Clinical trial NCT02979613
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2016-12-29; Completion date: 2020-01-30
Enrollment: 490 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of switching to tenofovir alafenamide (TAF) versus continuing tenofovir disoproxil fumarate (TDF) in virologically suppressed adults with chronic hepatitis B virus (HBV) infection.

Detailed description:

Arms: arm 1: Double-blind (DB) phase: TAF 25 mg + TDF placebo for up to 53 weeks. Open-label extension (OLE) phase: TAF 25 mg for up to 52 weeks. arm 2: DB phase: TDF 300 mg + TAF placebo for up to 50 weeks. OLE phase: TAF 25 mg for up to 52 weeks.
Interventions: intervention 1: TAF intervention 2: TDF intervention 3: TAF Placebo intervention 4: TDF Placebo
Intervention descriptions: intervention 1: 25 mg tablet administered orally once daily intervention 2: 300 mg tablet administered orally once daily intervention 3: Tablet administered orally once daily intervention 4: Tablet administered orally once daily

Protocol documents:
SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Switching from Tenofovir Disoproxil 
Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide 
(TAF) 25 QD in Subjects with Chronic Hepatitis B who are 
Virologically Suppressed
Name of Test Drug:
Tenofovir Alafenamide (TAF)
Study Number:
GS-US-320-4018
Protocol Version (Date):
Amendment 1 (21 December 2016)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
11 March 2020
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.2.1.
Design Configuration and Subject Population .......................................................................9
1.2.2.
Treatment Groups and Randomization...................................................................................9
1.2.3.
Key Eligibility Criteria...........................................................................................................9
1.2.4.
Study Periods and Phases.....................................................................................................10
1.2.5.
Schedule of Assessments......................................................................................................10
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
Data Monitoring Committee (DMC) Analysis.......................................................................................12
2.2.
Week 48 Analysis (Primary Analysis) ...................................................................................................12
2.3.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
Randomized Analysis Set.....................................................................................................13
3.1.2.
Safety Analysis Set...............................................................................................................13
3.1.3.
Open-Label Safety Analysis Set...........................................................................................13
3.1.4.
Treatment-Free Follow-up Safety Analysis Set ...................................................................14
3.1.5.
Full Analysis Set ..................................................................................................................14
3.1.6.
Open-Label Full Analysis Set ..............................................................................................14
3.1.7.
TFFU Full Analysis Set........................................................................................................14
3.1.8.
Serologically Evaluable Full Analysis Set ...........................................................................14
3.1.9.
Open-Label Serologically Evaluable Full Analysis Set .......................................................14
3.1.10.
TFFU Serologically Evaluable Full Analysis Set.................................................................15
3.1.11.
DXA Analysis Set ................................................................................................................15
3.1.12.
Open-Label DXA Analysis Set ............................................................................................16
3.2.
Subject Grouping ...................................................................................................................................16
3.3.
Strata and Covariates..............................................................................................................................16
3.4.
Missing Data and Outliers......................................................................................................................16
3.4.1.
Missing Data ........................................................................................................................16
3.4.2.
Outliers.................................................................................................................................17
3.5.
Data Handling Conventions and Transformations .................................................................................17
3.6.
Analysis Visit Windows.........................................................................................................................18
3.6.1.
Definition of Study Day 1 and Other Definitions.................................................................18
3.6.2.
Analysis Windows................................................................................................................19
3.6.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................22
4.
SUBJECT DISPOSITION ..................................................................................................................................24
4.1.
Subject Enrollment and Disposition.......................................................................................................24
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................25
4.2.1.
Duration of Exposure to Blinded Study Drug ......................................................................25
4.2.2.
Adherence with Blinded Study Drug Regimen ....................................................................25
4.2.3.
Duration of Exposure to Open-Label Study Drug................................................................26
4.2.4.
Adherence with Open-Label Study Drug Regimen..............................................................26


