities
Joint pain causing inability to 
perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic 
self-care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing greater than minimal 
interference with usual social 
& functional activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score
–2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening 
consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening 
consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater 
than minimal interference 
with usual social & 
functional activities
Muscle pain causing inability 
to perform usual social & 
functional activities
Disabling muscle pain 
causing inability to perform 
basic self-care functions
Osteonecrosis
NA
Asymptomatic with 
radiographic findings AND 
No operative intervention 
indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings 
causing inability to perform 
basic self-care functions


Tenofovir Alafenamide (TAF)
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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 [e.g., 
tube feeding or total 
parenteral nutrition]


Tenofovir Alafenamide (TAF)
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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 
(e.g., upper arm/thigh)
Erythema OR Induration OR 
Edema involving 50% 
surface area of the extremity 
segment (e.g., 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 (e.g., 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 
(e.g., 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 
(e.g., 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
(e.g., myxedema coma)
Lipoatrophy (e.g., 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


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


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Amendment 3.1
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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations
1. Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential
The risks of treatment with study drug have not been evaluated. If females are using hormonal 
agents for contraception, the safety and/or efficacy may be affected by possible drug-drug 
interaction. However, it is recommended that the hormonal agent be continued and that a 
non-hormonal method(s) be used concurrently. If females utilize hormonal agents as one of their 
contraceptive methods, it is required that the same hormonal method be used for at least 
3 months before study dosing. Please refer to the latest version of the Investigator’s Brochure for 
GS-7340 for additional information
2. Definition of Female of Childbearing Potential

For the purposes of this study, a female subject of childbearing potential is a nonmenopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure. This definition includes a pubertal female who has not yet started 
menstruating. A woman who has had a tubal sterilization is considered to be of childbearing 
potential.

A female subject ≤54 years in age, with the absence of normal menses is considered to be of 
childbearing potential. Exceptions must be discussed with the medical monitor.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (ie, surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

Age > 54 years, with the cessation (for > 12 months) of previously occurring menses due to 
ovarian failure, will not be considered to be childbearing potential. 
3. Contraceptive Requirements for Female Subjects
Female subjects of childbearing potential who engage in intercourse must agree to utilize 
protocol specified methods of contraception from the screening visit throughout the study period 
and for 30 days following the last dose of study drug. Female study subjects who are not 
heterosexually active must provide periodic confirmation of continued abstinence from 
heterosexual intercourse and regular pregnancy testing while participating in the study. The 
investigator will counsel subjects on the protocol specified method(s) for avoiding pregnancy in 
case the subject chooses to engage in heterosexual intercourse.
Protocol specified contraceptive methods are as follows: (1) a combination of one hormonal 
method and one barrier method; (2) two barrier methods where one method is the male condom; 
or (3) use of an intrauterine device (IUD) or tubal sterilization; see Appendix Table 1 below; or 
(4) complete abstinence from intercourse. Periodic abstinence from intercourse (e.g. calendar, 
ovulation, sumptothermal, post-ovulation methods) is not permitted.


Tenofovir Alafenamide (TAF)
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Amendment 3.1
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Acceptable hormonal methods include injectable progesterone, progesterone implants, 
combination oral contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable 
barrier methods include diaphragm with spermicide, cervical cap with spermicide, and the male 
condom. The use of spermicide is not recommended if the subject or subject’s partner is infected 
with HIV. Female subjects must use either a hormonal method or a barrier method if the partner 
has a vasectomy. If a subject has undergone tubal sterilization or has had a Copper T 380A IUD 
or LNg 20 IUD inserted, no other contraception is needed.  
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least 
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of study 
drug. Lactating females must discontinue nursing before IMP administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with 
a barrier method)
Barrier Methods
(use both OR choose one and use with 
a hormone method)
Intrauterine Devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicide
OR

Cervical cap with spermicide

Male condom (with or without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
The investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.
4. Contraceptive Requirements for Male Subjects
Male subjects must agree to use protocol specified method of contraception during heterosexual 
intercourse and avoid sperm donation from the time of the first dose of study drug and 
throughout the study period, and for at least 30 days after administration of the last dose of study 
medication 


Tenofovir Alafenamide (TAF)
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Amendment 3.1
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Use of condoms, except for lambskin, has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.
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. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.6.2.1.

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number 
ClinicalT rials.gov 
Identifier 
Indication: 
Protocol ID: 
Gilead Sciences Study 
Director: 
Gilead Sciences Medical 
Monitor 
Protocol Version/Date: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg-Negative, Chronic Hepatitis B 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
115, 561 
2013-000626-63 
NCT01940341 
HBeAg-negative Chronic Hepatitis B 
GS-US-320-0108 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Name: 
Telephone: 
Fax (paper): 
Mobile: 
Email: 
Amendment 2.1 
John Flaherty, Phatm D 
PD 
PPD 
PPD 
PPD 
Benedetta Massetto, MD, PhD 
PPD 
PPD 
PPD 
PPD 
I 
20 Febmmy 2015 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, patticularly lmpublished data, is the propetty 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, yom staff, and an applicable Institutional 
Review Bom·d or Independent Ethics Committee. The inf01mation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the inf01m ation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaty to obtain inf01m ed consent from those 
persons to whom the dmg may be administered. 


Tenofovir Alafenamide (TAF), GS-7340
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Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Background ............................................................................................................................................23
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................25
1.2.1.
General Information .............................................................................................................25
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................26
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................29
1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF).........................................................................................................................40
1.3.
Rationale for This Study ........................................................................................................................49
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B .................................49
1.3.2.
Rationale for the Current Study............................................................................................50
1.3.3.
Rationale for Dose Selection................................................................................................52
1.4.
Compliance ............................................................................................................................................53
2.
OBJECTIVES.....................................................................................................................................................54
3.
STUDY DESIGN................................................................................................................................................56
3.1.
Treatment Plan and Regimen .................................................................................................................56
3.2.
Biomarker Testing..................................................................................................................................57
3.2.1.
Biomarker Samples to Address the Study Objectives:.........................................................57
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................58
3.3.
Intensive PK Substudy (Optional)..........................................................................................................58
3.4.
Opthalmologic Substudy (Optional) ......................................................................................................58
4.
SUBJECT POPULATION..................................................................................................................................59
4.1.
Number of Subjects and Subject Selection ............................................................................................59
4.2.
Inclusion Criteria....................................................................................................................................59
4.3.
Exclusion Criteria...................................................................................................................................60
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................62
5.1.
Randomization and Blinding..................................................................................................................62
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................62
5.2.
Description and Handling of Tenofovir Alafenamide (TAF), GS-7340, Tenofovir Disoproxil 
Fumarate (TDF) and Matched Placebos.................................................................................................63
5.2.1.
Formulation..........................................................................................................................63
5.2.2.
Packaging and Labeling .......................................................................................................64
5.2.3.
Storage and Handling...........................................................................................................64
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos ...................................................64
5.4.
Prior and Concomitant Medications.......................................................................................................65
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos...................................................................................................................................66
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................67
6.
STUDY PROCEDURES ....................................................................................................................................68


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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................68
6.2.
Pretreatment Assessments......................................................................................................................68
6.2.1.
Screening Visit .....................................................................................................................68
6.2.2.
Baseline Assessments...........................................................................................................69
6.3.
Treatment Assessments..........................................................................................................................70
6.3.1.
Double Blind Visits..............................................................................................................70
6.3.2.
Open Label Visits.................................................................................................................79
6.4.
Post-treatment Assessments ...................................................................................................................81
6.4.1.
HBsAg Loss and  Seroconversion Subjects .........................................................................81
6.4.2.
All other subjects who discontinue study drug.....................................................................81
6.4.3.
Follow up visit assessments (all subjects)............................................................................81
6.5.
Early Discontinuation (ED) from Study.................................................................................................82
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................82
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................83
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................83
6.9.
Resistance Surveillance..........................................................................................................................84
6.10.
End of Study...........................................................................................................................................84
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................85
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................85
7.1.1.
Adverse Events.....................................................................................................................85
7.1.2.
Serious Adverse Events........................................................................................................85
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................86
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................86
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................86
7.2.2.
Assessment of Severity ........................................................................................................87
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................87
7.4.
Gilead Reporting Requirements.............................................................................................................90
7.5.
Toxicity Management ............................................................................................................................90
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................91
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................91
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................91
7.5.4.
Management of Bone Evaluation.........................................................................................92
7.5.5.
Management of Potential Nephrotoxicity.............................................................................92
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................93
7.5.7.
Management of Potential Posterior Uveitis Cases................................................................95
7.6.
Special Situations Reports......................................................................................................................95
7.6.1.
Definitions of Special Situations..........................................................................................95
7.6.2.
Instructions for Reporting Special Situations.......................................................................96
8.
STATISTICAL CONSIDERATIONS................................................................................................................98
8.1.
Analysis Objectives and Endpoints........................................................................................................98
8.1.1.
Analysis Objectives..............................................................................................................98
8.1.2.
Primary Endpoint .................................................................................................................99
8.1.3.
Secondary Endpoints............................................................................................................99
8.1.4.
Other Endpoints of Interest ..................................................................................................99
8.2.
Analysis Conventions...........................................................................................................................100
8.2.1.
Analysis Sets ......................................................................................................................100
8.2.2.
Data Handling Conventions ...............................................................................................100
8.3.
Multiplicity Adjustments......................................................................................................................101
8.4.
Demographic Data and Baseline Characteristics .................................................................................102


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8.5.
Efficacy Analysis .................................................................................................................................102
8.5.1.
Primary Analysis................................................................................................................102
8.5.2.
Analyses of Other Endpoints of Interest.............................................................................103
8.6.
Safety Analysis.....................................................................................................................................103
8.6.1.
Key Secondary Safety Analyses.........................................................................................103
8.6.2.
Extent of Exposure.............................................................................................................104
8.6.3.
Adverse Events...................................................................................................................104
8.6.4.
Laboratory Evaluations ......................................................................................................104
8.7.
Pharmacokinetic Analysis....................................................................................................................105
8.7.1.
Biomarker Analysis............................................................................................................105
8.8.
Sample Size..........................................................................................................................................105
8.9.
Data Monitoring Committee ................................................................................................................106
9.
RESPONSIBILITIES........................................................................................................................................107
9.1.
Investigator Responsibilities ................................................................................................................107
9.1.1.
Good Clinical Practice........................................................................................................107
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................107
9.1.3.
Informed Consent...............................................................................................................107
9.1.4.
Confidentiality....................................................................................................................108
9.1.5.
Study Files and Retention of Records ................................................................................108
9.1.6.
Case Report Forms.............................................................................................................109
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................110
9.1.8.
Inspections..........................................................................................................................110
9.1.9.
Protocol Compliance..........................................................................................................110
9.2.
Sponsor Responsibilities ......................................................................................................................111
9.2.1.
Protocol Modifications.......................................................................................................111
9.2.2.
Study Report and Publications ...........................................................................................111
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................111
9.3.1.
Access to Information for Monitoring................................................................................111
9.3.2.
Access to Information for Auditing or Inspections ............................................................112
9.3.3.
Study Discontinuation........................................................................................................112
10.
REFERENCES .................................................................................................................................................113
11.
APPENDICES ..................................................................................................................................................115
Appendix 1.
Investigator Signature Page..................................................................................................116
Appendix 2.
Study Procedures Table........................................................................................................117
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])............................................................................123
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................124
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............125
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations.........................................................................................148


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Gilead Sciences, Inc. 
Amendment 2.1
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LIST OF IN-TEXT TABLES
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection......................................30
Table 1-2.
GS-US-320-0101:  Baseline Demographics and Disease Characteristics ..............................33
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and Laboratory 
Abnormalities: Overall Summary, Safety Analysis Set..........................................................34
Table 1-4.
GS-US-320-0101: HBV DNA Results: Median Change from Baseline at Day 15 
and Day 29 by Treatment Group ............................................................................................36
Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on Day 1 ........................38
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on Day 1 ........................40
Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: Overall Summary, Safety 
Analysis Set............................................................................................................................44
Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities, 
Safety Analysis Set.................................................................................................................45
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine and Hip Bone 
Mineral Density at Week 24, DXA Analysis Set ...................................................................47
Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by Gradation at Week 
24, DXA Analysis Set ............................................................................................................48
Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover Markers, 
Safety Analysis Set.................................................................................................................49
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution Due to the 
Potential for Drug-Drug Interaction with Study Medication..................................................66
LIST OF IN-TEXT FIGURES
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance (Cockcroft-Gault 
Method) in GS-US-320-0101.................................................................................................35
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV DNA (Log10 
IU/mL) by Treatment Group ..................................................................................................36
Figure 1-3.
GS-US-320-0101:  Mean (SD) Plasma Concentrations vs. Time on Day 1: TAF 
(GS-7340), Linear Scale.........................................................................................................37
Figure 1-4.
GS-US-320-0101:  Mean (SD) Plasma Concentrations vs. Time on Day 1: 
Tenofovir, Linear Scale..........................................................................................................39
Figure 1-5.
GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
Cockcroft-Gault by Visit, Safety Analysis Set.......................................................................46
Figure 3-1.
Study Schema.........................................................................................................................57


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
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20 February 2015
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Title of Study:
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety 
and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD versus 
Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment 
of HBeAg-Negative, Chronic Hepatitis B
IND Number:
EudraCT Number:
ClinicalTrials.gov 
Identifier
115,561
2013-000626-63
NCT01940341
Study Centers 
Planned:
Approximately 160 centers worldwide
Objectives:
The primary objectives of this study are as follows:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg 
QD versus tenofovir disoproxil fumarate (TDF) 300 mg QD for 
the treatment of HBeAg-negative, chronic hepatitis B at Week 48 
in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with 
plasma HBV DNA levels below 29 IU/mL. 

To compare the safety and tolerability of TAF 25 mg QD versus 
TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Week 48 in treatment-naïve and treatment-
experienced subjects
The key secondary safety objectives of this study are as follows:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD 
as determined by the percent change from baseline in hip and 
spine bone mineral density (BMD) at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD 
as determined by the change from baseline in serum creatinine at 
Week 48


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Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA levels 
below 29 IU/mL at Week 96

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg 
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA levels 
below 29 IU/mL (target not detected) at Weeks 48 and 96

To compare the biochemical (ALT normalization) response of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48 and 96

To compare the serological response (loss of HBsAg with 
seroconversion to anti-HBs) of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis 
B at Weeks 48 and 96

To compare the change in fibrosis as assessed by FibroTest® of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48 and 96

To compare the incidence of drug resistant mutations of TAF 
25 mg QD versus TDF 300 mg QD at Weeks 48, 96 and 144

To compare the change from baseline in ophthalmologic findings 
by fundoscopic examination of TAF 25 mg QD versus TDF 
300 mg QD at Weeks 24, 48, 72 and 96 in a subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir (TFV) 
and determine intracellular concentrations of tenofovir 
diphosphate (TFV-DP) within peripheral blood mononuclear cells 
(PBMCs) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy and safety of TAF 
25 mg QD from Week 96 through Week 144 in subjects initially 
randomized to TAF 25 mg QD and in subjects sequentially treated 
with TDF 300 mg QD for 96 weeks and then switched to 
open-label TAF


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Study Design:
This is a randomized, double-blind, non-inferiority study to compare 
the antiviral activity of TAF 25 mg QD versus TDF 300 mg QD. 
Approximately 390 subjects will be randomized in a 2:1 ratio (A:B) to 
the treatment arms and will be stratified by plasma HBV DNA level 
(< 7 log10 IU/mL, > 7 log10 IU/mL - < 8 log10 IU/mL, 
> 8 log10 IU/mL) and oral antiviral treatment status (treatment-naïve 
vs. treatment-experienced).
Treatment Arm A: 260 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD
For China, approximately 150 additional subjects (100 in Treatment 
Arm A and 50 in Treatment Arm B) will be enrolled for local 
registration purposes.
The duration of double-blind treatment is 96 weeks. All subjects who 
complete 96 weeks of treatment are eligible for participation in the 
open label TAF 25 mg QD extension period for an additional 
48 weeks (through Week 144). For the entire duration of the study, 
subjects and investigators will remain blinded to the initial treatment 
regimen to which they were randomized to during Years 1 and 2 
(through Week 96). 
Subjects with a confirmed creatinine clearance (CLCr) < 50 mL/min, 
and > 20 % decline in eGFR by CKD-EPI (cystatin C), at any time 
during the study will be required to undergo dose modification to 
every other day dosing of study drug. Subjects with confirmed 
creatinine clearance < 30 mL/min will have the study drug 
permanently discontinued.
The primary analysis will occur at Week 48 with the primary efficacy 
endpoint being the proportion of subjects with complete viral 
suppression, i.e., plasma HBV DNA level below 29 IU/mL.
Subjects who permanently discontinue study drug (either prematurely 
or at the end of study [Week 144]) for reasons other than HBsAg loss 
with confirmed seroconversion to anti-HBs will be followed every 
4 weeks for 24 weeks off treatment or until initiation of alternative, 
commercially available, HBV therapy, whichever occurs first. Use of 
commercial therapy is strongly encouraged.


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Subjects with HBsAg loss with confirmed seroconversion to anti-HBs 
should discontinue study drug within 3-6 months following 
confirmation of seroconversion to anti-HBs. Subjects with HBsAg 
loss with confirmed seroconversion to anti-HBs prior to Week 48 are 
not permitted to discontinue study drug prior to the Week 48 visit. 
Subjects who discontinue study drug for confirmed seroconversion to 
anti-HBs will be followed off treatment every 4 weeks for 12 weeks 
and then per the study visit schedule (Appendix 2) through Week 144. 
Discontinuation of study drug for subjects experiencing HBsAg loss 
with confirmed seroconversion, who have known bridging fibrosis or 
cirrhosis, should be considered on a case by case basis.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will review the progress and safety of this study 
approximately every 24 weeks following the time of randomization of 
the first subject during the double blind period of the study. During the 
open-label duration of the study, the DMC will convene 
approximately every 48 weeks. At each meeting, the DMC will review 
routine safety and dual energy X-ray absorptiometry (DXA) data and 
will make recommendations regarding modification of the study 
treatment.
Number of Subjects 
Planned:
390 subjects (260 subjects TAF 25 mg QD and matched placebo of 
TDF 300 mg QD, and 130 subjects TDF 300 mg and matched placebo 
of TAF 25 mg QD)
For China, approximately 150 additional subjects (100 subjects TAF 
25 mg QD and matched placebo of TDF 300 mg QD, and 50 subjects 
TDF 300 mg QD and matched placebo of TAF 25 mg QD) will be 
enrolled.
Target Population:
Subjects, who are 18 years of age and older, with HBeAg-negative, 
chronic hepatitis B
Duration of 
Treatment:
The duration of the double-blind treatment is 96 weeks. After 
completing 96 weeks of treatment, all subjects remaining on treatment 
will be eligible to receive open label TAF 25 mg QD for up to an 
additional 48 weeks (Week 96 through Week 144). Subjects who lose 
HBsAg with confirmed seroconversion to anti-HBs should discontinue 
study drug within 3-6 months following confirmation of 
seroconversion to anti-HBs, or after Week 48, if seroconversion 
occurs prior to this visit. 


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Diagnosis and Main 
Eligibility Criteria
Subjects must meet all of the following inclusion criteria to be eligible 
to participate in the study.
1) Must have the ability to understand and sign a written informed 
consent form, which must be obtained prior to initiation of study 
procedures.
2) Male and non-pregnant, non-lactating female subjects, 18 years of 
age and older, based on the date of the screening visit. A negative 
serum pregnancy test at Screening is required for female subjects 
of childbearing potential (as defined in Appendix 6).
3) Documented evidence of chronic HBV infection (e.g. HBsAg 
positive for more than 6 months)
4) HBeAg-negative, chronic hepatitis B with all of the following:
HBeAg-negative and HBeAb positive at Screening (if the 
subject is deemed ineligible for this study by HBV serology 
[i.e. HBeAg positive CHB], this information may be used to 
determine eligibility for  GS-US-320-0110 [another 
Gilead Sciences Phase 3 study in HBeAg-positive, CHB 
subjects; this study must also be IRB/EC approved at the 
participating center])
Screening HBV DNA ≥ 2 x 104 IU/mL 
Screening serum ALT level 60 U/L (males) or > 38 U/L 
(females) and ≤10 ULN (by central laboratory range)
5) Treatment-naïve subjects (defined as < 12 weeks of oral antiviral 
treatment with any nucleoside or nucleotide analogue), OR
treatment-experienced subjects (defined as subjects meeting all 
entry criteria [including HBV DNA and serum ALT criteria] and 
with ≥12 weeks of previous treatment with any nucleoside or 
nucleotide analogue) will be eligible for enrollment. 
Treatment-experienced subjects receiving oral antiviral treatment 
at Screening must continue their treatment regimen until the time 
of randomization, when it will be discontinued.
6) Any previous treatment with interferon (pegylated or 
non-pegylated) must have ended at least 6 months prior to the 
baseline visit.