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4.3.
Protocol Deviations................................................................................................................................28
5.
BASELINE CHARACTERISTICS....................................................................................................................29
5.1.
Demographics and Baseline Characteristics ..........................................................................................29
5.2.
Medical History......................................................................................................................................30
6.
EFFICACY ANALYSES ...................................................................................................................................31
6.1.
Primary Efficacy Endpoint.....................................................................................................................31
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................31
6.2.
Secondary Efficacy Endpoints ...............................................................................................................31
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................31
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................32
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................33
7.
SAFETY ANALYSES........................................................................................................................................34
7.1.
Adverse Events.......................................................................................................................................34
7.1.1.
Adverse Event Dictionary ....................................................................................................34
7.1.2.
Adverse Event Severity........................................................................................................34
7.1.3.
Relationship of AEs to Study Drug......................................................................................34
7.1.4.
Relationship of AEs to Study Procedure..............................................................................34
7.1.5.
Serious AEs..........................................................................................................................35
7.1.6.
Treatment-Emergent AEs.....................................................................................................35
7.1.7.
Summaries of AEs and Deaths.............................................................................................37
7.2.
Laboratory Evaluations ..........................................................................................................................39
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................39
7.2.2.
Graded Laboratory Values ...................................................................................................41
7.2.3.
ALT Elevation......................................................................................................................43
7.3.
Bone Safety Analyses ............................................................................................................................43
7.3.1.
Bone Mineral Density (BMD)..............................................................................................43
7.3.2.
Bone Biomarkers..................................................................................................................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).........................................................................48
7.4.5.
Urine Creatinine, Urine RBP to Creatinine Ratio and 
Beta-2-Microglobulin to Creatinine Ratio............................................................................48
7.4.6.
Proteinuria by Quantitative Assessment...............................................................................48
7.4.7.
Other Renal Biomarkers.......................................................................................................49
7.5.
Child-Pugh-Turcotte Score ....................................................................................................................50
7.6.
Body Weight ..........................................................................................................................................50
7.7.
Concomitant Medications ......................................................................................................................51
7.8.
Electrocardiogram (ECG) Results..........................................................................................................52
7.9.
Other Safety Measures ...........................................................................................................................52
7.10.
Changes From Protocol-Specified Safety Analyses...............................................................................52
8.
PATIENT REPORTED OUTCOMES................................................................................................................53
8.1.
Definition of Patient Reported Outcomes ..............................................................................................53
8.1.1.
SF-36....................................................................................................................................53
8.1.2.
CLDQ...................................................................................................................................54
8.1.3.
WPAI:SHP ...........................................................................................................................55
8.2.
Analysis Methods for Patient Reported Outcomes.................................................................................56


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8.3.
Changes From Protocol-Specified Patient Reported Outcomes Analyses .............................................56
9.
REFERENCES ...................................................................................................................................................57
10.
SOFTWARE.......................................................................................................................................................58
11.
SAP REVISION..................................................................................................................................................59
12.
APPENDICES ....................................................................................................................................................60
Appendix 1.
Study Procedures Table..........................................................................................................61
Appendix 2.
Bone Events............................................................................................................................64
Appendix 3.
Fracture Events.......................................................................................................................79
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and Liver 
Function Tests, Urinalysis, Urine Pregnancy Test, eGFRCG, PTH, FEPO4, 
TmP/GFR, UPCR, UACR, Weight, and Vital Sign Assessments ..........................................20
Table 3-2.
Analysis Windows for Safety ECG and Child Pugh Score ....................................................20
Table 3-3.
Analysis Windows for Fibrotest and Health Related Quality of Life Questionnaires............20
Table 3-4.
Analysis Windows for BMD Results from DXA...................................................................21
Table 3-5.
Analysis Windows for Fasting Glucose, Fasting Lipid Panel, Serum HBsAg 
(Quantitative) and HBV Serology ..........................................................................................21
Table 3-6.
Analysis Windows for Fasting Renal and Bone Biomarkers..................................................21
Table 3-7.
Analysis Windows for Post-Treatment Assessments .............................................................22
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
ANCOVA
analysis of covariance
ANOVA
analysis of variance
Anti-HBe
antibody to HBeAg
Anti-HBs
antibody to HBsAg
AST
aspartate aminotransferase
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
CFR
Code of Federal Regulations
CHB
chronic hepatitis B
CI
confidence interval
CK
creatine kinase
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
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DILI
drug-induced liver injury
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


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GFR
glomerular filtration rate
Gilead
Gilead Sciences, Inc.
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
HDL
high density lipoproptein
HDV
hepatitis D virus
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ITT
intent to treat
IWRS
interactive web response system
LDL
low density lipoprotein
LLN
lower limit of the normal range
LTT
lower-level term
LOQ
limit of quantitation
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
PCR
polymerase chain reaction
PP
per protocol
PT
preferred term
PVE
Pharmacovigilance and Epidemiology
Q1, Q3
first quartile, third quartile
QD
once daily
RBP
retinol binding protein
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation


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SI (units)
international system of units
SOC
system organ class
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate (Viread®)
TFLs
tables, figures, and listings
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
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in the tables, figures, and listings (TFLs) in the final clinical study report 
(CSR) for Study GS-US-320-4018. The final efficacy and safety analysis will be performed after 
all subjects have completed the study or prematurely discontinued the study. This SAP is based 
on the study protocol Amendment 1 dated 21 December 2016 and the electronic case report form 
(eCRF). The SAP will be finalized before database finalization for the final analysis. Any 
changes made after the finalization of the SAP will be documented in the CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

To evaluate the efficacy of switching to tenofovir alafenamide (TAF) 25 mg once daily (QD)
versus continuing tenofovir disoproxil fumarate (TDF) 300 mg QD in virologically 
suppressed subjects with chronic hepatitis B virus (HBV) as determined by the proportion of 
subjects with HBV DNA ≥ 20 IU/mL (as defined by the modified United States (US) Food 
and Drug Administration (FDA) defined snapshot algorithm) at Week 48

To compare the safety and tolerability of switching to TAF 25 mg QD versus continuing 
TDF 300 mg QD in virologically suppressed subjects with chronic HBV at Week 48
The key secondary objectives of this study are as follows:

To compare the safety of switching to TAF 25 mg QD versus continuing 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 switching to TAF 25 mg QD versus continuing TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 48
Other secondary objectives of this study are as follows: 

To evaluate the proportion of subjects with HBV DNA < 20 IU/mL and target detected/not 
detected (ie, < lower limit of detection [LLOD]) at Week 48 in subjects who switched to 
TAF 25 mg QD versus those who continued TDF 300 mg QD

To compare the safety of switching to TAF 25 mg QD for 96 weeks versus continuing TDF 
300 mg QD for 48 weeks followed by open-label TAF for 48 weeks as determined by the 
percent change from baseline in hip and spine BMD at Week 96


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
To compare the safety of switching to TAF 25 mg QD for 96 weeks versus continuing TDF 
300 mg QD for 48 weeks followed by open-label TAF for 48 weeks as determined by the 
change from baseline in eGFRCG at Week 96

To compare the serological response (loss of hepatitis B surface antigen [HBsAg] and 
seroconversion to antibody against hepatitis B surface antigen [anti-HBs], and loss of 
hepatitis B e antigen [HBeAg] and seroconversion to antibody against hepatitis B e antigen 
[anti-HBe] in HBeAg-positive subjects) of switching to TAF 25 mg QD versus continued 
TDF 300 mg QD at Week 48

To compare biochemical response (normal alanine aminotransferase [ALT] and normalized 
ALT) of switching to TAF 25 mg QD versus continued TDF 300 mg QD at Week 48

To compare the change in fibrosis as assessed by FibroTest® after switching to TAF 25 mg 
QD versus continued TDF 300 mg QD at Week 48

To evaluate the comparative open-label efficacy (virologic, serological, and biochemical) and 
safety of switching to TAF 25 mg QD from Week 48 through Week 96 in subjects initially 
randomized to TAF 25 mg QD and in subjects sequentially treated with continued TDF 
300 mg QD for 48 weeks and then switched to open-label TAF 25 mg QD at Week 96
1.2.
Study Design
1.2.1.
Design Configuration and Subject Population
This is a randomized, double-blind, multicenter, active-controlled study to evaluate the safety 
and efficacy of TAF 25 mg QD in virologically suppressed chronic hepatitis B (CHB) subjects 
who switch from TDF to TAF compared to continued TDF treatment.
Approximately 460 adult (about half ≥50 years old) subjects with CHB, who are currently 
virologically suppressed while receiving therapy with TDF, will be randomized in a 1:1 ratio to 
receive either TAF 25 mg QD and matched placebo of TDF 300 mg QD or Gilead-provided TDF 
300 mg QD and matched placebo of TAF 25 mg QD.
1.2.2.
Treatment Groups and Randomization
At randomization, subjects will be stratified by screening HBeAg status (HBeAg-negative vs. 
HBeAg-positive) and age (≥ 50 or < 50 years). 
1.2.3.
Key Eligibility Criteria
Subjects were to have met all eligibility criteria, including the following key eligibility criteria:

Documented evidence of chronic HBV infection previously (eg, documented HBsAg positive 
for more than 6 months)


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
Maintained on TDF 300 mg QD for at least 48 weeks, and as monotherapy for CHB for at 
least 24 weeks prior to screening and with viral suppression (HBV DNA < lower limit of 
quantitation [LOQ] by local laboratory assessment) for a minimum of 12 weeks prior to 
screening, and including a screening HBV DNA value of < 20 IU/mL (by a central 
laboratory)

Estimated creatinine clearance ≥50 ml/min (using the Cockcroft-Gault method) based on 
serum creatinine and actual body weight as measured at screening

Did not have co-infection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV), 
evidence of hepatocellular carcinoma or recent (≤ 5 years) history of clinical hepatic 
decompensation, and abnormal hematological and biochemical parameters
1.2.4.
Study Periods and Phases
The duration of double-blind treatment is 48 weeks. All subjects who complete 48 weeks of 
treatment are eligible for participation in the open label TAF 25-mg extension period for an 
additional 48 weeks (through Week 96). During the double-blind period only, subjects with a 
confirmed eGFRCG < 50 ml/min, and > 20% decline in estimated glomerular filtration rate 
(eGFRCysC) by CKD-EPI (cystatin C) compared to baseline during the study, were required to 
undergo dose modification to every other day dosing of study drug. Subjects with confirmed 
creatinine clearance < 30 mL/min during the double-blind period of the study were to have the 
study drug discontinued.
1.2.5.
Schedule of Assessments
Laboratory analyses (serum chemistry and liver tests, hematology, eGFRCG, urinalysis, plasma 
HBV DNA levels), pregnancy testing [for females of childbearing potential]), vital signs, 
adverse events, and concomitant medications will be measured or assessed at screening baseline, 
Weeks 4, 8, 12, 24, 36, 48, 60 ,72, and 96 (and at early discontinuation [ED]). Fasting metabolic 
panels will be measured at baseline, and Weeks 12, 24, 36, 48, 60, 72, and at 96 (and at ED). 
HBV serology (HBsAg, HBeAg, reflex hepatitis B antibody [HBeAb], hepatitis B surface 
antibody [HBsAb], and quantitative HBsAg) will be conducted at screening, baseline, Weeks 12, 
24, 36, 48, 60 72, and 96 (and at ED).
Dual energy x-ray absorptiometry (DXA) scans of the hip and spine will be performed at 
baseline and Weeks 24, 48, 72, and 96 (and at ED). Bone and renal biomarker testing will be 
performed at baseline and Weeks 4, 12, 24, 48, 72, and 96 (and at ED). FibroTest® and the Child 
Pugh Score will be performed at baseline, Week 48, and Week 96 (and at ED).
Complete physical examination will be performed at screening, baseline, and Weeks 24, 48, 72, 
and 96 (and at ED). Symptom-driven physical examinations including body weight assessment 
will be conducted at all other visits. Electrocardiogram (ECG) will be performed at screening, 
Week 48, and Week 96 (and at ED). Health-related quality of life questionnaires including 
Chronic Liver Disease Questionnaire (CLDQ), SF-36, and Work Productivity and Activity 
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Follow-up assessments will occur every 4 weeks for 12 weeks for subjects who discontinue 
study drug due to HBsAg loss and for 24 weeks for subjects who permanently discontinue study 
drug for other reasons, and will include the following: concomitant medications, adverse events, 
body weight, vital signs, symptom driven physical examinations, laboratory analyses, and HBV 
serology.
1.3.
Sample Size and Power
With respect to the primary efficacy endpoint of proportion of subjects with HBV DNA 
≥20 IU/mL (the lower LOQ of the current polymerase chain reaction [PCR] assay), as 
determined by the modified US FDA-defined snapshot algorithm, at Week 48, when the sample 
sizes are 230 (TAF 25 mg arm) and 230 (TDF 300 mg arm), a two-group, large-sample normal 
approximation test of proportions with a one-sided 0.025 significance level will have 80% power 
to establish non-inferiority of TAF to TDF. It is assumed that both treatment arms will have 
subjects who have HBV DNA ≥ 20 IU/mL (as defined by the modified US FDA-defined 
snapshot algorithm) at a rate of 2.4% at Week 48 (based on the rates of suppressed subjects 
having HBV DNA ≥ 29 IU/mL, the lower LOQ of the assay used in those studies, after 48 weeks 
of treatment from the combined data from TDF studies GS-US-174-0102 and GS-US-174-0103 
with the ratio of HBeAg- to HBeAg+ subjects assumed to be 2:1), with a non-inferiority margin 
of 4%.
The proposed sample size (n
230 for the TAF 25 mg arm, n
230 for the TDF 300 mg arm) 
also provides > 99% power to detect a 1.81% difference in the percentage change from baseline 
in hip BMD at Week 48 (assuming a 1.47% [SD 2.71%] change from baseline in the TAF 25 mg 
arm and 0.34% [SD 2.83%] change from baseline in the TDF 300 mg arm, with a two-sided 
α
0.05); a > 99% power to detect a 2.00% difference in the percentage change from baseline in 
spine BMD at Week 48 (assuming a 1.56% [SD 3.84%] change from baseline in the TAF 25 mg 
arm and 0.44% [SD 4.14%] change in the TDF 300 mg arm, with a two-sided α  0.05); 
a 97% power to detect a 4.9 mL/min difference in the change from baseline in eGFRCG at 
Week 48 (assuming a 1.3 mL/min [SD 13.2] change from baseline in the TAF 25 mg arm and 
3.6 mL/min [SD 13.0] change from baseline in the TDF 300 mg arm, with a two-sided 
α
0.05). These assumptions were derived from an HIV switch study (GS-US-292-0109) due to 
the unavailability of stable and suppressed switch data from TAF HBV studies.