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7) Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the 
Cockcroft-Gault method) based on serum creatinine and actual 
body weight as measured at the Screening evaluation, as follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8) Normal ECG (or if abnormal, determined by the Investigator not 
to be clinically significant)
9) Must be willing and able to comply with all study requirements.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in the study.
1) Pregnant women, women who are breastfeeding or who believe 
they may wish to become pregnant during the course of the study.
2) Males and females of reproductive potential who are unwilling to 
use an “effective”, protocol-specified method(s) of contraception 
during the study.  For a list of protocol-specified contraceptive 
methods, refer to Appendix 6.
3) Co-infection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent 
imaging)
5) Any history of, or current evidence of, clinical hepatic 
decompensation (e.g., ascites, encephalopathy or variceal 
hemorrhage).
6) Abnormal hematological and biochemical parameters, including:
Hemoglobin < 10 g/dL 
Absolute neutrophil count < 750/mm3
Platelets ≤50,000/mm3
AST or ALT > 10 x ULN
Total bilirubin > 2.5 x ULN
Albumin < 3.0 g/dL
INR > 1.5 x ULN (unless stable on anticoagulant regimen)
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator


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9) Significant bone disease (eg, osteomalacia, chronic osteomyelitis, 
osteogenesis imperfecta, osteochrondroses), or multiple bone 
fractures
10) Malignancy within 5 years prior to screening, with the exception 
of specific cancers that are cured by surgical resection (basal cell 
skin cancer, etc). Subjects under evaluation for possible 
malignancy are not eligible
11) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), investigational agents, nephrotoxic agents, or 
agents capable of modifying renal excretion
12) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
13) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
14) Any other clinical condition or prior therapy that, in the opinion of 
the Investigator, would make the subject unsuitable for the study 
or unable to comply with dosing requirements.
15) Subjects on prohibited concomitant medications (See Table 5-1). 
Subjects on prohibited medications, otherwise eligible, will need a 
wash out period of at least 30 days.
Study Procedures/
Frequency:
Laboratory analyses (serum chemistry, liver tests, hematology, 
urinalysis, plasma HBV DNA levels, pregnancy testing [for females of 
childbearing potential]), vital signs, adverse events and concomitant 
medications will be performed at Screening, Baseline, and every 
4 weeks thereafter through Week 48, every 8 weeks through Week 96 
and every 12 weeks through Week 144/Early Discontinuation (ED) 
visit. HBV serology (HBeAg and HBeAb, HBsAg and reflex HBsAb 
[anti-HBs]) will be performed at Screening and Baseline, and HBsAg 
and reflex HBsAb will be performed every 12-16 weeks until 
Week 144/ED and at Follow up Weeks 12 and 24. Quantitative serum 
HBsAg will be assessed at Screening and Baseline, and every 
12-16 weeks until Week 144/ED and at Follow up visits. Bone and 
renal biomarker testing will be performed at Baseline and then at 
defined intervals (see Schedule of Assessments, Appendix 2)
throughout the study. IL28B polymorphism genotype, HBV 
genotyping and vitamin D level will be performed at Baseline only. 
Fibrotest® will be performed at Baseline and at Weeks 48, 96 
and 144/ED. Fasting metabolic assessments (fasting glucose and lipid 
panel) will be conducted at Baseline, every 24 weeks until Week 96, 
and at the Week 144/ED visit.


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Complete physical examinations will be performed at Screening, 
Baseline, and Weeks 24, 48, 72, 96, and 144/ED. Height assessment 
will be conducted at Screening only. Symptom directed physical 
exams with body weight assessment will be conducted at all other 
visits. ECG will be performed at Screening and every 48 weeks 
thereafter.  At sites in China with the capability only, DXA scans of 
the hip and spine will be conducted during the screening period, and 
should be conducted at least 14 days prior to the first dose of study 
drug, and will be subsequently conducted at Weeks 24, 48, 72, 96, 
144, and the ED visit, if not done within the last 12 weeks of this visit. 
Genotypic analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance will be performed at Baseline for 
all subjects and attempted for all viremic subjects (HBV DNA > 69 
IU/mL) at Weeks 48, 96 and 144/ED. As it may not be known at the 
time of the visit whether a patient is viremic or if it will be their last 
study visit, a separate virology sample for potential resistance 
surveillance will be collected at each study visit. Plasma, serum, and 
urine will be collected at Baseline and at every visit thereafter for 
storage. 
A single pharmacokinetic (PK) blood sample will be collected at all 
study visits from Weeks 4 through 48 for all subjects. At the Week 4 
and 12 visits, dosing will occur in-clinic and a single PK blood sample 
will be collected between 15 minutes and 4 hours post-dose. It is 
preferred that subjects take their study drug according to a morning 
dosing schedule; however, evening dosing is allowable. Subjects who 
elect to dose in evening are not required to have in-clinic dosing and 
the single PK blood sample collection performed at the Week 4 and 12 
visits.
Pharmacokinetic Substudy
For subjects who provide a separate informed consent (n=16 and up to 
n=32), an intensive PK substudy will be conducted once at either of 
the Week 4, 8 or 12 visits at select sites. Blood (plasma) samples will 
be collected at 0 (≤30 minutes pre-dose), at 5, 15 , 30, 45 minutes, 
and at 1, 1.5, 2, 3, 4, 5, 8, 12, and 24 hours post dose. Subjects will be 
dosed in-clinic and should be in a fasted state (no food or drinks 
8 hours prior except water up to 1 hr) prior to the intensive PK visit. 
The subjects will then be provided a standardized meal 4 hours post 
dose. Subjects participating in the PK substudy (at sites which can 
process PBMCs) will also be asked to provide a PBMC (pre-dose) 
sample at the time of the intensive PK substudy.  Please refer to the 
PK manual for specific restrictions on food and water intake.


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Ophthalmologic Substudy
For subjects who provide a separate informed consent (n = 30, at 
select sites), a substudy will be conducted to assess ophthalmologic 
findings, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes), anytime during the screening period, but 
must be completed prior to the first dose of study drug, and at Weeks 
24, 48, 72, 96 and 144/ED visit, if not done within the last 12 weeks of 
this visit.
Pharmacogenomic Substudy
An optional blood sample may be obtained for exploratory biomarker 
and pharmacogenomic discovery research. This sample may only be 
collected following approval of the national and local regulatory 
bodies and Ethical Committees. This sample should be collected at 
Baseline, prior to the first dose of study drug, but may be collected at 
any time during the study or at a separate unscheduled study visit, if 
necessary. Subjects who agree to have blood drawn for these purposes 
will sign a separate informed consent form prior to obtaining this 
sample.
Subjects who receive at least one dose of study drug and permanently 
discontinue study drug for reasons other than HBsAg loss and 
seroconversion to anti-HBs, either prematurely or at the end of the 
study (Week 144), will be followed every 4 weeks for 24 weeks 
post-treatment or up to initiation of alternative, commercially 
available HBV therapy, whichever occurs first. The following 
evaluations will occur every 4 weeks: vital signs, hematology, serum 
chemistry, liver function tests, and plasma HBV DNA. Plasma, serum, 
and urine will be collected for storage. HBsAg and reflex HBsAb will 
be evaluated at Follow up Weeks 12 and 24. 
Subjects who lose HBsAg with confirmed seroconversion to anti-HBs 
should discontinue study drug within 3-6 months following 
confirmation of HBsAg loss and seroconversion to anti-HBs or after 
Week 48, if seroconversion occurs prior to this visit. These subjects 
will be followed off treatment every 4 weeks for 12 weeks and then 
per the study visit schedule (Appendix 2) through Week 144.
Test Product, Dose, 
and Mode of 
Administration:
Double-Blind Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration and 
matched placebo of Tenofovir DF (TDF) 300 mg QD, oral 
administration
Open-Label Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 


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Reference Therapy, 
Dose, and Mode of 
Administration:
Double-blind Treatment: 

Tenofovir DF 300 mg QD, oral administration and matched 
placebo of Tenofovir alafenamide (TAF) 25 mg QD, oral
administration
Open-label Treatment:  NA
Criteria for 
Evaluation:
Safety:
Key secondary safety endpoints include the percent change from 
baseline at Week 48 in hip and spine BMD, and change from baseline 
at Week 48 in serum creatinine.
If a subject has confirmed creatinine clearance < 50 mL/min, and 
> 20% decline in eGFR by CKD-EPI (cystatin C), at any time during 
the study, the subject will be required to undergo dose modification to 
every other day dosing of study drug. Subjects with confirmed 
creatinine clearance < 30 mL/min will have the study drug 
permanently discontinued.
The proportion of subjects in each treatment arm with tolerability 
failure (defined as an adverse event [AE] leading to permanent 
discontinuation of study drug) at Weeks 48, and 96 will be 
summarized. Change from baseline in serum creatinine will be 
assessed at every visit and summarized through Week 96. Change 
from baseline in BMD by DXA of the spine and hip will be assessed 
at Weeks 24, 48, 72, and 96. 
Ophthalmologic changes from baseline by fundoscopic examination at 
Weeks 24, 48, 72, 96 and 144/ED will be summarized for a subset of 
subjects (n = 30). In addition, for any subject who develops signs or 
symptoms of posterior uveitis, the investigator should contact the 
Gilead Medical Monitor to discuss the need for additional 
ophthalmologic evaluation including dilated fundoscopy and optical 
coherence tomography (OCT).
Adverse events and clinical laboratory tests will be collected at every 
visit and summarized through Week 96. Additionally, summaries of 
AEs, discontinuations due to AEs, and laboratory data including BMD 
measurements (via DXA scans, serum creatinine and creatinine 
clearance by Cockcroft-Gault) by original treatment arms (TAF versus 
TDF) will continue on an annual basis through Week 144. Fracture 
risk assessment will be evaluated at Baseline. In China, this fracture 
risk assessment will be evaluated at sites with DXA capability only.


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Efficacy:
The primary efficacy endpoint is the proportion of subjects with 
plasma HBV DNA levels below 29 IU/mL at Week 48. 
Other secondary efficacy endpoints are:

The proportion of subjects with plasma HBV DNA < 29 IU/mL at 
Weeks 96 and 144

The proportion of subjects with plasma HBV DNA < 29 IU/mL 
(target not detected) at Weeks 48, 96 and 144

The proportion of subjects with ALT normalization at Weeks 48, 
96 and 144

The proportion of subjects with HBsAg loss at Weeks 48, 96 
and 144

The proportion of subjects with HBsAg seroconversion to 
anti-HBs at Weeks 48, 96 and 144

The change from baseline in fibrosis as assessed by FibroTest® at 
Weeks 48, 96 and 144

The incidence of drug resistant mutations at Weeks 48, 96 and 144
Pharmacokinetics:
The following TAF and TFV plasma pharmacokinetic parameters will 
be calculated for the substudy population (n = 30): 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½
Single PK plasma samples collected at Weeks 4-48 may be used for 
estimation of population pharmacokinetics of TAF and TFV.
Single PBMC samples at selected PK substudy sites collected at the 
intensive PK substudy visit will be used for TFV-DP concentration 
determination
Statistical Methods:
The primary analysis will be performed when approximately 
390 subjects complete 48 weeks of the double-blind treatment period 
or discontinue prematurely. The analysis will compare the TAF arm to 
the TDF arm.


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Analysis Methods:
A two-sided 95% confidence interval, based on large sample theory, 
adjusted for the randomization stratification factors, for the difference 
(TAF-TDF) between treatments will be evaluated to compare 
treatment groups with respect to the primary efficacy endpoint. A 
missing equals failure approach will be employed for the primary 
analysis. Non-inferiority will be declared if the lower bound of this 
confidence interval exceeds -0.10 (i.e., 10% non-inferiority margin). If 
non-inferiority is established, the lower bound of the 95% confidence 
interval (CI) will be compared to 0; if the lower bound of the 95% CI 
is greater than 0, then superiority of TAF over TDF will be established 
using the same CI.
The percent change from baseline in hip and spine BMD at Week 48 
will be analyzed using an analysis of covariance (ANCOVA) model. 
The model will include baseline hip or spine BMD as a covariate, and 
randomization strata and, treatment, group as fixed effects.
The change from baseline in serum creatinine at Week 48 will be 
analyzed using an ANCOVA model similar to the analysis of BMD.
All secondary continuous endpoints will be summarized using an 
8-number summary (n, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum). All categorical secondary endpoints will be 
summarized by number and percentage of subjects who meet the 
endpoint.
Sample Size:
With respect to the primary efficacy endpoint of proportion of subjects 
with plasma HBV DNA levels below 29 IU/mL at Week 48, when the 
sample sizes are 260 (TAF 25 mg arm) and 130 (TDF 300 mg arm), a 
two-group, large-sample normal approximation test of proportions 
with a one-sided 0.025 significance level will have 90% power to 
reject the null hypothesis, that the TAF 25 mg arm is inferior to the 
TDF 300 mg arm (the difference in proportions [TAF-TDF] having a 
lower bound of the one-sided 97.5% confidence interval of less 
than -0.10, i.e., 10%) in favor of the alternative hypothesis that the 
TAF 25 mg arm is not inferior to the TDF 300 mg arm. This assumes 
the expected difference (TAF-TDF) in proportion of subjects with 
HBV DNA < 29 IU/mL is 0 and the proportion of subjects with HBV 
DNA < 29 IU/mL in the TDF 300 mg arm is 0.91. 
The TDF virologic rate of 0.91 was calculated using the observed rate 
in Study GS-US-174-0102. 


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This sample size also provides 90% power to detect a 1% difference in 
the percentage change from baseline in hip BMD at Week 48 
(assuming a -1.17% change from baseline in TDF 300 mg arm and -
0.17% change in TAF 25 mg arm, with a common standard deviation 
of 2.20% and a two-sided α = 0.025); a 77% power to detect a 1% 
difference in the percentage change from baseline in spine BMD at 
Week 48 (assuming a -1.69% change from baseline in the TDF 
300 mg arm and -0.69% change in the TAF 25 mg arm, with a 
common standard deviation of 3.08% and a two-sided α = 0.025); a 
52% power to detect a 0.03 mg/dL difference in the change from 
baseline in serum creatinine at Week 48 (assuming a 0.04 mg/dL 
change from baseline in the TDF 300 mg arm and 0.01 mg/dL change 
from baseline in the TAF 25 mg arm, with a common standard 
deviation of 0.12). These assumptions were derived from studies 
GS-98-437, GS-98-438, GS-US-174-0102, GS-US-174-0103, and 
GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects TAF 
25 mg QD and matched placebo of TDF 300 mg QD, and 50 subjects 
TDF 300 mg QD and matched placebo of TAF 25 mg QD) will be 
enrolled.
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
ADV
Adefovir dipivoxil
AE
Adverse event
AhR
Aryl hydrocarbon receptor
AK
Adenylate kinase
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil counts
ANCOVA
Analysis of covariance
AR
Adverse reaction
AST
Aspartate aminotransferase (SGOT)
AUCinf
Area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUC0last + (Clast/z)
AUCtau
Area under the plasma concentration versus time curve over the dosing interval (tau)
bsAP
Bone specific alkaline phosphatase
BMD
Bone mineral density
CatA
Cathepsin A
CD4
Cluster of differentiation 4 cells
CD8
Cluster of differentiation 8 cells
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKF-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI / C
Cobicistat
CRF/eCRF
case report form(s)/electronic case report form(s)
CRO
Contract (or clinical) research organization
CTX
C-type collagen sequence
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry
E2
Estradiol
EC
Ethics committee


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
EudraCT
European clinical trials database
E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
EFV
Efavienz
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FEPO4
Fractional excretion of Phosphate
FRAX
Fracture Risk Assessment Tool
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
Hb
Hemoglobin
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B s antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
ITT
Intent-to-treat (analysis or subset)
IRB
Institutional review board
IV
Intravenous


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LdT
Telbivudine
LAM
Lamivudine
LLN
Lower limit of the normal range
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mmHg
Millimeters mercury
NK
Natural killer cells
NOEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Osteocalcin
OCT
Optical coherence tomography
OL
Open-label
PBMC
Peripheral blood mononuclear cells
PCR
Polymerase chain reaction
PD
Pharmacodynamic
P-gp
P-glycoprotein
P1NP
Procollagen type 1 amino-terminal propeptide
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT
Preferred Term
PT/INR
Prothrombin time/ International normalized ratio
QD
Once daily (use only in tables)
RNA
Ribonucleic acid
RPV
Rilpivirine
RT
Reverse transcriptase
SA
Single agent
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
Tenofovir Alafenamide, GS-7340
TAF Fumarate
Tenofovir Alafenamide Fumarate, GS-7340-03
TDF
Tenofovir Disoproxil Fumarate
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TLOVR
Time to loss of virologic response
Tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
T3
Triiodothyronine
TSH
Thyroid stimulating hormone
UACR
Urine albumin-to-creatinine ratio
UGT1A1
Uridine glucuronosyltransferase 1 family, polypeptide A1 
ULN
Upper limit of the normal range
UPCR
Urine protein-to-creatinine ratio
US
United States
WHO
World Health Organization


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a serious global health care problem and one of the principal causes 
of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Of the estimated 
2 billion people worldwide who have been acutely infected with the hepatitis B virus (HBV), 
approximately 400 million have developed CHB, and approximately 1 million people die 
annually from complications of CHB {2331}. Despite the availability of HBV vaccine programs 
in many countries, new HBV infections are still common even in areas of low endemicity. For 
example, approximately 80,000 people in the United States (US) become acutely infected each 
year, according to an estimate from the Centers for Disease Control and Prevention {5047}. 
Following acute HBV infection, approximately 5% to 10% of adults and up to 90% of children 
fail to produce an immune response adequate to clear the infection; these individuals become 
chronic carriers of the virus {3273}.
Chronic hepatitis B has a broad clinical spectrum, ranging from asymptomatic, slowly 
progressive illness to severe, and more rapidly progressive liver disease. Chronic hepatitis B may 
remain quiescent for many years and represent a risk factor for progression to cirrhosis, liver 
failure, and death within a few years. Approximately 25% of subjects with CHB will ultimately 
develop serious liver disease such as hepatic decompensation, cirrhosis, or HCC {3273}. The 
development of nucleos(t)ide analogues has been a major breakthrough for the treatment of 
CHB, providing effective suppression of viral replication and reducing the risk of long term 
complications. However, if viral replication resumes as a result of resistance mutation 
development, the clinical benefit is lost. The rate of resistance development in treatment-naive 
subjects varies depending on the treatment: up to 70% after 4 years with lamivudine (LAM), up 
to 29% after 5 years with adefovir dipivoxil (ADV), 25%/11% in hepatitis B e antigen 
positive/negative (hepatitis B e antigen [HBeAg]+/) subjects after 2 years with telbivudine 
(LdT), and 1.2% after 5 years with entecavir (ETV). To date, resistance to TDF has not been 
documented {18841}.
Tenofovir DF (Viread) 300 mg once daily was first approved for the treatment of CHB in 
Turkey on 28 March 2008, and is currently approved in 101 countries, including the US, Canada, 
and Europe. Approval of TDF for CHB was based primarily on 48 week data from 375 adult 
subjects with HBeAg− CHB and 266 subjects with HBeAg+ CHB who enrolled in the similarly 
designed pivotal studies GS-US-174-0102 (HBeAg− subjects) and GS-US-174-0103 (HBeAg+ 
subjects). In study GS-US-174-0102, TDF 300 mg once daily was shown to be superior to ADV 
10 mg once daily for the treatment of HBeAg/antibody to hepatitis B e antigen 
(anti-HBe)-positive (presumed precore mutant) chronic HBV infection. At 48 weeks, 70.8% of 
subjects in the TDF group (n = 250) had a complete response (plasma HBV deoxyribonucleic 
acid [DNA] < 69 IU/mL [400 copies/mL] and histologic improvement characterized by ≥2 point 
reduction in the Knodell necroinflammatory score and no worsening of Knodell fibrosis), 
compared to 48.8% of subjects in the ADV group (n = 125; p < 0.001) {11363}. In study 
GS-US-174-0103 (HBeAg+ subjects), at 48 weeks, 66.5% of subjects in the TDF group 


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(n = 176) had a complete response, compared to 12.2% in the ADV group (n = 90; p < 0.001) 
{11362}. Subjects in both studies who completed the 48-week double-blind treatment period 
(including the end-of-blinded-treatment biopsy) were eligible to continue in an open-label (OL) 
extension phase consisting of treatment with TDF up to Week 480 (Year 10). 
In both Phase 3 studies, for viremic subjects originally randomized to ADV who rolled over to 
open-label TDF at Week 48, HBV DNA values decreased sharply during the first 16 weeks of 
TDF therapy. At Week 96, the percentages of subjects with plasma HBV DNA < 400 copies/mL 
were not significantly different between treatment groups in both studies. Viral suppression was 
maintained through Week 240 of these 2 pivotal studies in those subjects receiving continued 
treatment with TDF for 240 weeks (TDFTDF group), and in those subjects who received 
192 weeks of TDF treatment following an initial 48 weeks of treatment with ADV (ADVTDF 
group). Based on results from a pooled histology analysis at Year 5 for these 2 studies, 96.2% of 
subjects on open-label TDF experienced either improvement or no change in fibrosis (by Ishak 
fibrosis scoring). Further, of the 96 subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 
25% experienced no change in Ishak fibrosis score while 73% experienced reversal of cirrhosis 
by Week 240 with a reduction in Ishak fibrosis score of at least 2 points (missing = excluded 
[M = E], data after addition of emtricitabine [FTC] included) {24192}. Importantly, viral 
suppression (HBV DNA < 69 IU/mL or < 400 copies/mL was documented in 330/334 (99%) of 
subjects with available histology who were maintained on therapy with an available HBV DNA 
measurement at Week 240. No mutations associated with TDF resistance developed in subjects 
treated with TDF for up to 5 years in the pivotal studies.{24192} No phenotypic resistance to 
TDF has been observed among subjects with virologic breakthrough or who developed 
conserved-site changes in the HBV polymerase (pol)/reverse transcriptase (RT) during TDF 
treatment for up to 5 years. Continued treatment with TDF for 5 years revealed no new adverse 
reactions inconsistent with the known safety profile of TDF. Importantly, these results 
demonstrate that achievement and maintenance of long term viral suppression with TDF 
translates into a histological benefit (i.e. fibrosis regression) in the majority of subjects.
While liver biopsy provides important information regarding severity of necroinflammatory 
activity and fibrosis in diseases such as CHB, it is no longer considered routine in clinical 
practice for ongoing disease monitoring, and the procedure itself is challenging to perform within 
the context of clinical trials.  Additionally, liver biopsy is costly and limited by sampling error as 
well as patient reluctance to undergo this invasive procedure. With the availability of non-
invasive tests, including FibroTest® (also known as FibroSURE in the U.S.) and Fibroscan®, 
which have been shown to correlate with histology in liver diseases such hepatitis B {24463}, 
hepatitis C {24462}, and non-alcoholic fatty liver disease {12037}, the need for liver biopsy has 
been largely replaced, particularly for ongoing monitoring of changes in fibrosis.
Tenofovir DF is also approved worldwide in many markets for administration in combination 
with other antiretroviral agents for treatment of human immunodeficiency virus (HIV)-1 
infection (first approval in 2001). Tenofovir DF is also a component of Truvada(FTC 
200 mg/TDF 300 mg), a marketed fixed-dose combination product for treatment of HIV-1 
infection in combination with other antiretroviral agents. More recently, TDF has been included 
in single tablet regimens (STRs) for treatment of HIV infection. Three STRs are currently 