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2.
TYPE OF PLANNED ANALYSIS
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 the safety data in order to protect subject welfare and 
preserve study integrity. To ensure the best interests of the participants, the DMC will
recommend to the sponsor if the nature, frequency, and severity of adverse effects associated 
with the study treatment warrant the early termination of the study, the continuation of the study, 
or the continuation of the study with modifications.
The initial review was conducted after all subjects completed 24 weeks of the study. No 
additional meetings were requested by the DMC.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Week 48 Analysis (Primary Analysis)
The Week 48 analysis was conducted after the last subject completed the Week 48 visit or 
prematurely discontinued study drug.
2.3.
Final Analysis
The final analysis for the study will be conducted after all subjects have completed the study or 
prematurely discontinued the study, for all study data from double-blind phase to open-label 
phase to treatment-free follow-up.
This SAP described the plan for the final analysis.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the Randomized Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as 
adverse events (AEs), will be presented in chronological order within the subject. The treatment 
group to which subjects were randomized will be used in the listings. Age, sex at birth, race, and 
ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects who were included out of all 
randomized subjects will be summarized by treatment group and overall.
A listing of reasons for exclusion from analysis sets will be provided by subject.
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 will include 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-blind phase. The actual treatment received will differ from the randomized treatment 
only when their actual treatment differs from randomized treatment for the entire treatment 
duration during the double-blind phase. This is the primary analysis set for safety analyses. 
3.1.3.
Open-Label Safety Analysis Set
The Open-Label Safety Analysis Set includes all randomized subjects who have received at least
1 dose of open-label study drug. Subjects will be analyzed according to the treatment they 
actually received during the double-blind phase.