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approved for once-daily administration in the treatment of HIV-1 infection, efavirenz 
(EFV)/FTC/TDF (Atripla®), FTC/rilpivirine (RPV)/TDF (Complera/Eviplera), and more 
recently, elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TDF (Stribild™). The newly approved 
Stribild™STR tablet, which contains a fixed-dose combination of E/C/F/TDF 
(150/150/200/300 mg), has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HIV-1 infection in treatment-naïve adults. E/C/F/TDF 
is the first approved STR that combines an integrase strand transfer inhibitor (elvitegravir) with a 
nucleoside reverse transcriptase inhibitor (NRTI) backbone into a once-daily tablet. Since 
Viread® was first marketed on 31 October 2001, the overall exposure to TDF up to 31 May 2013 
from branded Viread®, Truvada®, Atripla®, Complera® and Stribild®, combined up to 
31 May 2013, is estimated to be in excess of 6 million patient years
TDF is a preferred oral N(t)RTIs for treatment of CHB infection by all current treatment 
guidelines.  For the majority of CHB subjects, life-long treatment is required as only a small 
percentage (< 10%) of subjects experience sustained loss of hepatitis B surface antigen (HBsAg), 
and as a consequence, achieve an effective cure of the disease. Though highly effective, long 
term use of TDF is associated with nephrotoxicity and reduced bone mineral density in some 
subjects {21769}. Thus, alternative therapies with high antiviral potency, a high genetic barrier to 
resistance development, and improved long term safety and tolerability are needed in order to 
further advance treatment of chronic HBV infection worldwide.
Tenofovir alafenamide (TAF), a novel “intracellular” prodrug of tenofovir (TFV), has the 
potential to advance treatment of chronic HBV infection.  In contrast to TDF, an oral prodrug 
that is rapidly cleaved by esterases in the intestines and plasma to TFV, TAF has been 
specifically synthesized to be more stable in resisting early enzymatic cleavage following oral 
administration and remain mostly intact until penetrating target cells. By virtue of this key 
distinguishing property, TAF when administered at a lower dose than TDF, is capable of 
efficiently delivering active drug (e.g. tenofovir diphosphate [TFV-DP]) to the cells where it is 
needed (e.g. HBV-infected hepatocytes, HIV-infected lymphoid cells) while systemic exposures 
of TFV are greatly reduced in comparison to oral administration of TDF 300 mg. These features 
are hypothesized to translate into the potential for effective suppression of viral replication and 
an improved tolerability and safety profile.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is a next generation oral 
prodrug of TFV, a nucleotide analog that inhibits reverse transcription in HIV-1 and HBV. TFV
is metabolized intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) and HBV pol/RT that terminates the 
elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance 
have been used in various studies: GS-7340, synonym for GS-7340 as the free base; 
GS-7340-02, synonym for TAF monofumarate (1:1); and GS-7340-03 as the hemifumarate (2:1). 
GS-7340-03, also known as TAF fumarate, the form being used in GS-US-292-0102 (Phase 2 


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study in HIV subjects) and GS-US-320-0101 (Phase 1b study in HBV subjects), is considered 
comparable to GS-7340-02 based on physical/chemical properties of GS-7340-02, the form that 
has been used in previous studies and a number of currently ongoing studies. Importantly, both 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids.
For further information on TAF (GS-7340), please refer to the latest Investigator’s Brochure for 
GS-7340.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
TAF is converted intracellularly by cathepsin A (CatA) and carboxylesterase-1 (Ces1) to form 
TFV (i.e, a nucleoside monophosphate analog) which is not dependent on an intracellular 
nucleoside kinase activity for the first step in the conversion to the active metabolite, and is 
subsequently converted to TFV-DP by cellular kinases. The cellular enzymes responsible for 
TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) {13} and 
nucleotide diphosphate kinase, which are highly active and ubiquitous. AK exists as multiple 
isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most efficiently by AK2. 
Analysis of primary cells showed that CatA activity varied minimally in both human cluster of 
differentiation 4 (CD4+) T-lymphocytes and macrophages.  CatA activity was equivalent in 
resting and activated CD4s and approximately 2-fold higher in macrophages.  Intracellular 
metabolites of TAF were similar among individual donors in both CD4+ T-cells and 
macrophages. Carboxylesterease-1 (Ces1) which is highly expressed in liver, contributes to TAF 
conversion to TFV, particularly in hepatocytes {20205}, {21378}.
The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T-cells, NK cells, B-cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite 
TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations. 
Additionally, a 24-hour continuous incubation of TAF in primary human hepatocytes in vitro 
resulted in approximately 120- or 5-fold higher levels of TFV-DP compared to incubation of 
TFV or TDF, respectively (AD-120-2017).
1.2.2.2.
Safety Pharmacology
TAF monofumarate (GS-7340-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006) and 
gastrointestinal systems (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). GS-7340-02 (at 1000 mg/kg) reduced distal 
transit and increased stomach weights starting 2 hours post dosing with reversibility beginning 
by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. The IC50 for the 
inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current was estimated to be 
greater than 10 μM.


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1.2.2.3.
Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate (GS-7340-02), and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of GS-7340-02 is equivalent to 80 mg of the GS-7340 free 
base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with 
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted), and 8.1 to 
12.5 hours in rhesus monkeys. 
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the 
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that 
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug based on 
IV studies of TFV. Following oral administration of GS-7340-02, approximately 15% of a 
radiolabeled dose is recovered in dog urine in 24 hrs. TFV was the major species present in the 
urine (90%), with about 3.4% of TAF also present. Biliary excretion of TFV in dogs and fecal 
elimination of TFV in rats and dogs are negligible.
Tenofovir was the only species found in the intestinal contents and feces. In human systems, 
TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed 
oxidation (AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4, inhibition 
or induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has 
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1 
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or 
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma 
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by 
clinically relevant drug-drug interactions is very low.
The hepatic extraction of TAF was estimated to be 70% suggesting that TAF was rapidly cleaved 
by hepatic hydrolases including Ces1 and CatA {23907}.  An in vitro study to evaluate effects of 
inhibitors of CatA or Ces1 on TAF metabolism in primary human hepatocytes is ongoing. Single 
and repeat dose dog liver pharmacokinetic studies are planned.


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1.2.2.4.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months and was negative in genetic toxicology studies.
In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. GS-7340-02 also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above.  In chronic 
studies in dogs after 9 months of treatment with GS-7340-02, the primary target organs were 
kidney and bone.  
GS-7340-02 had no discernible electrocardiograph (ECG/EKG) effect at the low dose of 
2 mg/kg/day and slightly prolonged PR intervals at 6 and 18/12 mg/kg/day (started at 
18 mg/kg/day, then reduced to 12 mg/kg/day at Weeks 7-8). Additionally, at Week 39, 
GS-7340-02 appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but was 
reversible at the 3 month recovery period. Minor hematological and biochemistry parameters 
changes were observed but remained within normal historical ranges with the following 
exceptions: AST (~ 100% increase) and total bilirubin (~ 40% increase). There were no clear 
treatment-related effects observed in monkeys following 28 days of treatment, including no 
changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day (tenofovir 
AUC = 3758 ng•h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day (tenofovir 
AUC = 1180 ng•h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (tenofovir AUC = 5870 ng•h/mL). In conjunction with the nonclinical data with 
TDF and the clinical experience with TDF and TAF, these toxicology studies support studies in 
humans of doses up to 150 mg/day (equivalent to 120 mg free base, the highest anticipated 
human dose) for chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable TFV exposures 
less than previously tested in chronic and carcinogenicity studies with TDF, carcinogenicity 
studies in mice and rats with TAF are currently not required per agreement with FDA and EMA.
Also, TAF does not need to be evaluated in perinatal-postnatal reproductive toxicology studies
per agreement with FDA and EMA. Reproductive tissues were examined in repeat-dose 
toxicology studies in the rat, dog, and monkey. There were no clearly treatment-related 
histologic alterations or changes in organ weights in the rat and the dog following chronic daily 
dosing, or in the monkey. 
The TAF fumarate (GS-7340-03) oral rat fertility study is ongoing (Report No. TX-120-2012;
report in progress). 


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1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
To date, a total of 8 Phase 1 and Phase 1/2, or Phase 2, clinical trials of tenofovir alafenamide 
(TAF) have been conducted or are ongoing in 528 subjects. This includes seven HIV studies 
(total of 477 subjects; 2 completed Phase 1/2 studies [68 subjects], 3 completed Phase 1 studies 
[83 subjects], and 2 ongoing Phase 2 studies [326 subjects]), and 1 Phase 1b HBV study 
(completed enrollment; 51 subjects).  TAF is presently in Phase 3 for treatment of HIV-1 
infection in combination with E, C and F, and a Phase 1b study has completed enrollment and 
dosing for treatment of chronic HBV. 
Clinical trials entailing the use of TAF (dose[s] studied) for HIV-1 infection and other Phase 1 
studies include:

GS-120-1101, a Phase 1/2 study of the pharmacokinetics and antiviral activity of TAF 
(GS-7340 [50 mg and 150 mg]) in HIV infected subjects (completed)

GS-US-120-0104, a Phase 1b study of the pharmacokinetics and antiviral activity of 
GS-7340 (8 mg, 25 mg, 40 mg) in HIV infected subjects (completed)

GS-US-120-0107, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-7340 (25 mg and 150 mg) on the QT/QTc interval in 
healthy subjects (completed)

GS-US-120-0108, A Phase 1, Open-Label, Parallel-Design Study to Evaluate the 
Pharmacokinetics of GS-7340 (25 mg) in Subjects with Severe Renal Impairment 
(completed)

GS-US-120-0109, A Phase 1 Study to Evaluate the Pharmacokinetics, Metabolism and 
Excretion of GS-7340 (25 mg [completed])
Further details regarding these studies are provided in the table below (Table 1-1). In Phase 1/2 
studies in HIV-infected subjects (Studies 120-1101 and 120-0104), the short-term 
safety/tolerability, PK, and antiviral activity of TAF when given as a stand alone agent (SA) 
were evaluated over a range of doses.  In Study 120-0104, at TAF doses of 25 mg or higher, 
near-maximal HIV RNA suppression was observed at Day 10, and importantly, single dose PK 
assessments of TAF (8 mg, 25 mg, or 40 mg) and TDF (300 mg) demonstrated that the 
TAF-generated TFV systemic exposures (AUCinf) were markedly lower (approximately 90% 
lower at TAF 25 mg) than the TFV exposure generated with TDF 300 mg.  For HIV Phase 2 
(and Phase 3) studies, however, a 10 mg dose of TAF was selected for inclusion as a component 
of the elvitegravir (E)/ cobicistat (COBI, or “C”)/emtricitabine(F)/TAF single tablet regimen 
(STR) in comparison to the E/C/F/TDF STR control arm. A reduction in dose from 25 mg to
10 mg of TAF in the E/C/F/TAF STR is required based on a drug-drug interaction between TAF 
and COBI resulting in increased exposures of both TAF and TFV which is likely a consequence 
of Pgp-mediated inhibition of TAF and TFV efflux within the gut by COBI. Importantly, the 
resultant TFV exposures when TAF is dosed at 10 mg with COBI in the E/C/F/TAF STR 


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formulation are similar to TFV exposures generated with TAF 25 mg given as a SA.  Given that 
TAF exposures with E/C/F/TAF 
10 mg are comparable to those with TAF given alone, safety results in HIV trials using this 
formulation are being assessed at a TAF dose that is considered therapeutically equivalent to 
TAF 25 mg.  Thus, HIV studies conducted at TAF exposures similar to those expected in HBV 
provide the basis for supporting safety data for the TAF HBV development program.
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection
Study #
Population
Design
Dosing/Duration
Rationale
HIV Studies (Phase 1/2)
120-1101
N = 30
Treatment naïve
Dose escalation
3 treatment 
cohorts
TAF 50 mg, 150 mg, TDF 
300 mg; multiple dosing for 
14 days
Short-term proof of 
concept study;
safety, PK, and antiviral 
efficacy
120-0104
N = 38
Treatment naïve
(no ARV within 90 
days of screening)
Randomized 
(2:2:2:1:2) 
partially blinded
TAF 8 mg, 25 mg, 40 mg, 
TDF 300 mg, or placebo 
(PBO) for 10 days; off 
treatment follow up to Day 
21
Confirmatory study for 
Study 1101 using a TAF 
reformulation; more 
rigorous design, evaluate 
lower TAF doses
Ongoing Supportive Phase 1 Studies
120-0107
N = 48
Males/females, 
age 18-45
Thorough QT 
(TQT)
TAF 25 mg, 125 mg;
each subject dosed 3 times 
for 37 days (with 10 day 
wash-out period)
Regulatory requirement
120-0108
N = 27 
(14 with severe 
renal impairment 
[CrCL 15-29 
mL/min] and 
13 matched 
controls [CrCL 
≥90 mL/min])
PK in Renal 
impairment
TAF 25 mg single dose 
with 14 days of follow up
Characterizing TAF and 
TFV PK in severe renal 
impairment (to 
demonstrate no need for 
TAF dose adjustment)
120-0109
N = 8
healthy volunteer, 
male subjects
Mass Balance
Single radio-labeled TAF 
25 mg dose with  21 days of 
follow up
Regulatory requirement
Clinical trials entailing the use of TAF for the treatment of CHB virus:

GS-US-320-0101 A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess 
the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naïve Adults 
with Chronic Hepatitis B (CHB) Infection (enrollment and dosing completed)


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The two proof-of concept studies, GS-120-1101 and GS-US-120-0104, as well as 
GS-US-292-0101, a STR bioequivalence study, were performed using TAF monofumarate 
(GS-7340-02). All subsequent studies discussed herein were performed using TAF fumarate 
(GS-7340-03). 
GS-120-1101 was a Phase 1/2 randomized double-blind, active-controlled, dose escalation study 
of the safety, tolerance, pharmacokinetics, and antiviral activity of TAF in antiretroviral-naïve 
subjects who are chronically infected with HIV-1. The subjects were randomized to receive 
14 days of monotherapy, fasting, with GS-7340-02 50 mg (40 mg GS-7340 [free base]
equivalent) QD, 150 mg (120 mg GS-7340 [free base] equivalent) QD, or tenofovir DF 300 mg 
QD (n = 10 per group). TAF was rapidly absorbed into the systemic circulation, and 
subsequently following attainment of Cmax, was eliminated rapidly with a short plasma half-life 
(20-40 minutes). Compared with TDF, GS-7340-02 50 mg provided a ~16-fold lower TFV Cmax
(207 ng/mL vs 13 ng/mL), about 2-fold longer elimination half-life (26 hours vs 48 hours) and 
lower overall systemic tenofovir exposure (AUCinf: 1814 ng.h/mL vs 383 ng.h/ml). TAF 
monofumarate 150 mg provided lower Cmax (42 ng/mL), but comparable AUCinf: (1740 ng.h/mL) 
as TDF. In PBMCs, TFV was detected earlier, more frequently, and in higher concentrations 
following dosing of TAF monofumarate as compared to TDF. The intracellular delivery of TFV
is approximately 30-fold greater for GS-7340-02 versus TDF. The decrease from Baseline to 
Day 14 in plasma HIV-RNA levels was greater for groups treated with GS-7340-02 50 mg 
(p = 0.02757) or 150 mg (p = 0.0010) than the group that received TDF 300 mg. The median 
changes from baseline in plasma HIV-1 RNA after 14 days of monotherapy were 
−0.96 log10 copies/mL for TDF 300 mg, −1.65 log10 copies/mL for GS-7340-02 50 mg, and 
−1.68 for GS-7340-02 150 mg. 
A second proof-of-concept study, GS-US-120-0104, evaluated monotherapy, fasting, with three 
lower doses of TAF compared with TDF 300 mg, or placebo, administered for 10 days. Potent 
antiviral activity was achieved with TAF in treatment-naïve HIV-1 infected subjects; mean viral 
load declines for both the 25 mg and 40 mg doses were statistically better than the 8 mg dose. 
TAF exposure (AUC) was best associated with antiviral activity despite its short plasma half-life 
(~ 30 min). TFV AUC values were 97%, 87%, and 80% lower at 8 mg, 25 mg, and 40 mg TAF
respectively, compared to TDF administration. When compared to 40 mg and historical 120 mg 
data, 25 mg TAF provides near maximal anti-HIV-1 activity. From this PK-PD analysis, a target 
exposure of a dose of 25 mg TAF monotherapy is expected to provide near maximal antiviral 
activity and ~ 90% reduction in circulating TFV. 
Study GS-US-120-0107 is a Phase 1, partially-blinded, randomized, placebo- and 
positive-controlled study to evaluate the effect of TAF on the QT/QTc interval in healthy 
subjects. This was a negative thorough-QTc study.  No effect of TAF was observed on the QTcF 
interval (ie, no QTc interval prolongation > 10 msec at any time point post-dose and assay 
sensitivity was confirmed via the positive control [moxifloxacin]). As such, these findings satisfy 
the guidelines set forth in the International Conference on Harmonization (ICH) E14 guidance 
and support the conclusion that there is no significant effect of TAF on the QT/QTc interval.
Study GS-US-120-0108 is a Phase 1, open-label, parallel-design study to evaluate the PK of TAF 
in subjects with severe renal impairment. TAF was well tolerated in the study. Subjects with 


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severe renal impairment had < 2-fold higher TAF and 5-6 fold higher TFV systemic exposures as 
assessed by AUC relative to subjects with normal renal function. TFV exposures in subjects with 
severe renal impairment are comparable to those with normal renal function receiving 300 mg 
TDF QD. Given the extensive safety data available for TDF at a dose of 300 mg, TFV exposures 
in severely renally impaired subjects similar to those associated with TDF 300 mg are deemed 
appropriate for further study of TAF in HIV-infected subjects without TAF dose modification.
Preliminary results from Study GS-US-120-0109, a Phase 1 PK, metabolism and excretion study 
demonstrated that TAF is eliminated in both feces and urine. TAF and its metabolites are 
eliminated in both feces and urine. The predominant species detected in feces and urine is TFV, 
accounting for 31.4% ± 10.4% and 22.2% ± 4.47% respectively of the total radioactive dose.
These human data are consistent with the established preclinical profile of TAF. Following
administration of TAF, plasma [14C] radioactivity showed a time dependent profile with TAF as 
the most abundant species in the initial few hours and uric acid, a byproduct of TAF metabolism, 
in the remaining period. The whole blood-to-plasma concentration ratio of [14C] radioactivity 
increased from 0.511 at 0.25 hours post dose to 2.32 at 216 hours post dose, suggesting a 
relatively slower clearance of [14C] radioactivity from blood cells relative to the plasma [14C]
radioactivity time-course. In addition to TFV and uric acid, additional low quantities of 
metabolites were formed, including xanthine, hypoxanthine, and adenine. They are identical to 
the endogenous products of purine metabolism and therefore should not cause any safety risk. 
TAF 25 mg tablets administered together with tracer dose of [14C] radiolabeled TAF as a single 
oral tablet, were well tolerated.
HBV Study – GS-US-320-0101 
In HBV subjects, a 28 day Phase 1b study (GS-US-320-0101), was conducted to evaluate 
safety/tolerability, pharmacokinetics, and antiviral activity of TAF at doses of 8 mg, 25 mg, 
40 mg, and 120 mg compared to TDF 300 mg control in 50 subjects (10/cohort). As of 
April 2, 2013, enrollment was completed (n = 51) and all subjects have completed study drug 
dosing through Day 29.
Preliminary data suggest that all treatment groups were generally well matched (Table 1-2) and 
representative of the chronic HBV population. Overall, the majority of subjects were male 
(66.7%), and of Asian descent (56.9%). Of the 51 randomized subjects, 27 (53%) and 24 (47%) 
were HBeAg-negative and HBeAg-positive, respectively.  Median age ranged among groups 
from 34 years in the 8 mg and 25 mg TAF groups to 40 and 42 years in the 40 mg and 120 mg 
TAF groups, respectively; median age in the TDF group was 34 years.  The most common HBV 
genotype at enrollment was genotype C (16/51; 31%), the proportions of other genotypes were: 
A (7/51; 14%), B (10/51; 20%), D (9/51; 18%), and E (9/51; 18%).  The distribution of HBV 
genotypes was similar within groups, with the exception of a higher proportion (5 of 11 [45.5%]) 
of subjects in the 40 mg TAF group having genotype B.




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experienced this abnormality at Day 29 which was associated with a corresponding serum 
glucose elevation (212 mg/dL); the subject also had a history of diabetes mellitus.
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and 
Laboratory Abnormalities: Overall Summary, Safety Analysis Set
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(N = 10)
TDF 300 mg
(N = 10)
Subjects Experiencing Any 
Treatment-Emergent Adverse 
Event
7 (70%)
6 (60%)
6 (55%)
8 (80%)
5 (50%)
Subjects Experiencing Any 
Treatment-Emergent Study
Drug-Related Adverse Event
2 (20%)
4 (40%)
3 (27%)
4 (40%)
5 (50%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-
Emergent Adverse Event
1 (10%)
1 (10%)
0
4 (40%)
2 (20%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-
Emergent Study Drug-Related 
Adverse Event
0
0
0
3 (30%)
1 (10%)
Subjects Experiencing Any 
Grade 3 or 4 Treatment-
Emergent Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Grade 3 or 4 Treatment-
Emergent Laboratory 
Abnormality
0
0
3 (27%)
2 (20%)
1 (10%)
Subjects Experiencing Any 
Treatment-Emergent Serious 
Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Treatment-Emergent Adverse 
Event Leading to Premature 
Study Drug Discontinuation
0
0
0
0
0
Given the significantly smaller declines in creatinine clearance (CLCr) observed at Week 24 with 
TAF relative to TDF in the HIV Phase 2 study (GS-US-209-0102; Section 1.2.4), changes in 
CLCr were also assessed in HBV subjects participating in GS-US-320-0101.  After 4 weeks of 
dosing, numerically smaller changes in CLCr at Day 29 were seen in HBV subjects receiving 
TAF compared with TDF (Figure 1-1).  At Day 29, median (range) change from baseline in CLCr
was -2.0 (-13.2, 9.6) mL/min for the TAF 25 mg group compared with a change of -10.4 (-35.7, 
13.0) mL/min in the TDF group.  Further, there were no notable differences in CLCr change 
among the two lowest dose groups (TAF 8 mg and TAF 25 mg), and the highest dose group 
(120 mg). An early decline in CLCr, similar to that observed in the TDF group was noted in the 
TAF 40 mg group; however, by Day 29 the change in CLCr was similar to the other TAF groups. 


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These results are consistent with findings in HIV subjects receiving the E/C/F/TAF 10 mg STR 
and provide additional evidence to support the concept that lower TFV exposures with TAF 
relative to TFV exposures with TDF are associated with notable differences in renal function as 
determined by estimated CLCr.
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance 
(Cockcroft-Gault Method) in GS-US-320-0101
Baseline is defined as Day 1.
Over 28 days of study drug treatment, similar median declines in HBV DNA levels were 
observed among treatment groups (Figure 1-2).  Overall, viral decay results among subjects who 
received treatment with TAF demonstrated the absence of a dose effect. In addition, the HBV 
DNA declines with TAF (n = 41) over 28 days of dosing were similar to HBV DNA declines 
observed in the TDF 300 mg group (n = 10).  A summary of change from baseline in HBV DNA 
results at Day 15 and Day 29 is provided in the table below (Table 1-4) below.  Among TAF 
groups, median change from baseline in HBV DNA at Day 29 ranged from -1.98 log10 IU/mL for 
the TAF 40 mg group to -2.76 log10 IU/mL for the TAF 8 mg group. For TAF 25 mg, the change 
from baseline in HBV DNA at Day 29 was -2.67 log10 IU/mL.  Consistently smaller declines in 
HBV DNA over time, and slightly lower median change from baseline in HBV DNA were
observed in the TAF 40 mg group at Day 29. The reason for this is unclear and possibly related 
to a lower median HBV DNA value at Baseline (Table 1-4).  In this group, 5/11 (45.5%) subjects 
had a baseline HBV DNA value below 5.0 log10 IU/mL.  In comparison to TAF groups, the
change from baseline in HBV DNA at Day 29 was -2.60 log10 IU/mL with TDF 300 mg. 




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Plasma concentration-time profiles were generated after intensive pharmacokinetic sampling 
following a single dose on Day 1 for subjects who were randomized to receive TAF 8, 25, 40, or 
120 mg, or TDF 300 mg (N=51). The respective plasma concentration-versus-time profiles are 
shown in Figure 1-3 and Figure 1-4 (TFV). Pharmacokinetic parameters were calculated via 
non-compartmental analysis. 
TAF Pharmacokinetic Results
In general, the concentration-time profiles for TAF over the range of doses studied in CHB 
subjects were consistent with previous results in the healthy volunteers and HIV subjects 
receiving TAF either as a single agent or as a component of the E/C/F/TAF STR.
Figure 1-3.
GS-US-320-0101:  Mean (SD) Plasma Concentrations vs. Time on 
Day 1: TAF (GS-7340), Linear Scale
TAF plasma pharmacokinetic parameters are summarized in Table 1-5. Day 1 pharmacokinetic 
results in CHB subjects participating in GS-US-320-0101 are consistent with previously reported 
results in the HIV Phase 1/2 study GS-US-120-0104, which evaluated TAF single-dose 
pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 40 mg (n=8), versus TDF 
300 mg (n=6). In GS-US-120-0104, mean (%CV) AUC0-last was 38.4 (80.6) ng∙h/mL, 
139.7 (57.8) ng∙h/mL, and 322.1 (42.0) ng∙h/mL after single doses of TAF 8 mg, 25 mg, and 
40 mg, respectively. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to the results generated in GS-US-120-0104.
Similar findings to the present study were also observed when TAF pharmacokinetic parameters 
were assessed after multiple doses at steady-state in the ongoing Phase 2 study, 


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GS-US-292-0102, which compares STRs of E/C/F/TAF 10 mg to E/C/F/TDF 300 mg in HIV-1 
infected, treatment-naive subjects. Mean (%CV) AUClast, and Cmax values for TAF at the 10 mg 
dose in combination with COBI were 230.4 (47.3) ng∙h/mL and 232.8 (64.6) ng/mL, 
respectively. As TAF exposures at the 10 mg dose, when included as a component of the 
E/C/F/TAF STR, have been shown to be comparable to those with TAF 25 mg given as the 
stand-alone agent, these results indicate similar TAF exposures in both subjects infected with 
HIV and those infected with HBV.  
Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on 
Day 1
TAF PK Parameter
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(N = 11)
TAF 120 mg
(N = 10)
AUC0-last (ngh/mL)
59.2 (54.1)
153.0 (41.1)
328.1 (58.4)
832.4 (39.1)
AUCinf (ngh/mL)
60.6 (52.8)
154.4 (41.0)
329.8 (58.1)
834.6 (38.9)
Cmax (ng/mL))
83.2 (46.3)
249.5 (45.9)
527.4 (50.6)
1128.7 (33.7)
Tmax (h)
median
0.5
0.5
0.5
0.5
T1/2 (h)
0.36 (23.8)
0.51 (32.6)
0.59 (30.7)
0.76 (30.8)
All results expressed as mean (%CV) unless otherwise stated
TFV Pharmacokinetic Results
Mean (SD) plasma concentration versus time profiles for TFV following single dose 
administration of ascending doses of TAF and TDF 300 mg are shown in Figure 1-4. At each 
TAF dose evaluated, plasma TFV concentrations resulting from TAF administration were lower 
than plasma TFV concentrations following TDF administration. The TFV concentrations 
achieved from all TAF dose levels in HBV subjects in GS-US-320-0101 are comparable to TFV 
concentrations achieved after TAF administration in the HIV program.


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Figure 1-4.
GS-US-320-0101:  Mean (SD) Plasma Concentrations vs. Time on 
Day 1: Tenofovir, Linear Scale
Tenofovir (TFV) plasma pharmacokinetic parameters are summarized in Table 1-6. As with 
TAF, Day 1 TFV pharmacokinetic results in CHB subjects participating in GS-US-320-0101 are 
consistent with those previously reported in the HIV Phase 1/2 study GS-US-120-0104, which 
evaluated TAF single-dose pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 
40 mg (n=8), versus TDF 300 mg (n=6). In GS-US-120-0104, mean (%CV) AUCinf for TFV 
were 49.4 (30.3) ng∙h/mL, 195.9 (27.2) ng∙h/mL, and 287.3 (33.7) ng∙h/mL after single doses of 
TAF 8 mg, 25 mg, and 40 mg, respectively. Mean (%CV) AUCinf for TFV following TDF 
300 mg was 1719.2 ng∙h/mL. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to results seen in HIV subjects in GS-US-120-0104. As stated 
earlier, When TAF is included as a component of the E/C/F/TAF STR, a reduced dose (10 mg) is
required due to a drug-drug interaction (inhibition of P-gp in the gut by cobicistat) that results in
increased exposures of both TAF and TFV (see Section 1.2.4).


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Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on 
Day 1
TFV PK 
Parameter
TAF 8 mg
(n=10)
TAF 25 mg
(n=10)
TAF 40 mg
(n=11)
TAF 120 mg
(n=10)
TDF 300 mg
(n=10)
AUC0-last 
(ngh/mL)
32.9 (35.0)
90.6 (25.8)
213.4 (40.2)
607.7 (35.4)
1682.1 (28.0)
AUCinf 
(ngh/mL),
74.0 (41.2)
171.4 (29.9)
444.6 (43.0)
1572.0 (47.2)
2309.8 (27.9)
Reduction in 
AUCinf, 
TAF/TDF (%)
97
93
81
32
N/A
Cmax (ng/mL),
3.0 (34.5)
8.3 (41.6)
20.3 (43.2)
61.0 (33.5)
306.8 (24.5)
Reduction in 
Cmax, 
TAF/TDF (%)
99
97
93
80
N/A
Tmax (h)
median
1.25
1.0
1.0
1.0
1.0
t1/2 (h)
26.7 (23.4)
20.7 (39.6)
26.3 (33.8)
31.4 (38.6)
10.8 (17.4)
The following Section (1.2.4) provides a summary of experience with TAF in HIV-1 infection, 
including the final Week 24 analysis results for TAF when used as a component of the 
E/C/F/TAF STR in the HIV Phase 2 study GS-US-292-0102.  Because TAF exposures in this 
ongoing trial are similar to those expected in the TAF HBV development program, these results 
provide important supporting safety data.
1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)
Phase 1 and 2 clinical trials using TAF, coformulated into the E/C/F/TAF STR for the treatment 
of HIV-1 infection include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI when administered as E/C/F/TAF STR relative to E/C/F/TDF or 
TAF (completed)

GS-US-292-0103, a Phase 1 healthy volunteer study to evaluate the pharmacokinetics and 
relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
GS-7340 doses of 10 mg (STR) or 25 mg SA (completed)

GS-US-292-0102, a Phase 2 randomized, double-blinded study of the safety and efficacy of 
E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, antiretroviral treatment-naive 
adults (ongoing)


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1.2.4.1.
Summary of Phase 1 Studies (Study GS-US-292-0102, GS-US-292-0103)
Study GS-US-292-0101 is a completed Phase 1 study of 40 subjects evaluating the relative 
bioavailability of two different formulations of E/C/F/TAF STR, each with TAF dose of 25 mg 
or 40 mg, versus E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, and FTC 
were comparable between E/C/F/TAF vs E/C/F/TDF regardless of formulation (monolayer or 
bi-layer). In contrast, TAF exposures were ~2.2-fold higher (and corresponding tenofovir 
exposures ~ 3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 25 mg for both 
formulations of the E/C/F/TAF. This is likely mediated by inhibition of Pgp-mediated intestinal 
secretion of TAF by COBI and consistent with data from Study GS-US-311-0101 described 
below. 
Study GS-US-292-0103 is a completed Phase 1 healthy volunteer study which evaluated the PK 
and relative bioavailability of the E/C/F/TAF STR relative to the individual components at TAF 
doses of 10 mg (as STR) or 25 mg SA. Results indicate that when dosed as the E/C/F/TAF 
10 mg STR, TAF and TFV exposures were comparable to those observed with TAF 25 mg dosed 
alone. Exposures of EVG, COBI, and FTC were also comparable between the STR and 
individually dosed formulations. 
1.2.4.2.
Week 24 Summary of Phase 2 Study (Study GS-US-292-0102)
GS-US-292-0102 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of E/C/F/TAF STR versus E/C/F/TDF in 
HIV-1 infected, antiretroviral treatment-naive adults with plasma HIV-1 RNA levels 
≥5,000 copies/mL at Screening. 
Eligible subjects were randomized in a 2:1 ratio to 1 of the following 2 treatment arms and 
randomization was stratified by HIV-1 RNA level (≤ 100,000 copies/mL or 
> 100,000 copies/mL) at Screening:

Treatment Arm 1: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TAF 10 mg 
(E/C/F/TAF) + placebo-to-match STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TDF 
300 mg (E/C/F/TDF) once daily (n = 100)

Treatment Arm 2: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TDF 300 mg 
(E/C/F/TDF) + placebo-to-match STR EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TAF 
10 mg (E/C/F/TAF) once daily (n = 50)
The Independent Data Monitoring Committee (IDMC) reviewed the safety and study conduct at 
Week 12 and determined that no changes were required for study GS-US-292-0102. Interim data 
at Week 24 is presented below.


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1.2.4.3.
Week 24 Subject Disposition and Demographics
A total of 170 subjects were randomized and treated in this study: 112 subjects in the E/C/F/TAF 
group and 58 subjects in the E/C/F/TDF group. The full analysis set (FAS) and safety analysis 
set (SAS) each included all randomized and treated subjects from each group. A total of 
24 subjects were included in the pharmacokinetic substudy analysis set.  At the time of the 
Week 24 data analysis, 6 subjects (2.4%) had been discontinued from treatment and 4 subjects 
(2.4%) had been discontinued from study. 
Of the 170 subjects in the FAS and SAS, 165 (97.1%) were male; 115 (67.6%) were white and 
50 (29.49%) were black; and the mean age was 36 years (range: 18 to 71 years). Demographic 
and baseline disease characteristics were similar between the 2 treatment groups.
1.2.4.4.
Week 24 Efficacy Results
Proportion of Subjects with Plasma HIV-1 RNA < 50 copies/mL at Week 24
The proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at Week 24 was 86.6% in 
the E/C/F/TAF group and 89.7% in the E/C/F/TDF group, with a stratum-adjusted difference in 
the response rate between the 2 treatment groups of -4.9% (95% CI: −15.7% to 5.9%; p = 0.36).
Results of the secondary efficacy endpoint confirmed those of the primary analysis. The
proportion of subjects with suppression of plasma HIV-1 RNA < 50 copies/mL at Week 24 
(time-to-loss of virologic-response [TLOVR] analysis) was 88.4% (99/112) in the E/C/F/TAF 
group and 84.5% (49/58) in the E/C/F/TDF group. The stratum-adjusted difference in the 
response rate between the 2 treatment groups was −0.1% (95% CI: −10.4% to 10.2%; p = 0.99).
The mean increase in CD4 cell count from baseline to Week 24 was 163 cells/μL in the 
E/C/F/TAF group and 177 cells/μL in the E/C/F/TDF group (-6 difference in LSM, 95% CI -44 
to 33).
1.2.4.5.
Week 24 Pharmacokinetic Results
Results from the intensive pharmacokinetic substudy demonstrated that, consistent with data in 
healthy subjects and HIV-infected subjects treated with TAF monotherapy, E/C/F/TAF (10 mg) 
produced substantially lower tenofovir systemic exposures than E/C/F/TDF (TDF 300 mg). TAF 
exhibited a short median (min-max) plasma half-life of 0.47 (0.37 to 0.87) hours with no 
detectable drug after 8 hours post-administration. Steady-state mean (CV%) AUCtau was
230 ng•hr/mL (47%). PK results for the other components EVG, COBI and FTC were similar to 
historical data for these agents when administered as E/C/F/TDF (data not shown). In addition, 
TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) in subjects in the 
E/C/F/TAF group showed that TFV-DP was detectable within PBMCs at greater exposures 
(approximately 5-fold) after administration of E/C/F/TAF than with E/C/F/TDF.


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1.2.4.6.
Week 24 Safety Results
1.2.4.6.1.
Overall Safety
At the time of the 24-week interim analysis, 112 subjects had been treated with E/C/F/TAF for a 
median duration of 21.1 weeks and 58 subjects had been treated with E/C/F/TDF for a median 
duration of 21.3 weeks. The overall subject incidence of treatment-emergent adverse events 
(AEs) was balanced between treatment groups (81.3% E/C/F/TAF, 81.0% E/C/F/TDF) 
(Table 1-7). The most frequent treatment-emergent AEs (> 10% in either treatment group) were 
(17.9% E/C/F/TAF, 12.1% E/C/F/TDF) nausea, diarrhea (11.6% E/C/F/TAF, 12.1%
E/C/F/TDF), fatigue (11.6% E/C/F/TAF, 8.6% E/C/F/TDF), upper respiratory tract infection 
(7.1% E/C/F/TAF, 12.1% E/C/F/TDF), and headache (9.8% E/C/F/TAF, 10.3% E/C/F/TDF), 
respectively.  
Most treatment-emergent AEs were assessed as Grade 1 or Grade 2 in severity. The incidence of 
Grade 3 or 4 AEs was higher in the E/C/F/TAF group (7.1%) compared to the E/C/F/TDF group 
(3.4%). No Grade 3 or 4 event occurred in > 1 subject; the system organ class (SOC) with the 
highest subject incidence of Grade 3 or 4 events was Nervous System Disorders (2.7% 
E/C/F/TAF, 0% E/C/F/TDF). The only Grade 3 or 4 event that was considered by the 
investigator to be related to investigational product was Grade 3 diarrhea in 1 subject (0.9%) in 
the E/C/F/TAF group; there were no treatment-related Grade 3 or 4 AEs in the E/C/F/TDF 
group. Based on these data, there do not appear to be any signature, higher grade AEs associated 
with the use of E/C/F/TAF through 24 weeks of treatment.
More subjects in the E/C/F/TAF group compared to the E/C/F/TDF group also had treatment-
emergent serious AEs (SAEs) (5.4% vs 3.4%) or AEs leading to premature treatment 
discontinuation (3.6% vs 0). None of these events occurred in > 1 subject, and none of the SAEs 
were considered by the investigator to be related to treatment with investigational product. The 
system organ class (SOC) with the highest subject incidence of treatment-emergent SAEs was 
Infections and Infestations (4.5% E/C/F/TAF, 0% E/C/F/TDF). No deaths or pregnancies 
occurred.


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Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: Overall 
Summary, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Subjects Experiencing Any Treatment-Emergent Adverse Event
91 (81.3%)
47 (81.0%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent 
Adverse Event
42 (37.5%)
17 (29.3%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent 
Adverse Event
8 (7.1%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-
Related Adverse Event
38 (33.9%)
15 (25.9%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent 
Study-Drug-Related Adverse Event
6 (5.4%)
1 (1.7%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent 
Study-Drug-Related Adverse Event
1 (0.9%)
0
Subjects Experiencing Any Treatment-Emergent Serious Adverse 
Event
6 (5.4%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-
Related Serious Adverse Event
0
0
Subjects Experiencing Any Treatment-Emergent Adverse Event 
Leading to Premature Study Drug Discontinuation
4 (3.6%)
0
Subjects who had Treatment-Emergent Death
0
0
Treatment-emergent death refers to a death occurring between the first dose date and the last dose date plus 30 days (inclusive).
At least 1 treatment-emergent laboratory abnormality (ie, at least 1 grade level increase in graded 
abnormality) was reported for 103/111 subjects (92.8%) in the E/C/F/TAF group and 
46/58 subjects (79.3%) in the E/C/F/TDF group. The majority of laboratory abnormalities were 
Grade 1 or 2 in severity. Subject incidence of Grade 3 or 4 treatment-emergent laboratory 
abnormalities is summarized in Table 1-8.


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Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Maximum Post-Baseline Toxicity Grade 3 or 4
19 (17.1%)
8 (13.8%)
Neutrophils
5 (4.5%)
1 (1.7%)
WBC
1 (0.9%)
0
Amylase
2 (1.8%)
1 (1.7%)
Creatine Kinase (CK)
6 (5.4%)
2 (3.4%)
Lipase
0
1 (12.5%)
Serum Glucose (Hyperglycemia)
0
1 (1.7%)
Total Cholesterol (Fasting, Hypercholesterolemia)
1 (0.9%)
0
Triglycerides (Fasting)
1 (0.9%)
1 (1.7%)
LDL (Fasting)
7 (6.4%)
2 (3.4%)
Urine Protein (Proteinuria)
1 (0.9%)
0
Urine RBC (Hematuria, Quantitative)
1 (0.9%)
0
Denominator for percentage is the number of subjects in the SAS with at least 1 post-baseline laboratory value (for the test).
Subjects were counted once for the maximum postbaseline severity for each laboratory test.
Lipase test was only performed for subjects with serum amylase > 1.5 x upper limit of normal.
Urine RBC (hematuria, quantitative) was graded based on DAIDS grading scale (with the modification of urine RBC > 75 cells 
/HPF as Grade 3).
For Urinalysis (i.e., urine glucose, urine protein, and urine RBC), the highest grade is up to Grade 3.
No clinically significant changes in mean thyroid function tests (TSH, free T3, free T4) or serum 
immunoglobulins (IgG and IgM) were observed.
1.2.4.6.2.
Renal Safety
On multiple objective laboratory tests of renal function, subjects receiving E/C/F/TAF had a 
lower magnitude of change than subjects receiving E/C/F/TDF through 24 weeks.  
The change from baseline in serum creatinine (sCr) was lower in the E/C/F/TAF group compared 
to the E/C/F/TDF group at most assessments through Week 24. At Week 24, median change 
from baseline in serum creatinine was 0.07 mg/dL (range through Week 24: 0.05 mg/dL to 
0.08 mg/dL) for the E/C/F/TAF group and 0.11 mg/dL (range through Week 24: 0.08 mg/dL to 
0.11 mg/dL) for the E/C/F/TDF group (Week 24 p = 0.016).
Accordingly, the decrease from baseline in estimated glomerular filtration rate (GFR) by 
Cockcroft-Gault formula for CLCr was lower in the E/C/F/TAF group compared to the 
E/C/F/TDF group at most assessments through Week 24 (Figure 1-5). At baseline, the mean 
(SD) estimated GFRC-G was similar between groups (120.1 [30.22] (mL/min) for subjects in the 
E/C/F/TAF group and 114.7 [21.68] (mL/min) for subjects in the E/C/F/TDF group. At Week 24, 