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3.1.4.
Treatment-Free Follow-up Safety Analysis Set
The treatment-free follow-up (TFFU) Safety Analysis Set includes all randomized subjects who 
entered the TFFU period. Subjects will be analyzed according to the treatment they actually 
received during the double-blind phase. 
3.1.5.
Full Analysis Set
The Full Analysis Set (FAS) will include 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-blind phase. This is the primary analysis set for efficacy analyses, 
unless otherwise specified.
3.1.6.
Open-Label Full Analysis Set
The Open-Label FAS includes all randomized subjects who have received at least 1 dose of 
open-label study drug. Subjects will be analyzed according to the treatment to which they were 
randomized during the double-blind phase. 
3.1.7.
TFFU Full Analysis Set
The TFFU FAS includes all randomized subjects who entered the TFFU period. Subjects will be 
analyzed according to the treatment to which they were randomized during the double-blind 
phase. 
3.1.8.
Serologically Evaluable Full Analysis Set
3.1.8.1.
Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion
The Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drug, and with 
HBeAg positive and HBeAb negative or missing values at baseline. Subjects will be analyzed 
according to the treatment they were randomized to during the double-blind phase.
3.1.8.2.
Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion
The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion will include all 
subjects who were randomized and had received at least 1 dose of study drug, and with 
HBsAg positive and HBsAb negative or missing values at baseline. Subjects will be analyzed 
according to the treatment they were randomized to during the double-blind phase.
3.1.9.
Open-Label Serologically Evaluable Full Analysis Set
3.1.9.1.
Open-Label Serologically Evaluable Full Analysis Set for HBeAg 
Loss/Seroconversion
The Open-Label Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion 
includes all subjects who were randomized and had received at least 1 dose of open-label study 


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drug, and with HBeAg positive and HBeAb negative or missing at open-label baseline. Subjects 
will be analyzed according to the treatment they were randomized to during the double-blind 
phase.
3.1.9.2.
Open-Label Serologically Evaluable Full Analysis Set for HBsAg 
Loss/Seroconversion
The Open-Label Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion 
includes all subjects who were randomized and had received at least 1 dose of open-label study 
drug, and with HBsAg positive and HBsAb negative or missing at open-label baseline. Subjects 
will be analyzed according to the treatment they were randomized to during the double-blind 
phase.
3.1.10.
TFFU Serologically Evaluable Full Analysis Set
3.1.10.1.
TFFU Serologically Evaluable Full Analysis Set for HBeAg Loss/Seroconversion
The TFFU Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion includes all 
subjects who were randomized and entered the TFFU period, and with HBeAg positive and 
HBeAb negative or missing at TFFU baseline. Subjects will be analyzed according to the 
treatment they were randomized to during the double-blind phase.
3.1.10.2.
TFFU Serologically Evaluable Full Analysis Set for HBsAg Loss/Seroconversion
The TFFU Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion includes all 
subjects who were randomized and entered the TFFU period, and with HBsAg positive and 
HBsAb negative or missing at TFFU baseline. Subjects will be analyzed according to the 
treatment they were randomized to during the double-blind phase.
3.1.11.
DXA Analysis Set
3.1.11.1.
Hip DXA Analysis Set
The Hip DXA Analysis Set will include 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-blind phase.
3.1.11.2.
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-blind phase.


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3.1.12.
Open-Label DXA Analysis Set
3.1.12.1.
Open-Label Hip DXA Analysis Set
The Open-Label Hip DXA Analysis Set includes all subjects in the Open-Label Safety Analysis 
Set who had nonmissing open-label baseline hip BMD values. Subjects will be analyzed 
according to the treatment received in double-blind phase.
3.1.12.2.
Open-Label Spine DXA Analysis Set
The Open-Label Spine DXA Analysis Set includes all subjects in the Open-Label Safety 
Analysis Set who had nonmissing open-label baseline spine BMD values. Subjects will be 
analyzed according to the treatment received in double-blind phase.
3.2.
Subject Grouping
For analyses based on the FAS, Open-Label FAS, and TFFU FAS, including the serologically 
evaluable FASs, subjects will be grouped according to the treatment to which they were 
randomized to during the double-blind phase. For analyses based on the Hip and Spine DXA 
Analysis Sets, Safety Analysis Set, Open-Label Hip and Spine DXA Analysis Sets, Open-Label 
Safety Analysis Set, and TFFU Safety Analysis Set, subjects will be grouped according to the 
actual treatment received during the double-blind phase.
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive voice or web response 
system (IXRS) in a 1:1 ratio using a stratified randomization schedule. Stratification will be 
based on screening for HBeAg status (HBeAg-negative vs HBeAg-positive) and age (≥ 50 or 
< 50 years). For statistical analyses, the HBeAg status and age strata recorded in the clinical 
database will be reclassified using the corresponding baseline value and used for analysis. If the 
number of subjects in a stratum is too small, the stratum may be combined with other strata for 
analysis.
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 subject permanently discontinuing from the study before reaching the window
In general, values for missing data will not be imputed, unless methods for handling missing data 
are specified.