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median change from baseline estimated GFR.c-G was -6.6 mL/min for the E/C/F/TAF group 
and -10.6 mL/min for the E/C/F/TDF group (p = 0.009). At Week 24, 3 (5.2%) subjects in the 
E/C/F/TDF group would be classified as new Stage 3 CKD (eGFR 30-59 mL/mi.n) vs. 1 (1.0%) 
subjects in the E/C/F/TAF group, and 15 (14.4%) subjects in the E/C/F/TAF group would be 
classified as new Stage 2 CKD (eGFR 60-89 mL/mi.n) vs. 20 (34.5%) subjects in the E/C/F/TDF 
group. 
Figure 1-5. 
GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in 
Estimated GFR by Cockcroft-Gault by Visit, Safety Analysis Set 
Bl 
4 
• 
EI.G'COBIIFTCIT.AF (n=): 
112 
109 
109 
o 
STB (n=): 
58 
54 
58 
8 
110 
58 
12 
107 
58 
16 
Week 
107 
58 
24 
104 
58 
32 
18 
11 
At Week 24, a trend towards reduced proteinuria was observed in the E/C/F/TAF group. By 
urine dipstick, the frequency of maximum post-baseline proteinuria (any grade) was 13.5% in 
EICIFITAF vs. 20.7% in E/C/F/TDF. The median change from baseline in urine albumin to 
creatinine ratio (UACR) was -0.84 mg/g in E/C/F/TAF vs -0.07 in E/C/F/TDF. The median 
change :ft·om baseline in urine protein to creatinine ratio (UPCR) was -5.6 mg/ g and 1.6 mg/g in 
the E/C/F/TAF and E/C/F/TDF groups, respectively. Explorat01y biomarkers of tubular 
proteinuria were also assessed, and demonstrated a statistically significant reduction in tubular 
proteinuria in the E/C/F/TAF group. At Week 24, median change from baseline beta-2-
mi.croglobulin to creatinine ratio was -35.9 ~tg/g for E/C/F/TAF vs -1.1 J.!g/g for E/C/F/TDF 
(p = 0.004), and median change from baseline in retinol binding protein to creatinine ratio 
was -0.7 J.!g/g for E/C/F/TAF vs 11.9 J.!g/g for E/C/F/TDF (p = 0.006). 
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A treatment difference for other laboratory markers of kidney function were not observed, 
including median change from baseline for serum phosphate and fractional excretion of 
phosphate (fractional excretion of phosphate [FEPO4] using adjusted sCr).
1.2.4.6.3.
Bone Safety
DXA scans of the spine and hip were performed at the Baseline and Week 24 visits (and at the 
early study drug discontinuation visit, if applicable) to measure changes from baseline in BMD. 
The percent changes from baseline in BMD values in the lumbar spine and hip are summarized 
in Table 1-9. The median percentage decrease from baseline was significantly less for subjects in 
the E/C/F/TAF group compared with that for subjects in the E/C/F/TDF group for both spine 
(p = 0.002) and hip (p < 0.001) BMD. 
The categorical distribution of subjects in each treatment group with percentage changes in BMD 
from baseline within specified ranges at Week 24 is summarized for spine and hip in Table 1-10. 
At Week 24, a significantly higher proportion of subjects in the E/C/F/TAF group than in the 
E/C/F/TDF group had no decreases in BMD at the hip (40.6% vs 22.8%; p < 0.001) and spine 
(37.5% vs 12.1%; p = 0.003). Substantially fewer subjects in the E/C/F/TAF group had 
decreases in BMD of >3% at the hip than in the E/C/F/TDF group (3.0% vs 31.6%) at Week 24.
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine 
and Hip Bone Mineral Density at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Change at Week 24
Spine
N
104
58
0.002
Mean (SD)
-0.84 (3.411)
-2.48 (2.519)
Median (Q1, Q3)
-0.92 (-3.00, 0.99)
-2.34 (-3.65, -0.33)
Min, Max
-8.49, 17.12
-10.37, 2.43
Hip
N
101
57
< 0.001
Mean (SD)
-0.30 (1.774)
-2.103 (2.677)
Median (Q1, Q3)
-0.42 (-1.44, 0.71)
-2.08 (-3.60, -0.48)
Min, Max
-4.68, 7.84 
-8.55, 4.86
P-values were from the Wilcoxon rank sum test.
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 E/C/F/TDF post baseline 
visit were included in the DXA substudy analysis set.


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Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by 
Gradation at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Percentage Change at Week 24
Spine
No Decrease
39/104 (37.5%)
7/58 (12.1%)
0.003
> 0 to < = 1% Decrease
14/104 (13.5%)
11/58 (19.0%)
> 1 to < = 3% Decrease
25/104 (24.0%)
17/58 (29.3%)
> 3 to < = 5% Decrease
18/104 (17.3%)
15/58 (25.9%)
> 5% Decrease
8/104 (7.7%)
8/58 (13.8%)
Hip
No Decrease
41/101 (40.6%)
13/57 (22.8%)
< 0.001
> 0 to < = 1% Decrease
23/101 (22.8%)
7/57 (12.3%)
> 1 to < = 3% Decrease
34/101 (33.7%)
19/57 (33.3%)
> 3 to < = 5% Decrease
3/101 (3.0%)
12/57 (21.1%)
> 5% Decrease
0/101
6/57 (10.5%)
P-value was from the CMH test for ordinal data (row mean scores differ statistic was used).
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 postbaseline visit were included in 
DXA substudy analysis set.
Clinical BMD status was assessed using BMD T-scores. Changes from baseline in BMD status 
at Week 24 were determined using T-scores. At Week 24, 6 of 99 subjects (6.1%) in the 
E/C/F/TAF group and 2 of 58 subjects (3.4%) in the E/C/F/TDF group showed a deterioration 
from baseline in spine BMD T-score category, and 1 of 99 subjects (1.1%) in the E/C/F/TAF 
group and 5 of 54 subjects (9.3%) in the E/C/F/TDF group showed a deterioration from baseline 
in hip BMD T-score category. In the E/C/F/TAF group at Week 24, 5 subjects had improvement 
in spine BMD T-score category and 1 subject had improvement in hip BMD T-score category. 
One subject in the E/C/F/TDF group showed improvement in the hip BMD T-score category. As 
a continuous variable, median decrease from baseline BMD T-score was significantly less for 
E/C/F/TAF vs E/C/F/TDF at both spine (-0.08 vs. -0.22, p = 0.005) and hip (-0.03 vs -0.14, 
p < 0.001).
Bone turnover markers, including one for bone resorption (C-type collagen sequence [CTX]) and 
three for formation (bone specific alkaline phosphatase [bsAP], osteocalcin [OC], and 
procollagen type 1 N-terminal propeptide [P1NP]), were assessed to support the BMD data. 
Comparisons of percent change from baseline for each bone turnover marker at Weeks 12 and 24 
demonstrated statistically significantly less change in the E/C/F/TAF arm, and provide evidence 
of less bone turnover at both timepoints in the E/C/F/TAF arm vs the E/C/F/TDF arm 
(Table 1-11). These results are consistent with the observations made in the BMD analyses.


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Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover 
Markers, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
E/C/F/TAF vs E/C/F/TDF
p-value
Week 12
CTx, % change in mean (SD)
37.9 (62.0)
103.7 (109.1)
<0.001
bsAP, % change in mean (SD)
-13.4 (16.0)
2.0 (16.3)
<0.001
OC, % change in mean (SD)
22.0 (32.5)
46.9 (49.1)
<0.001
P1NP, % change in mean (SD)
2.6 (32.2)
30.1 (36.1)
<0.001
Week 24
CTx, % change in mean (SD)
39.2 (79.2)
94.8 (107.9)
<0.001
bsAP, % change in mean (SD)
4.1 (17.2)
25.3 (24.9)
<0.001
OC, % change in mean (SD)
30.3 (43.5)
71.0 (74.3)
<0.001
P1NP, % change in mean (SD)
10.6 (38.7)
58.8 (61.4)
<0.001
P-values were from the Wilcoxon rank sum test; CTx = Type 1 collagen crosslinked C-telopeptide; bsAP = serum bone 
specific alkaline phosphatase; OC = osteocalcin; P1NP = procollagen Type 1 N-terminal propeptide.
1.2.4.6.4.
Week 24 Conclusions
Key conclusions from the Week 24 analysis of Study GS-US-292-0102 included the following:

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 24 was similar 
between treatment groups

Treatment was generally well tolerated as most AEs were mild and not associated with 
treatment discontinuation. No new or unexpected adverse events occurred.

The data shows that subjects taking E/C/F/TAF had more modest changes in creatinine and 
in bone mineral density than subjects taking E/C/F/TDF. The differences were statistically 
significant and may have important clinical relevance for individual subjects.
Other than renal lab abnormalities and biomarkers and bone biomarkers, the frequency and type 
of laboratory abnormalities was comparable between the two treatment arms.
1.3.
Rationale for This Study
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B
Approximately one-third of the world’s population has serological evidence of past or present 
HBV infection with over 350 million people globally who are chronic HBV surface antigen 


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(HBsAg) carriers.  The disease burden for HBV varies regionally, with greater than 50% of all 
subjects residing in Asian countries with the highest prevalence (e.g. China, India, Vietnam, 
Indonesia, South Korea, Taiwan, the Philippines, and Pakistan). The primary goal of treatment is 
to achieve and maintain virologic suppression, without resistance, which has been shown to 
translate to improvement in liver disease outcomes.  Current guidelines recommend treatment for 
subjects with evidence of ongoing viral replication along with liver injury based on elevated 
levels of serum ALT. 
TDF and ETV are highly potent first line therapies for CHB; however, each has specific 
limitations.  TDF has a potential to cause renal- and bone-related toxicities in a subset of 
subjects.  ETV has reduced activity in drug-treated populations, specifically 
lamivudine-experienced/resistant subjects {13870}, {24191}.  The latter is a key limitation for 
ETV use as LAM remains one of the most commonly prescribed HBV treatments in most 
regions of the world.  Thus, despite the availability of effective treatments there remains a clear 
need for newer oral HBV agents that are safe and well tolerated for long term use, and capable of 
achieving high rates of viral suppression with little or no potential for resistance development. 
Tenofovir alafenamide (TAF), a novel prodrug of TFV, has the potential to further advance the 
treatment of chronic HBV infection.  In contrast to TDF, an agent that is rapidly and completely 
cleaved by intestinal and plasma esterases to TFV, TAF is a more stable prodrug that efficiently 
resists early enzymatic cleavage following oral administration and remains more fully intact until 
it is taken up by target cells. As a consequence, TAF, when given at a lower dose than TDF, is 
capable of efficiently delivering active drug (e.g. TFV-DP) to the virally-infected cells (e.g. 
HBV-infected hepatocytes and HIV-infected lymphoid cells) while systemic exposures of TFV 
are reduced compared with oral administration of TDF 300 mg. These features are hypothesized 
to translate into the potential for effective suppression of viral replication, and an improved 
tolerability and safety profile.
Results from GS-US-320-0101, a Phase 1b study evaluating the short-term (28 day) safety, 
efficacy (HBV DNA suppression), and PK of TAF at 4 dose levels (8 mg, 25 mg, 40 mg, and 
120 mg) compared to TDF 300 mg, has shown no dose effect in regard to viral suppression, and 
similar short-term safety and tolerability compared with TDF.  Intensive PK results show 93% or 
greater reductions in TFV exposures with doses of TAF 25 mg or lower compared to the TFV 
exposures generated with TDF 300 mg.  These results, taken together with 24 weeks safety 
results from the HIV Phase 2 study GS-US-292-0102, which directly compares TAF to TDF 
(each included as a component of an STR), suggest that TAF is safe and well tolerated and may 
have a lower potential for renal- and bone-related AEs compared to TDF. Importantly, TFV 
exposures for E/C/F/TAF 10 mg are comparable to TFV exposures generated with TAF 25 mg 
given as a stand alone agent.
1.3.2.
Rationale for the Current Study
TDF and ETV are highly potent first line therapies for chronic HBV; however, each has specific 
limitations.  TDF has a potential to cause renal- and bone-related toxicities in a subset of 
subjects.  ETV has reduced activity in drug-treated populations, specifically lamivudine 
(LAM)-experienced/resistant subjects.  Thus, despite the availability of effective treatments there 


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remains a clear need for newer oral HBV agents that are safe and well tolerated for long term 
use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development.  TAF has the potential to address each of these requirements. 
The current study is designed to evaluate non-inferiority of TAF compared to TDF in regard to 
the proportion of subjects with HBV DNA levels below 29 IU/mL at Week 48. The durability of 
TAF compared to TDF in regard to the proportion of subjects with HBV DNA < 29 IU/mL at 
Week 96 will also be assessed in a double blind fashion. In addition to treatment naïve subjects, 
treatment experienced CHB subjects who are viremic and with elevated ALT levels at screening 
are included. This is based on given results from GS-US-174-0106 (ADV suboptimal 
responders) and GS-US-174-0121 (LAM-resistant subjects) which demonstrated in viremic 
patients comparable rates of HBV DNA suppression, as described below, in comparison to 
results in mostly treatment naïve subjects participating in pivotal studies GS-US-174-0102 
(HBeAg-negative subjects) and GS-US-174-0103 (HBeAg-positive subjects).  Given the unique 
properties of TAF (efficient delivery of the active moiety, TFV-DP, to HBV-infected 
hepatocytes with reduced systemic TFV exposures), this study will also evaluate the potential 
safety differences (e.g. renal- and bone-related complications) of TAF relative to TDF at
Week 48 and long term comparative safety at Week 96, after which subjects will be further 
evaluated for longer-term safety and efficacy of TAF in an open-label TAF 25 mg QD extension 
phase through Week 144. The extension phase is important as it will enable the evaluation of 
subjects treated for the entire 144 week period with TAF as well as those who received 96 weeks 
of TDF initially in a double-blinded fashion followed by an additional 48 weeks of open-label 
TAF.  The latter group will allow an ongoing assessment, including possible resolution, of any 
potential bone- and/or renal-related (or other) complications during TAF treatment that might 
have arisen under initial treatment with TDF.
The primary endpoint of this study is the proportion of subjects with HBV DNA < 29 IU/mL  at 
Week 48; the lowest limit of susceptibility of the polymerase chain reaction (PCR) assay to be 
employed (Roche COBAS® Taqman® HBV test for use with the High Pure System). A
histological component of treatment response is not included. Alternatively, non-invasive means 
(i.e. Fibrotest®) will be used to assess the degree of fibrosis at baseline and the change in fibrosis 
on an annual basis for all subjects participating in the trial.  In support of this, 48 week results 
from studies, GS-US-174-0102 and GS-US-174-0103, which formed the basis for TDF approval 
for CHB, showed TDF to be superior to ADV based on a “complete response” to treatment (a 
composite endpoint of HBV DNA suppression and histologic improvement based on repeat liver 
biopsy). In GS-US-174-0102, conducted in HBeAg-negative (presumed pre-core mutant) 
subjects, 70.8% and 48.8% of subjects randomized to TDF and ADV, respectively, achieved a 
complete response at Week 48 (treatment difference: 23.5%; p < 0.001). Of the components, 
HBV DNA suppression (< 69 IU/mL) was achieved in 94.4% and 64.0% (treatment difference: 
30.3%; p < 0.001), while histologic improvement was achieved in 74.2% and 68.8% (treatment 
difference: 5.2%; p = 0.292) of TDF- and ADV-treated subjects, respectively.  Thus, the greater 
potency of TDF relative to ADV resulting in a significantly higher rate of viral suppression was 
the primary element associated with the superior treatment response at 48 weeks {11363}, 
{13280}. Similar findings were observed in HBeAg-positive subjects in GS-US-174-0103.


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After 48 weeks, subjects in GS-US-174-0102 and GS-US-174-0103 were eligible to continue 
open-label treatment with TDF. At Year 5 (Week 240), 331/641 (52%) of subjects on TDF 
(without addition of FTC) underwent a repeat liver biopsy, and regression of fibrosis 
(improvement in Ishak fibrosis score of ≥1 point) was seen in 52% (172/331) of subjects. 
Furthermore, in 94/331 (28%) subjects with cirrhosis (Ishak score ≥5) at baseline, 73% (69/94) 
were no longer cirrhotic at year 5 (≥1 unit decrease in Ishak score). These results confirm the 
benefits of long term viral suppression with TDF in terms of regression of fibrosis and reversal 
of cirrhosis in the majority of TDF-treated subjects {24192}.
The efficacy of TDF in viremic treatment experienced CHB populations has been shown to be 
similar to treatment naïve subjects. In a prospective, randomized (1:1), double-blind, Phase 3b 
study (GS-US-174-0121) which compared TDF alone to the combination of FTC/TDF in 280 
HBeAg-positive and HBeAg-negative subjects receiving treatment with LAM and having HBV 
DNA > 3 log10 IU/mL with documented LAM-resistance (rtM204I/V ± rtL180M mutation[s]), 
89.4% of TDF-treated subjects vs. 86.3% treated with FTC/TDF had HBV DNA < 69 IU/mL at 
Week 96 (primary endpoint, missing equals failure analysis; p = 0.43).  BMD was also assessed 
in GS-US-174-0121, and small declines in BMD (< 2%) of both hip and spine were seen with 
equal frequency in both groups which occurred by Week 24 (spine) and Week 72 (hip).  In 
another prospective, randomized, double-blind study of TDF vs. FTC/TDF in 
105 HBeAg-positive and HBeAg-negative subjects with a prior suboptimal response to ADV 
(GS-US-174-0106), no differences in HBV DNA suppression (proportion less than 69 IU/mL) 
were seen between treatment groups (82.4% TDF vs. 84.0% FTC/TDF; ITT, non-completer 
equals failure; p = 0.78). Taken together, these studies support the efficacy of TDF in treatment 
experienced subjects as being similar to results seen in treatment naïve subjects.
1.3.3.
Rationale for Dose Selection
In the Phase 1b study, GS-US-320-0101, which has completed enrollment, 4 doses (8, 25, 40, 
and 120 mg) of TAF monotherapy, and TDF 300 mg were evaluated in 51 treatment naïve CHB 
subjects. To date, all subjects have completed the 28 day dosing period. Results demonstrate that 
TAF when given in doses over a range of 8 to 120 mg results in similar HBV DNA declines over 
28 days.  Furthermore, HBV DNA suppression with TAF is comparable to that of TDF 300 mg.  
In GS-US-320-0101, increased rates of viral suppression were not observed with higher TAF 
doses (40 mg, 120 mg) relative to lower TAF doses (8 mg and 25 mg), and similar safety profiles 
were observed among TAF treatment groups. PK results demonstrate a 93% reduction in TFV 
exposures relative to TDF 300 mg when TAF is dosed at 25 mg. These results in CHB subjects 
are consistent with data in healthy volunteers and HIV-infected subjects given TAF 25 mg as a 
stand alone agent. Importantly, as previously stated, the TFV exposures seen with TAF 25 mg in 
CHB subjects are therapeutically comparable to those in HIV patients receiving E/C/F/TAF 
10 mg (due to an inhibitory drug-drug interaction between TAF and COBI when these agents are
included in the E/C/F/TAF STR) which provide safety data (from Phase 2 study 
GS-US-292-0102) supporting the development of TAF for hepatitis B at the 25 mg dose level.  
Further, in CHB subjects participating in the Phase 1b study who were dosed at the lowest TAF 
dose (8 mg), a 97% reduction in TFV exposures relative to TDF 300 mg was observed, 


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representing an incremental reduction in TFV exposure of only 5% at this dose level relative to 
TAF 25 mg.
Importantly, the TFV exposures at a 25 mg dose when given alone are consistent with TAF 
exposures generated with the E/C/F/TAF 10 mg STR currently in Phase 3 development for 
treatment of HIV infection. Thus, the efficacy and safety of TAF in HIV is also being evaluated 
at a dose level that is therapeutically equivalent to the dose selected for study GS-US-320-0108.
Final Week 24 results from GS-US-292-0102, a phase 2 study being conducted in HIV-1 
treatment naïve subjects, demonstrated similar safety and tolerability of TAF vs. TDF when each 
is included as a component of STRs containing elvitegravir, cobicistat, and emtricitabine. At 
Week 24, significant differences were noted between arms in regard to smaller declines in hip 
BMD, estimated CLCr (Cockcroft-Gault), and changes in various biomarkers of bone and renal 
function which are suggestive of differences in bone and renal tolerability of TAF vs. TDF.  
Similar assessments are included in the present trial in HBeAg-negative, chronic HBV subjects, 
and the study is sufficiently powered to demonstrate a potentially superior safety profile for TAF 
relative to TDF in regard to these bone and renal parameters.
In summary, a 25 mg dose was selected for TAF for use in this non-inferiority trial based upon 
the safety profile for TAF in treatment naïve HIV-1-infected subjects from GS-US-292-0102, 
which utilizes a therapeutically equivalent TAF dose (10 mg as a component of the E/C/F/TAF 
STR), the viral suppression results in chronic HBV subjects in GS-US-320-0101 showing 
comparable rates of HBV DNA decline for a TAF 25 mg dose compared to TDF 300 mg (the 
approved dose for treatment of HBV), and the reduced systemic TFV exposures (~93%) seen 
with TAF relative to TDF 300 mg, when dosed at this level.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus tenofovir 
disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The primary 
efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL 

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and 
treatment experienced subjects
The key secondary safety objectives of the study are:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Week 96

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48 and 96

To compare the biochemical (ALT normalization) response of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Weeks 48 and 96

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48 and 96

To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Weeks 48 and 96

To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96 and 144


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
To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72 and 96 in a 
subset of subjects

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, and safety of TAF 25 mg QD from 
Week 96 through Week 144 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD for 96 weeks and then switched to 
open-label TAF


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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a randomized, double-blind, non-inferiority study to compare the antiviral activity of 
TAF 25 mg QD versus TDF 300 mg QD. Approximately three hundred ninety (390) subjects 
will be randomized in a 2:1 ratio (A:B) to the treatment arms for 96 weeks, and will be stratified 
by plasma HBV DNA level (< 7 log10 IU/mL, ≥ 7 log10 IU/mL - < 8 log10 IU/mL, 
≥8 log10 IU/mL) and oral antiviral treatment status (treatment-naïve vs. treatment-experienced).
For China, approximately 150 additional subjects will be randomized in a 2:1 ratio (A: B) to the 
treatment arms for 96 weeks, and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced). 
If the subject is deemed ineligible for this study by HBV serology (i.e. HBeAg positive CHB), 
this information may be used to determine eligibility for GS-US-320-0110 (another 
Gilead Sciences Phase 3 study in HBeAg positive, CHB subjects; this study must also be 
IRB/EC approved at the participating center). 
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD
For China, approximately 150 additional subjects (100 in Treatment Arm A and 50 in Treatment 
Arm B) will be enrolled for local registration purposes.
Subjects with a history of or current diagnosis of compensated cirrhosis are eligible for 
enrollment. Acceptable diagnostic criteria for cirrhosis include a Metavir or Knodell fibrosis 
score ≥4 or Ishak fibrosis score ≥ 5 by liver biopsy, or previous Fibroscan result > 12kPa (in 
countries where locally approved).  Available information regarding the presence or absence of 
cirrhosis by these criteria will be captured in the electronic case report forms at Baseline, and any 
other time during the trial should an investigator opt to undertake additional studies. Importantly, 
the change in fibrosis as assessed by Fibrotest® will be performed in all subjects participating in 
the trial at Baseline, and annually thereafter through Week 144.
The duration of double-blind treatment is 96 weeks. At Week 96, all subjects remaining on 
treatment will be switched to the open label TAF 25 mg QD extension period for up to an 
additional 48 weeks (Week 96 through Week 144). All subjects who complete 96 weeks of 
treatment are eligible for participation in the open label TAF 25 mg extension period. Subjects 
who permanently discontinue study drug (either prematurely [ED] or at the end of study 
[Week 144]) for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs, will 
be followed every 4 weeks for 24 weeks off treatment or until initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 


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Subjects with HBsAg loss with confirmed seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion to anti-HBs prior to Week 48 are not permitted to 
discontinue study drug prior to the Week 48 visit. After Week 48, these subjects who discontinue 
study drug will be followed off treatment every 4 weeks for 12 weeks and then per the study visit 
schedule (Appendix 2) through Week 144. Discontinuation of study drug for subjects 
experiencing HBsAg loss with confirmed seroconversion to anti-HBs, who have known bridging 
fibrosis or cirrhosis, should be considered on a case by case basis.
Figure 3-1.
Study Schema
3.2.
Biomarker Testing
3.2.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected in this study and will be used to evaluate 
the association of exploratory systemic and/or tissue specific biomarkers with study drug 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of chronic hepatitis B. The specific analyses will include, but will not be limited 
to, the biomarkers and assays listed below.  Because biomarker science is a rapidly evolving area 
of investigation, and adverse events in particular are difficult to predict, it is not possible to 
specify prospectively all tests that will be done on the specimens provided.  The testing outlined 
below is based upon the current state of scientific knowledge. It may be modified during or after 
the end of the study to remove tests no longer indicated and/or to add new tests based upon the 
growing state of art knowledge. 

Blood sample for bone biomarkers – including, but not limited to, C-type collagen sequence 
(CTX) and procollagen type 1 N-terminal propeptide (P1NP)
Screening
Randomization 2:1 (A:B)
Arm B- TDF 300 mg QD & placebo to match TAF 25 mg QD
Week 144/Early Discontinuation Visit
Week 96 Open Label TAF 25 mg QD
Follow-up – 24 weeks
Arm A- TAF 25 mg QD & placebo to match TDF 300 mg QD


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
Urine sample for renal biomarkers - including, but not limited to, retinol binding protein and
beta-2-microglobulin
These specimens will be collected from all subjects in a fasted state.
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research
A separate, specific consent form will be required to document a subject’s agreement to provide 
additional samples for optional pharmacogenomic research. From subjects who agree to 
participate and provide their additional specific consent, a blood sample will be obtained. This
sample should be collected at the Baseline visit, prior to the first dose of study drug, but may be 
collected at any time during the study or at a separate unscheduled study visit, if necessary.  The 
specimens collected for optional pharmacogenomic research will be used to identify or validate 
genetic markers that may increase our knowledge and understanding of the biology of the study 
disease and related diseases and to study the association of genetic markers with disease 
pathogenesis, progression and/or treatment outcomes, including efficacy, adverse events, and the 
processes of drug absorption and disposition. These specimens may be used also to develop 
biomarker or diagnostic assays and establish the performance characteristics of these assays. The 
collection and analysis of optional future research specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for subjects in the future.
3.3.
Intensive PK Substudy (Optional)
For subjects who provide a separate informed consent (n=16 and up to n=32), an intensive 
pharmacokinetic substudy will be performed once at either of the Week 4, 8 or 12 visits, at select 
sites to assess intensive PK profiling in plasma. 
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the intensive PK substudy visit. This will be used to 
evaluate PBMC concentrations of tenofovir diphosphate (TFV-DP), the active form of tenofovir 
(TFV).
3.4.
Opthalmologic Substudy (Optional)
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to 
assess ophthalmologic findings, including fundoscopic examination with retinal photographs 
(both eyes), anytime during the screening period, and must be completed prior to the first dose of 
study drug, and at Weeks 24, 48, 72, 96 and 144/ED visits at select sites.
An examination of the full retinal field should be conducted noting changes or abnormalities. 
Photographs of the retina must be taken at each exam and filed in the subject’s source medical 
records. A central vendor will be used to assess the retinal photographs.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 390 subjects, who are 18 years of age and older, with HBeAg-negative chronic 
hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 300 mg 
matched placebo (n = 260) or TDF 300 mg and TAF 25 mg matched placebo (n = 130) for 
96 weeks.
For China, approximately 150 subjects, who are 18 years of age and older, with HBeAg-negative 
chronic hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 
300 mg matched placebo (n = 100) or TDF 300 mg and TAF 25 mg matched placebo (n = 50) 
for 96 weeks.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1. Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures.
2. Male and non-pregnant, non-lactating female subjects, 18 years of age and older, based on 
the date of the screening visit. A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in Appendix 6).
3. Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 
6 months)
4. HBeAg-negative, chronic hepatitis B with all of the following:
HBeAg-negative and HBeAb-positive at Screening (if the subject is deemed ineligible for 
this study by HBV serology [i.e. HBeAg-positive CHB], this information may be used to 
determine eligibility for  GS-US-320-0110 [another Gilead Sciences Phase 3 study in 
HBeAg-positive, CHB subjects; this study must also be IRB/EC approved at the 
participating center])
Screening HBV DNA ≥ 2 x 104 IU/mL
Screening serum ALT level 60 U/L (males) or > 38 U/L (females) and ≤10 ULN (by 
central laboratory range)


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5. Treatment-naïve subjects (defined as < 12 weeks of oral antiviral treatment with any 
nucleoside or nucleotide analogue), OR treatment-experienced subjects (defined as subjects 
meeting all entry criteria [including HBV DNA and serum ALT criteria] and with 
> 12 weeks of previous treatment with any nucleoside or nucleotide analogue) will be 
eligible for enrollment. Treatment-experienced subjects receiving oral antiviral treatment at 
Screening must continue their treatment regimen until the time of randomization, when it will 
be discontinued.
6. Any previous treatment with interferon (pegylated or non-pegylated) must have ended at 
least 6 months prior to the baseline visit. 
7. Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the Screening evaluation, 
as follows:
(140 – age in years) (body weight [kg])
     (72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8. Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
9. Must be willing and able to comply with all study requirements.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study.
2. Males and females of reproductive potential who are unwilling to use an “effective”, 
protocol-specified method(s) of contraception during the study.  For a list of 
protocol-specified contraceptive methods, refer to Appendix 6. 
3. Co-infection with HCV, HIV, or HDV
4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5. Any history of, or current evidence of, clinical hepatic decompensation (e.g., ascites, 
encephalopathy or variceal hemorrhage).  
6. Abnormal hematological and biochemical parameters, including:
— Hemoglobin < 10 g/dL
— Absolute neutrophil count < 750/mm3


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— Platelets ≤50,000/mm3
— AST or ALT > 10 x ULN
— Total Bilirubin > 2.5 x ULN
— Albumin < 3.0 g/dL
— INR > 1.5 x ULN (unless stable on anticoagulant regimen)
7. Received solid organ or bone marrow transplant
8. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator
9. Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures
10. Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible
11. Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational 
agents, nephrotoxic agents, or agents capable of modifying renal excretion
12. Known hypersensitivity to study drugs, metabolites, or formulation excipients
13. Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
14. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
15. Subjects on prohibited concomitant medications (See Table 5-1). Subjects on prohibited 
medications, otherwise eligible, will need a wash out period of at least 30 days.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
A centralized randomization procedure via an Interactive Voice/Web Response System 
(IVRS/IWRS) will be used for this study, whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. If the subject is deemed ineligible for this study by HBV serology 
(i.e. HBeAg-positive CHB), this information may be used to determine eligibility for 
GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg-positive, CHB subjects; this 
study must also be IRB/EC approved at the participating center). Eligible subjects will be 
randomized 2:1 to receive either blinded TAF 25 mg and TDF matched placebo or TDF 300 mg 
and TAF matched placebo for 96 weeks. Subjects will be stratified by plasma HBV DNA level 
(< 7 log10 IU/mL, ≥7 log10 IU/mL - < 8 log10 IU/mL, ≥ 8 log10 IU/mL) and oral antiviral 
treatment status (treatment-naïve vs. treatment-experienced). At Week 96, all subjects will be 
switched to open label TAF 25 mg QD up to an additional 48 weeks (Week 96 through 
Week 144). For the entire duration of the study, subjects and Investigators will remain blinded to 
the initial treatment regimen to which the subjects were randomized to during Years 1 and 2 
(through Week 96). 
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IVRS/IWRS
for that subject. Gilead recommends, but does not require that the investigator contact the Gilead
Medical Monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the case report form/ 
electronic case report form (CRF/eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead Medical Monitor promptly in 
case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of Tenofovir Alafenamide (TAF), GS-7340, 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
5.2.1.
Formulation
5.2.1.1.
Tenofovir Alafenamide (TAF) Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide (TAF). The tablets are yellow, round-shaped, and film-coated. 
The tablets are debossed with “GSI” on one side and “25” on the other side.  In addition to the 
active ingredient, each film-coated tablet contains the following inactive ingredients: lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. 
5.2.1.2.
Placebo to match TAF Tablets
Placebo tablets to match TAF 25 mg are yellow, round-shaped, and film-coated. The tablets are 
debossed with “GSI” on one side and “25” on the other side.  Each tablet contains the following 
inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow 
iron oxide. 
5.2.1.3.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF)
TDF 300 mg tablets contain 300 mg of tenofovir disoproxil fumarate (TDF), which is equivalent 
to 245 mg of tenofovir disoproxil.  The tablets are light blue, almond-shaped, plain-faced, and
film-coated . Each tablet contains the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose (hydroxypropyl methylcellulose), 
glycerol triacetate, titanium dioxide, and indigo carmine aluminum lake.
5.2.1.4.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF) to be Used in 
Developing Markets
TDF 300 mg tablets to be used in developing markets contain 300 mg of tenofovir disoproxil 
fumarate (TDF), which is equivalent to 245 mg of tenofovir disoproxil.  The tablets are white, 
almond-shaped, film-coated, debossed with “GILEAD” and “4331” on one side and plain-faced 
on the other side. Each tablet contains the following inactive ingredients: microcrystalline 
cellulose, lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium 
stearate. The film coating contains lactose monohydrate, hypromellose, triacetin and titanium 
dioxide.
5.2.1.5.
Placebo to match TDF Tablets
Placebo tablets to match TDF 300 mg are light blue, almond-shaped, plain-faced, film-coated 
tablets. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose 
(hydroxypropyl methylcellulose), triacetin, titanium dioxide, and indigo carmine aluminum lake. 


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5.2.1.6.
Placebo to Match TDF Tablets to be Used in Developing Markets
Placebo tablets to match TDF 300 mg for developing markets are white, almond-shaped, 
film-coated tablets, debossed with “GILEAD” and “4331” on one side and plain-faced on the 
other side. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose, 
triacetin, and titanium dioxide.
5.2.2.
Packaging and Labeling
TAF, TDF, and their matched placebo tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant and polyester coil. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap fitted 
with an induction-sealed, aluminum-faced liner. 
To ensure stability of the tablets and proper product identification, the drug should not be stored 
in a container other than the container in which it is supplied.
All labels for study drug bottles to be distributed to centers in the US, EU and the rest of the 
countries will meet all applicable requirements of the US Food and Drug Administration (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
TAF, TDF, and their matched placebo 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), inclusive. 
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures.
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos
Subjects will be randomly assigned (2:1) to receive one of the following treatments in a blinded 
fashion:
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD
For China, approximately 150 additional subjects will be randomized 2:1 to receive either 
Treatment A (n = 100) or Treatment B (n = 50) for 96 weeks.
After 96 weeks of blinded randomized treatment, each subject will switch to open-label TAF 
25 mg QD for up to an additional 48 weeks (Week 96 through Week 144). 


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It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
All study drugs should be taken at approximately the same time each day with food
Observed in-clinic study drug dosing is required at Weeks 4 and 12 visits. Subjects who elect to 
dose in evening are not required to have in-clinic dosing and the single PK blood sample 
collection at the Week 4 and 12 visits.
Study drug should be administered after assessing adverse events and concomitant medication(s).
5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the visit 4 weeks after discontinuation of study treatment, need to be recorded in the 
source documents and eCRFs.
Concomitant use of some medications including herbal/natural products/therapies and over the 
counter medications with TAF may result in PK interactions.
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
including herbal/natural products/therapies, and over the counter medications, the Gilead 
Sciences 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.
The following medications are excluded while subjects are participating in the study. These 
medications are prohibited during the screening period and for a minimum of 30 days prior 
to the Baseline/Day 1 visit through the end of treatment:

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir (e.g., 
cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)

Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or immunomodulating 
agents

Bisphosphonates

Investigational agents (unless approved by Gilead Sciences)

Medications excluded due to the potential for drug-drug interaction with TAF (Table 5-1)


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Treatment-experienced subjects (defined as subjects meeting all entry criteria [including HBV 
DNA and serum ALT criteria] and with ≥12 weeks of previous treatment with any nucleoside or 
nucleotide analogue) receiving oral antiviral treatment at Screening must continue their treatment 
regimen until the time of randomization/Baseline/Day 1, when it will be discontinued.
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution 
Due to the Potential for Drug-Drug Interaction with Study 
Medication
Medication Class
Prohibited Medications
Medications to be used with caution
Analeptic
Modafinil
Antiarrhythmics
Amiodarone, Quinidine: may increase 
concentration of TAF and/or TFV
Antibacterials
Clarithromycin: may increase concentration 
of TAF and/or TFV
Anticonvulsants
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Voriconazole
Itraconazole, Ketoconazole: may increase 
concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Calcium channel blockers
Diltiazem, Felodipine, Verapamil: may 
increase concentration of TAF and/or TFV
Digoxin
Digoxin: concomitant use may result in an 
increased or decreased level; use with caution 
and with appropriate monitoring of serum 
digoxin levels. Digoxin therapy should be 
initiated at the lowest dose, and the dose 
should be titrated to clinical response.
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk 
thistle (i.e., silymarin), Chinese 
herb sho-saiko-to (or Xiao-Shai-
Hu-Tang)
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil 
Fumarate (TDF) and Matched Placebos
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product (IMP) kits and/or bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP kits and/or bottles dispensed to subjects must be returned to the site.
Investigational product accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits and/or bottles returned, along with the 
initials of the person recording the information


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5.5.1.
Investigational Medicinal Product Return or Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for drug 
destruction, arrangements will be made between the site and Gilead Sciences (or Gilead 
Sciences’ representative) for return of unused study drug supplies. A copy of the site’s SOP will 
be obtained for central files. Where possible, study drug will be destroyed at the site. Upon study 
completion, a copy of the Investigational Drug Accountability records must be filed at the site. 
Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the investigator 
must maintain accurate records for all study drug kits and/or bottles destroyed. Records must 
show the identification and quantity of each unit destroyed, the method of destruction, and 
person who disposed of the drug. All study drug records must be maintained at the site and 
copies must be submitted to Gilead Sciences at the end of the study. 


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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 described in the text that follows. 
Any deviation from protocol procedures should be documented and the sponsor or the contract 
research organization (CRO) should be notified.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment. Once consent has been obtained, all screening tests and procedures 
have been completed, and study eligibility has been confirmed, subjects will be randomized
within 45 days using an IVRS/IWRS. Subjects will receive study drugs within their assigned 
treatment group as described in Section 5.1. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principal Investigator’s opinion, the retest value will be within accepted parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample); or due to an extenuating circumstance.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 45 days before Baseline to determine eligibility for participation 
in the study. The following will be performed and documented during the screening period:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history, including HBV history

Review concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Complete physical examination including vital signs (blood pressure, pulse, respiration rate 
and temperature), body weight, and height

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)


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
DXA scan of spine and hip (at sites in China with capability only).  DXA scan will be 
performed at any time during the Screening period and should be completed at least 14 days 
prior to the first dose of the study drug, in order to ensure an acceptable pre-dose DXA scan

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required) 
– to be performed at any time during the Screening period and prior to the first dose of the 
study drug 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HIV-1, HDV, HCV, serum pregnancy test (for females of child-bearing potential), α-
fetoprotein (AFP) and INR. An AFP > 50 ng/mL at Screening must have an appropriate 
evaluation (e.g. CT scan) in order to rule out HCC prior to being permitted to enter the study

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days for randomization into the study. If the subject is deemed ineligible for this 
study by HBV serology (i.e. HBeAg-positive CHB), this information may be used to determine 
eligibility for  GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg positive, 
CHB subjects; this study must also be IRB/EC approved at the participating center).
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the adverse events case report form (CRF/eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history are to 
be captured on the medical history CRF/eCRF.  See Section 7, Adverse Events and Toxicity 
Management for additional details.
6.2.2.
Baseline Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug. Subjects screened within 45 days before Baseline will be eligible to participate in the 
study. Initiation of treatment with study drug should take place on the day of the Baseline visit. 
The following will be performed at the Baseline visit:

Review of inclusion/exclusion criteria and confirm medical history

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

Review concomitant medications


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
Review adverse events 

Assess future risk of bone fracture using the Fracture Risk Assessment tool (FRAX®; at sites 
in China with DXA capability only)

Randomization

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HBV genotyping (A-H), virology (resistance surveillance), serum and plasma for storage, 
IL28B genotype, and vitamin D assessment

Cystatin C testing for estimated glomerular filtration rate (eGFR) by CKD-EPI (Chronic 
Kidney Disease Epidemiology Collaboration)

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Optional blood sample for biomarker/pharmacogenomics (separate consent required prior to 
obtaining sample)
6.3.
Treatment Assessments
6.3.1.
Double Blind Visits
Study visits Weeks 4 – 44 and Week 56 - 96 should be completed ± 3 days of the protocol 
specified visit date, based on the Baseline Visit.
6.3.1.1.
Week 4

Symptom directed physical exam

Body weight


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
Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to obtaining 
samples) – Can also be done at Weeks 8 or 12 
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours, except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

Dose in clinic and collect single blood sample for plasma PK between 15 minutes to 4 hours 
post-dose (subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample) 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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6.3.1.2.
Week 8

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Intensive PK Substudy only at select sites (separate consent required prior to obtaining 
samples) – If not done at Week 4; can also be done at Week 12
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and storage


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6.3.1.3.
Week 12

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to obtaining 
samples) – If not done at Weeks 4 or 8, must be completed by this visit.
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

Dose in clinic and collect single plasma PK sample between 15 minutes to 4 hours post-dose
(subjects who elect to dose in the evening the previous day are not required to have in-clinic 
dosing and provide the single PK sample)


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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.4.
Weeks 16, 20, 28, 32, 40, and 44

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.5.
Week 24

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

DXA scan of spine and hip (within + 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events 

Perform study drug accountability


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
Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb),  plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.6.
Week 36

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb),  plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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6.3.1.7.
Week 48 (the window for this visit is ONLY -3 days)

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (within -14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.8.
Weeks 56 and 88

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature


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
Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis,  pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.9.
Weeks 64, and 80

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage


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6.3.1.10.
Week 72

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

DXA scan of spine and hip (within + 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance),  and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.11.
Week 96

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within + 14 days of the expected Week 96 visit 
date; at sites in China with capability only)

Review concomitant medications


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
Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Retrieve blinded study drug and dispense open label TAF 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.2.
Open Label Visits
Study visits Weeks 108 - 144 should be completed ± 7 days of the protocol specified visit date, 
based on the Baseline Visit.
6.3.2.1.
Weeks 108, 120, and 132

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform open label study drug accountability

Dispense open label TAF


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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.2.2.
Week 144/Early Discontinuation (ED) Visit
The ED Visit should be performed within 72 hours (visit window is + 3 days) of the last 
study drug dose.