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For missing last dosing date of study drug, imputation rules are described in Section 3.6. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.6.2, and for 
concomitant medications in Section 7.7.
3.4.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.5.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen failures, 
the date the informed consent was signed will be used for age calculation. If only the birth year is 
collected on the eCRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “01” will be used for the 
unknown birth day.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
Logarithm (base 10) transformations will be applied to HBV DNA and quantitative HBsAg data, 
as appropriate, in efficacy analyses. 
For HBV DNA, if the value in IU/mL is above the upper limit of quantification, the 
corresponding diluted value, if available, will be used. HBV DNA results of “<20 IU/mL HBV 
DNA detected” or “No HBV DNA detected” will be imputed as 19 IU/mL.


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3.6.
Analysis Visit 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.
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. 
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, study days are calculated as (visit date 
Open-Label Study Day 1 + 1).
Follow-up days are for visits occurred during the 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 
Withdrawn” box checked for subjects who prematurely discontinued blinded study drug or who 
completed blinded study drug according to the 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 completed blinded study drug, or for subjects 
who are still on blinded study drug, the latest of non-missing blinded study drug start dates and 
end dates, the clinical visit dates, and the laboratory visit dates, excluding the dates during open-
label treatment and 24-week treatment-free follow up, 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 the 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 the 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 Withdrawn” 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 of 
open-label study drug is missing (eg, due to lost to follow up) for subjects who prematurely 
discontinued open-label study drug or who completed open-label study drug, or for subjects who 
are still on open-label study drug, the latest of non-missing open-label study drug start dates and 
end dates, the clinical visit dates, and the laboratory visit dates, excluding the dates during 
24-week treatment-free follow-up, 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 clinical visit dates, 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 the Study Completion eCRF.
3.6.2.
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 3-1 to Table 3-6) apply only to baseline and postbaseline
on-treatment assessments collected during the double-blind phase and open-label phase. For 
summaries and analyses, assessments will first be categorized into baseline and postbaseline
on-treatment assessments occurring during the double-blind or open-label phase before applying 
analysis windows.
Baseline value for the double-blind phase 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.
For subjects who completed blinded study drug and entered the open-label phase, laboratory 
assessments that occurred during the period from Study Day 2 up to and including the minimum 
of the Last Dose Date of Blinded Study Drug + 3 days and Open-label Study Day 1, will be 
considered as postbaseline on-treatment assessments during the double-blind phase. If a subject 
prematurely discontinued blinded study drug or did not enter open-label phase after completion 
of blinded study drug, then postbaseline on-treatment assessments during the double-blind phase 
will be defined as assessments that occurred during the period from Study Day 2 up to and 
including the Last Dose Date of Blinded Study Drug + 3 days. DXA assessments that occurred 
during the period from Study Day 15 up to and including the Last Dose Date of Blinded Study 
Drug + 14 days will be considered as postbaseline on-treatment assessments during the 
double-blind phase.
Baseline value for the open-label phase 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 value on or prior to 
Open-Label Study Day 14.
For subjects who entered the open-label phase, postbaseline on-treatment assessments during the 
open-label phase will be defined as assessments that occurred during the period from Open-label 
Study Day 2 up to the Last Dose Date + 3 days. DXA assessments that occurred during the 
period from Open-label Study Day 15 up to the Last Dose Date + 14 days will be considered as 
postbaseline on-treatment assessments during the open-label phase.
Baseline value for the TFFU phase is defined as the last nonmissing value obtained on or prior 
to the Last Dose Date + 3 days. 
The analysis windows for HBV DNA, hematology, serum chemistry and liver function tests, 
urinalysis, urine pregnancy test, eGFRCG, bone biomarker serum parathyroid hormone (PTH), 
urine fractional excretion of filtered phosphate (FEPO4), renal tubular maximum reabsorption 
rate of phosphate to the glomerular filtration rate (TmP/GFR), urine protein to creatinine ratio 