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within + 14 days of the expected Week 144 visit 
date; at sites in China with capability only)
At ED visit, DXA scan should be performed only if not done within the last 12 weeks

Review concomitant medications

Review adverse events 

Perform open label study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Retrieve open label TAF (no study drug will be dispensed at Week 144/ ED)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®


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
Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
At ED visit, ophthalmologic assessment should be performed only if not done within the 
last 12 weeks
6.4.
Post-treatment Assessments
6.4.1.
HBsAg Loss and  Seroconversion Subjects
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-
HBs on or after the Week 48 visit, will be followed off treatment every 4 weeks for 12 weeks 
and then per the study visit schedule through Week 144 (excluding drug dispensation and 
accountability).
6.4.2.
All other subjects who discontinue study drug
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be 
followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.4.3.
Follow up visit assessments (all subjects)

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature 

Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
HBV serology (HBsAg and reflex HBsAb at Follow Up visits Weeks 12 and 24), and serum 
HBsAg (quantitative) 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis


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6.5.
Early Discontinuation (ED) from Study
If a subject discontinues study medication dosing for reasons other than HBsAg loss with 
confirmed seroconversion to anti-HBs (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related visits 
and procedures. If this is not possible or acceptable to the subject or investigator, the subject may 
be withdrawn from the study. Early Discontinuation Assessments are described in 
Section 6.3.2.2.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in 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

Subjects with confirmed creatinine clearance of < 30 mL/min will have their study drug 
permanently discontinued

Lack of efficacy (virologic failure)

HBsAg loss with sero-conversion to anti-HBs. These subjects should discontinue study drug 
within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion before Week 48 are not permitted to discontinue 
study drug prior to the Week 48 visit

Discontinuation of study drug for subjects experiencing HBsAg loss with confirmed 
seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, should be 
considered on a case by case basis

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 6

Discontinuation of the study at the request of Gilead Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)


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6.7.
Intensive Pharmacokinetic Substudy (Optional)
A PK substudy will be performed in a subset of subjects (n=16 and up to n=32) at selected study 
sites. Separate consent for the PK substudy is required. The substudy will include intensive PK 
profiling in plasma and will be conducted once at either of the Weeks 4, 8 or 12 visits. 
Blood samples will be collected at 0 (≤30 minutes pre-dose), 5 minutes, 15 minutes, 30 minutes 
, 45 minutes, 1 hour, 1.5 hours, 2, 3, 4, 5, 8, 12 and 24 hours post dose. 
Subjects participating in the PK substudy should not take their dose on the morning of the PK 
visit. Study medication will be administered in clinic on the morning of intensive PK. Subjects 
who have been routinely dosing in the evening will need to switch to a morning dosing regimen 
at least 10 days prior to the intensive PK visit. In addition, subjects should fast (no food or drinks 
for a minimum of 8 hours except water for up to 1 hour) prior to the scheduled intensive PK visit
After collection of the pre-dose sample, subjects will be provided a standardized, moderate fat 
meal (approximately 600 cal, 27% fat; Details can be found in the PK Manual). Within 
5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive 
PK sampling at the following time points will occur: 5, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 8, 12 
and 24 hours post dose. Subjects will be restricted from further water intake until 2 hours after 
and food intake until 4 hours after dosing. The date and time of the subject’s previous dose will 
need to be collected in addition to the data at the PK substudy visit.
Details of pharmacokinetic blood sampling procedures and sample management will be 
documented in the Pharmacokinetic Sample Collection, Processing, Storage, and Shipment 
Manual.
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the time of the intensive PK substudy.
6.8.
Urine, Serum and Plasma for Storage
A portion of the blood samples collected at each visit starting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its research partners for HBV 
genotyping/phenotyping assays or their development, for retesting the amount of HBV in the 
blood, for measurement of antiviral drug levels in the blood, or for future testing to learn more 
about how the study drug has worked against HBV or clinical laboratory testing to provide 
additional safety data. No human genetic testing on this sample will be performed. 
A portion of the urine samples collected at each visit starting at Baseline will be frozen and 
stored. These stored urine samples may be used by Sponsor for future renal and bone biomarker 
testing (in addition to the tests planned for the study).
At the conclusion of this study, these samples may be retained in storage by Gilead Sciences, 
Inc. for a period up to 15 years.


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6.9.
Resistance Surveillance
Genotypic sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for 
resistance mutations will be conducted at Baseline for all subjects, and attempted for all viremic 
subjects (HBV DNA 69 IU/mL) at Weeks 48, 96, and 144/ED visit. 
At Baseline, resistance surveillance will be conducted by INNO-LiPA Multi-DR v3 
(Innogenetics), which will determine the presence of HBV pol/RT mutations known to confer 
resistance to lamivudine, adefovir, entecavir, clevudine and/or telbivudine.  
At Weeks 48, 96, and 144/ED visit (if viremic), resistance surveillance will be conducted by 
population sequencing of the HBV pol/RT.
As it may not be known at the time of the visit whether a patient is viremic or if it will be their 
last study visit, a separate virology sample for potential resistance surveillance will be collected 
at each study visit. 
6.10.
End of Study
The end of this study will be the last patient’s last observation (or visit).


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1

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.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
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, and urinalysis) that require medical or 
surgical intervention or lead to IMP interruption, modification, 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 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 


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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 procedures, (e.g., venipuncture)
7.2.2.
Assessment of Severity
Severity of adverse events is to be determined based on GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 5). 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: 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 7.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all serious adverse events (SAEs) and 
adverse events related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 4-weeks after last administration of study IMP. AEs must be reported to the CRF/eCRF 
database as instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. Gilead 
Sciences may request that certain AEs be followed beyond the protocol defined follow up period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. Any SAEs and deaths, regardless of causality, that occur during the post 
treatment follow-up period or within 30 days of the last dose of study drug, when subject 
transitions to alternative, commercially available HBV therapy, should also be reported.


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Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30-day 
period. However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and report the event to Gilead DSPH.

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 may be reported using a paper serious adverse event 
reporting form, but sites will transition to an electronic SAE (eSAE) system. Gilead will 
notify sites in writing and provide training and account information prior to implementing an 
eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH or to the designated CRO.
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 DSPH within 24 hours of the investigator’s knowledge of 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 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.


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Safety: 
Medical Monitor: 
CONFIDENTIAL 
North America - PRA 
Email: CHOsafety@praintl.com, 
Fax: 1-888-772-6919 
Europe (including Russian Federation), Asia Pacific- PRA 
Email: MHGSafety@PRAintl.com, Fax: +49-621-878-2181 
!!!.!!!.! - KlinEra 
Email: safety:rep01ti.ng@kli.nera. com, Fax: +91-22-250045 8 8 
China, Vietnam - Quintiles 
Email: Ph V _ Gilead@quintiles.com 
Fax: 
China, South 
10-800-265-0002 
China, N01th 
10-800-650-0002 
Japan- CMIC 
Email: GPV _ GileadHB@cmic.co.jp 
Fax: +81-3-3493-5523 
North America - Gilead 
Benedetta Massetto, MD 
Phone: PPD 
PPD 
Europe (including Russian Federation), Asia Pacific- PRA 
Phone: +44 179 252 5608 
Fax: +49 621 878 2181 
Email: MedicEU@PRAintl.com 
!!!.!!!.! - KlinEra 
Japan- CMIC 
Mistuhiro Omine 
Phone: PPD 
Email PPD 
Page 89 
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
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy. 
7.5.
Toxicity Management

All clinical and clinically significant laboratory toxicities will be managed according to 
uniform guidelines detailed in Appendix 4.

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 5).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.


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
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.

Administration of study drug may be discontinued due to a clinical or laboratory event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.5.2.
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 investsigational 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.
7.5.3.
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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7.5.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in 
bone mineral density for chronic HBV- infected patients, Gilead recommends that any subject 
who has a DXA scan that demonstrates a decrease from baseline of > 5% in bone mineral density 
of the spine region or the hip region be followed per local medical practice at the discretion of 
the Investigator.
7.5.5.
Management of Potential Nephrotoxicity
Creatinine clearance (CLCr), estimated according to the Cockcroft-Gault formula, will be 
followed post-baseline during the study. All subjects with estimated CLCr < 50 mL/min must 
have serum creatinine measured again within 3 calendar days of receipt of results.  At the time of 
this repeat serum creatinine assessment, Cystatin C will also be measured and the estimated 
glomerular filtration rate (eGFR) by CKD-EPI (cystatin C) will be calculated and compared with 
the baseline measurement of this parameter. Any subject, who has a confirmed CLCr estimated 
by the Cockroft-Gault formula < 50 mL/min and also experiences a > 20% reduction in eGFR by 
CKD-EPI (cystatin C) from baseline, will be managed as described below:
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499× max (Scys/0.8, 1)−1.328 ×
0.996Age [× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of
Scys/0.8 or 1, and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
Subjects meeting the above eGFR criteria (i.e. confirmed CLCr < 50 mL/min by Cockcroft-Gault 
equation and > 20% reduction from baseline in eGFR by CKD-EPI equation) will be managed as 
follows:

If the CLCr is confirmed to be ≥ 30 mL/min and < 50 mL/min, the subject will be required to 
undergo dose modification to every other day dosing of study drug

If the CLCr is confirmed ≥ 30 mL/min to < 50 mL/min and the subject has undergone dose 
modification to every other day dosing of study drug and subsequently develops a confirmed 
CLCr ≥50 mL/min, the subject may revert to once daily dosing of study drug after discussion 
with the Gilead Medical Monitor.

If the CLCr is confirmed to be < 30 mL/min, the subject will be required to permanently 
discontinue study drug

All subjects with a change from baseline serum creatinine of ≥ 0.4 mg/dL must have serum 
creatinine repeated, with a concurrent urinalysis and urine chemistry, within two weeks of 
receipt of results. The following management will be required dependent upon the 
corresponding creatinine clearance value:


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If creatinine clearance is < 50 ml/min, or the subject has other clinical and/or laboratory 
evidence of acute renal failure, the subject will be managed according to the guidance 
described above.
If creatinine clearance is ≥ 50 ml/min and the repeat testing of serum creatinine confirms 
a Grade 1 or Grade 2 serum creatinine elevation, it is recommended that subject be 
monitored weekly until the serum creatinine level returns to a value within the normal 
laboratory range.

All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis must have a urinalysis repeated, with a concurrent urinalysis and urine chemistry, 
within two weeks of receipt of results. Upon confirmation of new proteinuria, subjects will 
be asked to return to the clinic for a scheduled or unscheduled follow up visit for evaluation. 
It is recommended that the Investigator contact the Gilead Medical Monitor to discuss if 
further consultation with a nephrologist is clinically warranted.
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management
On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 baseline 
value and >10 ULN, with or without associated symptoms
7.5.6.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT 2 baseline and 10 ULN, the following is 
recommended:

Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after 
initial laboratory results were drawn). During the visit, a clinical assessment of the subject
will be performed. The assessment should include a physical examination and evaluation of 
the subject’s mental status. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
serum albumin.

If the ALT elevation is confirmed, request the central clinical laboratory to conduct reflex 
testing for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, 
HCV, and HEV
Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:


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Elevated Liver Enzymes, Normal or Stable relative to baseline Liver Function Tests
If ALT levels are elevated (i.e., 2 baseline and 10 ULN) with normal or stable total 
bilirubin and INR relative to baseline, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or baseline level. 
During monitoring, if the ALT values remain persistently elevated, the Investigator should 
discuss with the Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., 2 baseline and 10 ULN), and total bilirubin is confirmed 
to be 2 x baseline value, and INR is 0.5 above baseline, provided both are > ULN, the 
investigator should consider discontinuing study medication (upon discussion with the Gilead 
Medical Monitor, unless the safety of the patient is of immediate concern). 
The subject should be monitored weekly as long as ALT, total bilirubin, and INR values remain 
elevated or above baseline values.
During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
the Investigator should discuss with the Gilead Medical Monitor whether the study drug should 
be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
7.5.6.2.
Management of Exacerbation of Hepatitis in Subjects who have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation 2 baseline and 10 ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function 
(total bilirubin 2 x baseline, INR 0.5 above baseline, provided both are > ULN) and the subject is 
on no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
albumin.


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
If the ALT elevation is confirmed, request the clinical laboratory to conduct reflex testing for 
plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV and 
HEV. If Plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy. 

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or baseline up to a maximum of 6 months after the initial occurrence of the event. 
7.5.7.
Management of Potential Posterior Uveitis Cases
In a nine-month toxicology study conducted in dogs, some animals administered the highest dose 
of TAF (12-18mg/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 administered is lower than that given in the dog study, nor 
have there been reports of posterior uveitis in human clinical studies thus far. Nonetheless, if any 
subject develops 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).
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE.  Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject 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).


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Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. Refer to Section 7.3 and the CRF/eCRF completion guidelines for full 
instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion 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 AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Safety Dept. using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Special situations involving non-Gilead concomitant medications does 
not need to be reported on the special situations report form, however, for special situations that 
result in AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
form. Any inappropriate use of concomitant medications prohibited by this protocol should not 
be reported as “misuse,” but may be more appropriately documented as a protocol deviation.


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Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus tenofovir 
disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects.  The primary 
efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows: 

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Week 96

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48 and 96

To compare the biochemical (ALT normalization) response of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Weeks 48 and 96

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48 and 96

To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Weeks 48 and 96


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
To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96 and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72 and 96 in a 
subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in a subset of  subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, and safety of TAF 25 mg QD from 
Week 96 through Week 144 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD for 96 weeks and then switched to 
open-label TAF
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Week 48.
8.1.3.
Secondary Endpoints
The key secondary safety endpoints are:

The percent change from baseline at Week 48 in hip BMD 

The percent change from baseline at Week 48 in spine BMD 

The change from baseline at Week 48 in serum creatinine 
8.1.4.
Other Endpoints of Interest

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Weeks 96 and 144

The proportion of subjects with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96 and 144

The proportion of subjects with ALT normalization at Weeks 48, 96 and 144

The proportion of subjects with HBsAg loss at Weeks 48, 96 and 144

The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 48, 96 and 144

The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96 and 144


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
The incidence of drug resistant mutations at Weeks 48, 96 and 144

The change from baseline in ophthalmologic findings by fundoscopic examination at 
Weeks 24, 48, 72, 96, and 144 in a subset of subjects
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis the Full Analysis Set (FAS), defined as all 
randomized subjects who receive at least one dose of study drug.  Subjects will be analyzed 
according to the randomized treatment assignment.
8.2.1.2.
Safety
The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all 
randomized subjects who receive at least one dose of study drug.  Subjects will be analyzed 
according to the treatment actually received.
All data collected during treatment will be included in the safety summaries.  Data collected 
during treatment free follow up will be summarized or listed separately.
8.2.1.3.
Pharmacokinetics
The PK analysis set will include all subjects who are randomized and have received at least one 
dose of study medication and for whom concentration data of any analytes of interest (eg, TAF 
and TFV) are available. The PK analysis set will be used for analyses of general 
pharmacokinetics.
The PK substudy analysis set will include all subjects who are randomized and have received at 
least one dose of study medication and for whom steady-state PK parameters of analytes TAF 
and TFV are available. The PK substudy analysis set will be used for detailed pharmacokinetics 
analyses.
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.
8.2.2.
Data Handling Conventions
For the primary endpoint missing data will be handled using a missing = failure approach, unless 
otherwise specified.
For key secondary safety endpoints, missing data will be handled via a Last Observation Carried 
Forward (LOCF) method.


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For other categorical secondmy efficacy endpoints, missing data will be handled using a 
missing = failure approach. For the dmg resistant mutations endpoint, a missing = excluded 
approach will be employed. 
Sensitivity analyses will be perfo1med as wan anted. 
8.3. 
Multiplicity Adjustments 
The primary hypothesis of non-inferiority between T AF 25 mg QD and TDF 300 mg QD with 
respect to the propmtion of subjects with HBV DNA < 29 IU/mL will be tested first. If 
non-inferiority is established, then multiplicity adjustments will be perfo1med for the secondary 
endpoints with a fallback procedure using the following weights: 
a) Hip BMD (weight = 0.4) 
b) Spine BMD (weight = 0.2) 
c) Se1um creatinine (weight= 0.4) 
Is hip BMD statistically 
different between T AF 
and TDF? (a = 0.02) 
Is spine BMD statistically 
different between T AF 
and TDF? (a = 0.03) 
Is senun 
Is senun 
creatinine 
creatinine 
statistically 
statistically 
different 
different 
between TAF 
between T AF 
and TDF? 
and TDF? 
(a = 0.05) 
(a = 0.02) 
CONFIDENTIAL 
Is spine BMD statistically 
different between T AF 
and TDF? (a= 0.01) 
No 
Is semm 
Is semm 
creatinine 
creatinine 
statistically 
statistically 
different 
different 
between T AF 
between T AF 
and TDF? 
and TDF? 
(a = 0.03) 
(a = 0.02) 
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8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall.
Demographic summaries will include sex, race/ethnicity, geographical region, randomization 
stratification group, and age.
Baseline data will include a summary of body weight, height, body mass index, log10 HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous oral nucleoside/nucleotide 
treatment experience, previous interferon experience, and genotype. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be conducted when approximately 390 randomized subjects
complete 48 weeks of the double-blind treatment period or discontinue prematurely.  A 
two-sided 95% confidence interval, based on the large sample theory adjusted for the 
randomization stratification factors (the adjusted Mantel-Haenszel proportions), for the 
difference (TAF – TDF) in the proportion of subjects who achieved HBV DNA < 29 IU/mL will 
be used to compare the treatment groups.  A non-inferiority will be declared if the lower bound 
of this confidence interval exceeds a non-inferiority margin of –0.10. If non-inferiority is 
established, the lower bound of the 95% CI will be compared to 0; if the lower bound of the 95% 
CI is greater than 0, then superiority of TAF over TDF will be established using the same 
confidence interval. Details will be provided in the statistical analysis plan.
8.5.1.1.
Justification of the non-inferiority margin
At Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA < 29 IU/mL 
in the TDF arm was 91.2%.  At Week 48 in study GS-98-438, the proportion of subjects with 
HBV DNA < 29 IU/mL in the placebo was 0%.  The non-inferiority margin of 10% would 
preserve more than 88% of the lower bound of the 95% confidence interval of the difference 
between TDF and placebo.
NTDF
NPBO
Response rate 
in TDF
Response rate 
in PBO
Difference
95% confidence 
interval lower bound
250
61
91.2%
0%
91.2%
87.7%
Preserve at least 88% 
of lower bound
10%
Furthermore, at Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA 
< 29 IU/mL in the TDF arm was 91.2% and the proportion of subjects with HBV DNA 
< 29 IU/mL in adefovir (ADV) arm was 56.0%.  The non-inferiority margin of 10% would 
preserve more than 60% of the lower bound of the 95% confidence interval of the difference 
between TDF and adefovir (ADV).


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NTDF
NADV
Response 
rate in TDF
Response 
rate in ADV
Difference
95%confidence interval 
lower bound
Study 174-0103
250
125
91.2%
56.0%
35.2%
25.8%
Preserve at least 60% 
of lower bound
10%
8.5.2.
Analyses of Other Endpoints of Interest
Continuous secondary endpoints will be summarized using conventional descriptive statistics (n, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group and 
overall.  A Wilcoxon rank sum test will be used to compare the treatment groups, in an 
exploratory manner.
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint.  A two-sided Mantel-Haenszel test, controlling for the randomization strata,
will be used to compare the treatment groups, in an exploratory manner.  Missing data will be 
handled by the missing = failure approach.
For the incidence of drug resistant mutations, the missing = excluded approach will be employed.
An analysis of the China subpopulation will also be conducted when approximately 150 
randomized and treated China subjects complete 48 weeks of double-blind treatment or 
discontinue prematurely to examine the consistency of the responses between the China 
subpopulation and the overall population.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose  will be summarized by treatment group (according to the drug received). Data for the 
pretreatment and treatment-free follow-up periods will be included in data listings. 
8.6.1.
Key Secondary Safety Analyses
The percent change from baseline in hip and spine BMD at Week 48 will be analyzed using an
ANCOVA model with baseline hip or spine BMD as a covariate, and randomization strata and 
treatment group as fixed effects.  The details will be provided in the Statistical Analysis Plan 
(SAP).
The change from baseline in serum creatinine at Week 48 will be analyzed using an ANCOVA 
model with baseline serum creatinine as a covariate, randomization strata and treatment group as 
fixed effects. The details will be provided in the SAP.


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8.6.2.
Extent of Exposure
A subject’s extent of exposure to drug data will be generated from the drug administration data. 
Exposure data will be summarized by treatment group. 
8.6.3.
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.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event that begins on or after the date of first dose of 
treatment up to the date of last dose of treatment plus 7 days. Continuing adverse events 
diagnosed prior to the start of treatment and worsening in severity grade, or non-serious adverse 
events at baseline which become serious, or adverse events resulting in treatment discontinuation 
after the start of treatment will also be considered treatment-emergent.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided by treatment group:

Treatment-emergent adverse events

Treatment-emergent study drug-related adverse events

Grade 3 or 4 treatment-emergent adverse event

Grade 3 or 4 treatment-emergent study drug-related adverse event

Grade 2, 3, or 4 treatment-emergent adverse event

Grade 2, 3, or 4 treatment-emergent study drug-related adverse event

AE that caused permanent discontinuation from study drug

AE that caused change in dose or temporary interruption of study drug

Treatment-emergent serious adverse event

Treatment-emergent study drug-related serious adverse event
8.6.4.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.


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Graded laboratory abnormalities will be defined using the grading scheme in Appendix 5.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of treatment plus 7 days, will be summarized by treatment group. If baseline data are 
missing, then any graded abnormality (i.e., at least a Grade 1) will be considered treatment 
emergent. 
Laboratory abnormalities that occur before the first dose of treatment or after the subject has 
been discontinued from treatment for at least 7 days will be included in a data listing.
8.7.
Pharmacokinetic Analysis
Pharmacokinetic parameters will be listed and summarized for TAF and TFV using descriptive 
statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard 
deviation, median, minimum, and maximum). Plasma concentrations of TAF and TFV over time 
will be plotted in semi logarithmic and linear formats as mean standard deviation.
For the PK intensive substudy, the following pharmacokinetic parameters will be calculated: 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½.
8.7.1.
Biomarker Analysis
Selected bone biomarkers, including C-type collagen sequence (CTX) and procollagen type 1
N-terminal propeptide (P1NP), and selected renal biomarkers, including retinol binding protein, 
and beta-2-microglobulin, will be summarized by treatment group and visit using descriptive 
statistics. The difference in change from baseline in these biomarkers between two treatment 
arms will be tested using Wilcoxon rank sum test.
8.8.
Sample Size
With respect to the primary efficacy endpoint, a sample size of 130 for the TDF 300 mg group 
and 260 for the TAF 25 mg group will have 90% power to rule out the non-inferiority margin of 
10% at a one-sided significance level of 0.025.  This assumes a rate of 91% in the TDF 300 mg 
group and 91% in the TAF 25 mg group in the proportion of subjects with HBV DNA 
< 29 IU/mL. A similar response rate in the TDF group was observed in GS-US-174-0102
{11363}, {13280}.
This sample size (n=260 for the TAF 25 mg arm, n=130 for the TDF 300 mg arm) also provides 
at least 90% power to detect a 1% difference in the percentage change from baseline in hip BMD 
at Week 48 (assuming a -1.17% change from baseline in TDF 300 mg arm and -0.17% change 
from baseline in the TAF 25 mg arm, with a common standard deviation of 2.20% and a 
two-sided α = 0.025); a 77% power to detect a 1% difference in the percentage change from 
baseline in spine BMD at Week 48 (assuming a -1.69% change from baseline in the TDF 300 mg 
arm and -0.69% change in the TAF 25 mg arm, with a common standard deviation of 3.08% and 
a two-sided α = 0.025); a 52% power to detect a 0.03 mg/dL difference in the change from 


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baseline in serum creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in the 
TDF 300 mg arm and 0.01 mg/dL change from baseline in the TAF 25 mg arm, with a common 
standard deviation of 0.12). These assumptions were derived from studies GS-98-437, 
GS-98-438, GS-US-174-0102, GS-US-174-0103, and GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD, and 50 subjects TDF 300 mg QD and matched placebo of TAF 25 
mg QD) will be enrolled.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data and provide recommendation to Gilead whether 
the nature, frequency, and severity of adverse effects associated with study treatment warrant the 
early termination of the study in the best interests of the participants, whether the study should 
continue as planned, or the study should continue with modifications. The DMC may also 
provide recommendations as needed regarding study design
The DMC will convene approximately every 24 weeks following the time of randomization of 
the first subject during the blinded portion of the protocol and approximately every 48 weeks 
during the open label phase.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will 
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.


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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, 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. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any sub-investigator’s) participation in the study. The investigator and 
sub-investigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, 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) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial IRB/IEC approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
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 


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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or
local requirements. The consent form will inform subjects about pharmacogenomic testing and 
sample retention, and their right to receive clinically relevant pharmacogenomic analysis results.
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, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. Laboratory 
specimens must be labeled in such as way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the 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 
or IEC and governmental 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 sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in 


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Amendment 2.1
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the audit trail of the system.  Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy 
of the data entered by that site. This archive must be stored in accordance with the records
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, the site 
may destroy used (empty kits and/or bottles) and unused study drug supplies performed in 
accordance with the site’s (hospital/pharmacy) SOP. If the site does not have acceptable 
procedures in place for drug destruction, arrangements will be made between the site and 
Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug supplies. 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, 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.


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Amendment 2.1
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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. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
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 in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead 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. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s 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.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF 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 


Tenofovir Alafenamide (TAF), GS-7340
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Amendment 2.1
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verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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 and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


Tenofovir Alafenamide (TAF), GS-7340
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Gilead Sciences, Inc. 
Amendment 2.1
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10.
REFERENCES
13
Robbins BL, Greenhaw JJ, Connelly MC, Fridland A. Metabolic pathways for 
activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human 
lymphoid cells. Antimicrob Agents Chemother 1995;39 (10):2304-8.
2331
World Health Organization (WHO). Fact Sheet WHO/204.  October, 2000.
3273
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 
1996;38 (2):S1.
5047
Centers for Disease Control and Prevention (CDC). Hepatitis B Fact Sheet.  
Available at:  http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm. Accessed 
August 6, 2003, 
11362
Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A 
Randomized, Double-Blind Comparison of Tenofovir DF (TDF) Versus Adefovir 
Dipivoxil (ADV) for the Treatment of HBEAG-Positive Chronic Hepatitis B 
(CHB): Study GS-US-174-0103 [AASLD Abstracts]. Hepatology 2007;46 (4 
Supp1):861A.
11363
Marcellin P, Buti M, Kraslev Z, Germanidis G, Kaita K, Kotzev I, et al. A 
Randomized, Double-Blind Comparison of Tenofovir DF (TDF) Versus Adefovir 
Dipivoxil (ADV) for the Treatment of HBEAG-Negative Chronic Hepatitis B 
(CHB): Study GS-US-174-0102 [AASLD Abstracts]. Hepatology 2007;46 (4 
Suppl 1):290A-1A.
12037
Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-
analyses of FibroTest diagnostic value in chronic liver disease. BMC 
gastroenterology 2007;7:40.
13280
Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus 
adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359 (23):2442-55.
13870
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. 
Long-term monitoring shows hepatitis B virus resistance to entecavir in 
nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009;49 
(5):1503-14.
18841
Marcellin PE, Heathcote EJ, Corsa A, et al. No detectable resistance to tenofovir 
disoproxil fumarate (TDF) following up to 240 weeks of treatment in patients 
with HBEAG+ and HBEAG- chronic hepatitis B virus infection [Abstract 238]. 
Hepatology 2011;54 (4 Suppl.):480A.


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Gilead Sciences, Inc. 
Amendment 2.1
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20205
Birkus G, Bam R, Frey C, Tsai L, Stray K, Yant S, et al. Intracellular activation 
pathways for GS-7340 and the effect of antiviral protease inhibitors  [Poster 
#577]. Presented at: 19th Conference on Retroviruses and Opportunistic 
Infections (CROI); 2012 March 5-8; Seattle, WA. 
21378
Bam RA, Birkus G, Babusis D, Yant SR, Cihlar T. Minimal Donor Variation in 
Cathepsin A Expression and Antiviral Activity of GS-7340 in Primary Human 
CD4+ T Cells and Macrophages [Poster Number TUPE016]. XIX International 
AIDS Conference; 2012 July 22-27; Washington, D.C. . 
21769
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department 
of Health and Human Services. 1–239. Available at  
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 
2012 August 22.  
23907
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective 
Lymphoid Cell and Tissue Loading Following Oral Administration of Nucleotide 
Prodrug GS-7340. Mol Pharm 2013;10 (2):459-66.
24191
Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, et al. 
Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship 
between genotypic resistance and patient virologic response. J Hepatol 2008;48 
(6):895-902.
24192
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. 
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for 
chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381 
(9865):468-75.
24462
Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert-Bismut F, Thabut D, et al. 
A prospective analysis of the prognostic value of biomarkers (FibroTest) in 
patients with chronic hepatitis C. Clin Chem 2006;52 (10):1887-96.
24463
Poynard T, Zoulim F, Ratziu V, Degos F, Imbert-Bismut F, Deny P, et al. 
Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) 
during lamivudine therapy in patients with chronic hepatitis B infection. Am J 
Gastroenterol 2005;100 (9):1970-80.


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Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations


Tenofovir Alafenamide (T AF), GS-7340 
Protocol GS-US-320-0108 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 2.1 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 
Tenofovir Alafenamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 
300 mg QD for the Treatment of HBeAg-Negative, Chronic Hepatitis B 
GS-US-320-0108, Amendment 2.1, 20 February 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
John Flaherty, Pharm D 
Study Director 
PPD 
INVESTIGATOR STATEMENT 
I have read the protocol, including aU appendices, and 1 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 ali 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 116 
20 February 2015 


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Amendment 2.1
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Appendix 2.
Study Procedures Table
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48
(a)
56
64
72
80
88
96
108
120 
132
144/ 
ED(o
FU(p
Blinded Visits
(+ 3 days)
Open Label 
Visits (+ 7 
days)
+ 7 
days
Informed Consent 
X
Review of 
Inclusion/ Exclusion 
Criteria 
X
X
Medical History, 
including HBV 
history
X
Review 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Examination 
including vital 
signs, and weight 
X
X
X
X
X
X
X
Height
X
Symptom-directed 
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Final
Gilead Sciences, Inc. 
Amendment 2.1
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Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48
(a)
56
64
72
80
88
96
108
120 
132
144/ 
ED(o
FU(p
Blinded Visits
(+ 3 days)
Open Label 
Visits (+ 7 
days)
+ 7 
days
ECG (b)
X
X
X
X
Vital Signs (c)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXA (d)
(spine & hip 
+ 14 days) 
X
X
X
X
X
X
Fracture Risk 
Assessment (q)
X
Study Drug 
Accountability  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Dispensed/Retrieved 
(e)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing in-clinic (f)
X
X
Serum Chemistry 
and Liver Function 
Tests (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
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20 February 2015
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48
(a)
56
64
72
80
88
96
108
120 
132
144/ 
ED(o
FU(p
Blinded Visits
(+ 3 days)
Open Label 
Visits (+ 7 
days)
+ 7 
days
Estimated 
Creatinine 
Clearance (by 
Cockcroft-Gault 
Method)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin C (for 
estimated eGFR)
X
Plasma HBV DNA 
Levels 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg 
(quantitative)  
X
X
X
X
X
X
X
X
X
X
X
X
HBV Serology (h)
X
X
X
X
X
X
X
X
X
X
X
X
HBV Genotyping 
(A-H) 
X
Virology (resistance 
surveillance)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
Fibrotest®
X
X
X
X


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Final
Gilead Sciences, Inc. 
Amendment 2.1
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Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48
(a)
56
64
72
80
88
96
108
120 
132
144/ 
ED(o
FU(p
Blinded Visits
(+ 3 days)
Open Label 
Visits (+ 7 
days)
+ 7 
days
IL28B Genotype
X
Vitamin D
X
Plasma PK 
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood for 
Bone Biomarkers  (i)
X
X
X
X
X
X
X
X
Fasting Urine for 
Renal Biomarkers (i)
X
X
X
X
X
X
X
X
Fasting Metabolic 
Panel (j)
X
X
X
X
X
X
Serum Pregnancy 
Test (k)
X
Urine Pregnancy 
Test (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional Intensive 
PK substudy (l)
X
Optional PBMC (m)
X
Serum and plasma 
for storage 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 121
20 February 2015
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48
(a)
56
64
72
80
88
96
108
120 
132
144/ 
ED(o
FU(p
Blinded Visits
(+ 3 days)
Open Label 
Visits (+ 7 
days)
+ 7 
days
Urine for Storage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ophthalmologic 
substudy (n) –
fundoscopic 
examination with 
slit lamp (+ 14 days)
X
X
X
X
X
X
Optional Biomarker/ 
Pharmacogenomic 
Sample
For subjects who provide a separate informed consent, a blood sample should be collected at Baseline, prior to first dose of 
study drug, but may be collected at any time during the study or at a separate unscheduled study visit, if necessary.
a
The visit window for Week 48 visit is ONLY – 3 days. 
b
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording
c
Vital signs include blood pressure, pulse, respiration rate, and temperature 
d
DXA scans will be performed only at sites in China with capability. The initial DXA will be performed during Screening and should be completed at least 14 days prior to the 
first dose of study drug. The Week 48 DXA window is -14 days only. DXA required for Early Discontinuation (ED) visit if not done within the last 12 weeks.
e
At Week 144/ED, new study drug will not be dispensed
f
It is preferred that subjects take their study drug according to a morning dosing schedule; subjects who elect to dose in the evening the previous day are not required to have 
in-clinic dosing and provide the single PK sample being collected at Week 4 and 12 visits.
g
Serum chemistry and Liver Function Tests : alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects 
with total amylase > 1.5 X ULN), and PTH. PTH analyzed at all visits except for Screening. At Baseline, Weeks 24, 48, 72, 96, and 144/ED, analyses of glucose will be 
done as part of the fasting metabolic assessments and not as part of the chemistry panel. Liver function tests: INR will be done at Screening and then ass a reflex only test for 
ALT flares.
h
HBeAg and HBeAb will be done at Screening and Baseline visits. HBsAg and reflex HBsAb will be done at Screening and Baseline visits, and  every 12 to 16 weeks until 
week 144 and at Follow Up visits Weeks 12 and 24.  


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 122
20 February 2015
i
Blood for selected bone biomarkers and urine for selected renal biomarkers will be collected in a fasted state. Required for ED visit if the last sample  was collected 
>12 weeks
j
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). At Baseline, Weeks 24, 48, 72, 96, and 144/ED analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry panel.
k
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done
l
The optional intensive PK substudy will be conducted once at either of the Weeks 4,8 or 12 visits in a subset (n=16 and up to n= 32) of subjects who provide a separate 
consent form, at select sites. Subjects should fast (no food or drinks for a minimum of 8 hours except water for upto 1 hour) prior to the scheduled intensive PK visit. Subjects 
participating in the PK substudy should not take their dose on the morning of the PK visit. Study medication will be administered in clinic on the morning of intensive PK. 
Subjects who have been routinely dosing in the evening will need to switch to a morning dosing regimen at least 10 days prior to the intensive PK visit. After collection of the 
pre-dose sample and the PBMC sample (at sites which can process PBMCs), subjects will be provided a standardized meal (approximately 600 cal, 27% fat; details can be 
found in the PK Manual). Within 5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive PK sampling will then occur. Subjects will be 
restricted from further water intake for until 2 hours after  and food intake until 4 hours after dosing. 
m
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a PBMC (pre-dose) sample at the intensive PK substudy visit to 
assess intracellular TFV-DP concentration in PBMCs
n
For a subset of subjects (n = 30), who provide a separate consent form, a substudy will be conducted to assess ophthalmologic findings, including fundoscopic examination 
with retinal photographs (both eyes). The examination can be conducted anytime during the screening period, but must be completed prior to the first dose of the study drug,
and will be conducted at Weeks 24, 48, 72, 96 and 144/ED at select sites. Required for Early Discontinuation (ED) visit if not done within the last 12 weeks. An examination 
of the full retinal field should be conducted noting changes or abnormalities. Photographs of the retina must be taken at each exam and filed in the subject’s source medical 
records. A central vendor will be used to assess the retinal photographs.
o
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
p
Subjects who discontinue study drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks or up to 
initiation of alternative, commercially available HBV therapy, whichever occurs first. Subjects who lose HBsAg with confirmed seroconversion to anti-HBs should 
discontinue study drug within 3-6 months following confirmation of HBsAg loss and seroconversion to anti-HBs or after Week 48, if seroconversion occurs prior to this visit. 
These subjects will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule through Week 144.
q
Complete the Fracture Risk Assessment specific eCRF at sites in China with DXA capability only.


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 123
20 February 2015
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected 
sites in a subset of subjects [n=16 and up to n=32])
Time Point (Once at either of the Week 4, 8 or 12 visits)
0 (within 30 minutes of dose)*
5 minutes post dose
15 minutes post dose
30 minutes post dose
45 minutes post dose
1 hour post dose
1.5 hours post dose
2 hours post dose
3 hours post dose
4 hours post dose
5 hours post dose
8 hours post dose
12 hours post dose
24 hours post dose
*
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a 
PBMC (pre-dose) sample at the intensive PK substudy visit to assess intracellular TFV-DP concentration in 
PBMCs


Tenofovir Alafenam ide (T AF), GS-7340 
Protocol GS-US-320-0108 
Gilead Sciences, Inc. 
Final 
Amendment 2.1 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
L------G-ra_d_e_2----~~ 
Ll ------G-ra_d_e_3----~~ 
LI _________ G_r_ad_e_4--------~ 
May continue 
Repeat lab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
If confirmed and possibly and/or probably related to 
investigational medicinal products: 
l. Withhold investigational medicinal products until~ Grade 2 
2. 
Restart all investigational medicinal products at full dose 
l 
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, discontinue 
all investigational medicinal products dosing permanently 
l 
If c 
Repeat lab to 
confirm toxicity 
grade 
l 
inve 
onfirmed and unrelated to 
stigational medicinal products, 
ng may continue at the 
dosi 
disc retion of the investigator 
If confirmed and 
possibly or probably 
-.. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at pe1iodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
lf Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 
CONFIDENTIAL 
Page 124 
20 February 2015 


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 125
20 February 2015
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
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


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 126
20 February 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
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
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/ μL
200 to 300/mm3
200 to 300/ μL
100 to 200/mm3
100 to 200/ μL
100/mm3
100/ μL
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
100.0 to 125.0 GI/L
50,000 to 100,000/mm3
50.0 to 100.0 GI/L
25,000 to 50,000/mm3
25.0 to 50.0 GI/L
25,000/mm3
25.0 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.0 GI/L to 2.5 GI/L
1.5 to 2.0 GI/L
1.0 to 1.5 GI/L
1.0 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 127
20 February 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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
40 to 50 μg /mL
50 to 60 μg /mL
60 μg /mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
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% 


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 128
20 February 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 mEq/L to LLN
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 mmol/L to LLN
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146 to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146 to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/
3.0 to 3.4  mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
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
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4 mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 129
20 February 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 mg/dL to LLN
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63 mmol/L to LLN 
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 130
20 February 2015
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
ULN to 597 μmol /L
597 to 716 μmol /L
716 to 895 μmol /L
895 μmol /L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol /L to LLN
57 to 87 μmol /L
27 to 57 μmol /L
27 μmol /L
Creatinine 
1.50 to 2.0 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol /L
177 to 265 μmol /L
265 to 530 μmol /L
530 μmol /L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
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
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*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
2.0 to 3.0 g/dL
2.0 g/dL
NA
30 g/L to LLN
20 to 30 g/L
20 g/L


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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
Note: 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)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 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 
(e.g., 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 
(e.g., 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 
(e.g., 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
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., 
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


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RESPIRATION
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 Respiration
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 
Respiration failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiration 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%
Respiration 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)


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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, 
maculopapular, or 
morbilliform rash OR Target 
lesions 
Diffuse macular, 
maculopapular, or morbilliform 
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous membrane limited to 
one site
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson syndrome 
OR Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites 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


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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 [e.g., tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., 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 
(e.g., sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(e.g., 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 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
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 (e.g., 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 (e.g., 
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood (e.g., 
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 (e.g., 
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 


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
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
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 
Respiration 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


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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., refractory 
epilepsy)
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 (e.g., 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive (e.g., 
status epilepticus), or difficult 
to control (e.g., 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
See also Arthritis
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities
Joint pain causing greater than 
minimal interference with usual 
social & functional activities
Joint pain causing inability 
to perform usual social & 
functional activities
Disabling joint pain causing 
inability to perform basic self-
care functions
Arthritis
See also Arthralgia
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional activities
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities
Stiffness or joint swelling 
causing inability to perform 
usual social & functional 
activities
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care 
functions
Bone Mineral Loss
BMD t-score or z-score
–2.5 to –1.0 
BMD t-score or z-score –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Pediatric 21 Years
BMD z-score 
–2.5 to –1.0
BMD z-score < –2.5
Pathological fracture 
(including loss of vertebral 
height)
Pathologic fracture causing 
life-threatening consequences 
Myalgia
(non-injection site)
Muscle pain causing no or 
minimal interference with 
usual social & functional 
activities
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities
Muscle pain causing 
inability to perform usual 
social & functional activities
Disabling muscle pain causing 
inability to perform basic self-
care functions
Osteonecrosis
NA
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention 
indicated
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-
care functions


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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 [e.g., 
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 (e.g., upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment (e.g., 
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 (e.g., 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 
(e.g., 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 
(e.g., 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 
(e.g., myxedema coma)
Lipoatrophy (e.g., 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 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Systemic antimicrobial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences (e.g., septic 
shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations
1.
Pregnancy and Contraception Requirements for Males and Females of 
Childbearing Potential 
The risks of treatment with study drug have not been evaluated. If females are using hormonal 
agents for contraception, the safety and/or efficacy may be affected by possible drug-drug 
interaction. However, it is recommended that the hormonal agent be continued and that a 
non-hormonal method(s) be used concurrently. If females utilize hormonal agents as one of their 
contraceptive methods, it is required that the same hormonal method be used for at least 
3 months before study dosing. Please refer to the latest version of the Investigator’s Brochure for 
GS-7340 for additional information
2.
Definition of Female of Childbearing Potential

For the purposes of this study, a female subject of childbearing potential is a nonmenopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure. This definition includes a pubertal female who has not yet started 
menstruating. A woman who has had a tubal sterilization is considered to be of childbearing 
potential.

A female subject < 54 years in age, with the absence of normal menses is considered to be of 
childbearing potential. Exceptions must be discussed with the medical monitor.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (ie, surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

Age > 54 years, with the cessation (for > 12 months) of previously occurring menses due to 
ovarian failure, will not be considered to be childbearing potential. 
3.
Contraceptive Requirements for Female Subjects
Female subjects of childbearing potential who engage in intercourse must agree to utilize 
protocol specified methods of contraception from the screening visit throughout the study period 
and for 30 days following the last dose of study drug. Female study subjects who are not 
heterosexually active must provide periodic confirmation of continued abstinence from 
heterosexual intercourse and regular pregnancy testing while participating in the study. The 
investigator will counsel subjects on the protocol specified method(s) for avoiding pregnancy in 
case the subject chooses to engage in heterosexual intercourse.
Protocol specified contraceptive methods are as follows: (1) a combination of one hormonal 
method and one barrier method; (2) two barrier methods where one method is the male condom; 
or (3) use of an intrauterine device (IUD) or tubal sterilization; see Appendix Table 1 below; or 


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(4) complete abstinence from intercourse. Periodic abstinence from intercourse (e.g. calendar, 
ovulation, sumptothermal, post-ovulation methods) is not permitted.
Acceptable hormonal methods include injectable progesterone, progesterone implants, 
combination oral contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable 
barrier methods include diaphragm with spermicide, cervical cap with spermicide, and the male 
condom. The use of spermicide is not recommended if the subject or subject’s partner is infected 
with HIV. Female subjects must use either a hormonal method or a barrier method if the partner 
has a vasectomy. If a subject has undergone tubal sterilization or has had a Copper T 380A IUD 
or LNg 20 IUD inserted, no other contraception is needed.  
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least 
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of study 
drug. Lactating females must discontinue nursing before IMP administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with a 
barrier method)
Barrier Methods
(use both OR choose one and use 
with a hormone method)
Intrauterine Devices (IUDs)
—
Copper T 380A IUD
—
LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone
—
Oral contraceptives
—
Transdermal patch
—
Vaginal ring
Progesterone
—
Injection
—
Implant
—
Diaphragm with spermicide
OR
—
Cervical cap with spermicide
—
Male condom (with or without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
The investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.


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4.
Contraceptive Requirements for Male Subjects
Male subjects must agree to use protocol specified method of contraception during heterosexual 
intercourse and avoid sperm donation from the time of the first dose of study drug and 
throughout the study period, and for at least 30 days after administration of the last dose of study 
medication 
Use of condoms, except for lambskin, has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.
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. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.6.2.1.