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(UPCR), urine albumin to creatinine ratio (UACR), weight, and vital sign assessments are 
presented in Table 3-1.
Table 3-1.
Analysis Windows for HBV DNA, Hematology, Serum Chemistry and 
Liver Function Tests, Urinalysis, Urine Pregnancy Test, eGFRCG, 
PTH, FEPO4, TmP/GFR, UPCR, UACR, Weight, and Vital Sign 
Assessments
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
Week 60
420
379
462
Week 72
504
463
588
Week 96
672
589
840
The analysis windows for safety ECG and Child Pugh Score are presented in Table 3-2.
Table 3-2.
Analysis Windows for Safety ECG and Child Pugh Score
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 48
336
2
504
Week 96
672
505
840
The analysis windows for FibroTest and health-related quality of life questionnaires are 
presented in Table 3-3.
Table 3-3.
Analysis Windows for Fibrotest and Health Related Quality of Life 
Questionnaires
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 24
168
2
252
Week 48
336
253
504
Week 96
672
505
840


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The analysis windows for BMD results from DXA are presented in Table 3-4.
Table 3-4.
Analysis Windows for BMD Results from DXA
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
14
Week 24
168
15
252
Week 48
336
253
420
Week 72
504
421
588
Week 96
672
589
840
The analysis windows for fasting glucose, fasting lipid panel including total cholesterol, high 
density lipoprotein (HDL), direct low density lipoprotein (LDL), total cholesterol to HDL ratio,
and triglycerides, serum HBsAg (quantitative) and HBV serology are presented in Table 3-5.
Table 3-5.
Analysis Windows for Fasting Glucose, Fasting Lipid Panel, Serum 
HBsAg (Quantitative) and HBV Serology
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 12
84
2
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
Week 60
420
379
462
Week 72
504
463
588
Week 96
672
589
840
The analysis windows for fasting renal biomarkers including urine retinol binding protein (RBP), 
urine RBP to creatinine ratio, urine beta-2-microglobulin (B2M), urine B2M to creatinine ratio, 
and bone biomarkers including C-type collagen sequence (CTX), procollagen type 1 N-terminal 
propeptide (P1NP) are presented in Table 3-6.
Table 3-6.
Analysis Windows for Fasting Renal and Bone Biomarkers
Visit ID
Nominal Day
Lower Limit
Upper Limit
Baseline
1
Week 4
28
2
56
Week 12
84
57
126
Week 24
168
127
252
Week 48
336
253
420


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Visit ID
Nominal Day
Lower Limit
Upper Limit
Week 72
504
421
588
Week 96
672
589
840
Post-treatment assessments during the treatment free follow-up (TFFU) phase will be defined as 
assessments that occurred during the period after the Last Dose Date (LDD) + 3 days up to the 
Last Study Date. 
The analysis windows for post-treatment assessments are presented in Table 3-7.
Table 3-7.
Analysis Windows for Post-Treatment Assessments
Visit ID
Nominal Follow-Up Day
Lower Limit
Upper Limit
Follow-Up Week 4
28
LDD+4
42
Follow-Up Week 8
56
43
70
Follow-Up Week 12
84
71
98
Follow-Up Week 16
112
99
126
Follow-Up Week 20
140
127
154
Follow-Up Week 24
168
155
182
3.6.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
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 one value per analysis window. When a single value is 
needed, the following rule(s) will be used. 
For baseline of the double-blind, open-label, and TFFU phases, the last available record on or prior 
to the first dose of blinded study drug, open-label study drug, and last dose date + 4 days will be 
selected, respectively. For DXA BMD baseline, the last value on or prior to Study Day 14 and 
Open-Label Study Day 14 will be selected for the double-bind and open-label phases, respectively. 
If there are multiple records with the same time or no time recorded on the same day for numeric 
observations, the average will be computed for that day, except for HBV DNA and quantitative 
HBsAg the geometric mean will be taken instead. 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.


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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): The record on the latest day in the window will be selected. If there is 
more than 1 record on the selected day, the geometric mean will be taken.

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 and Disposition
Subject enrollment summaries were performed as part of the Week 48 analysis and will not be 
repeated in the final analysis. The randomization schedule used for the study will be provided as 
an appendix to the CSR.
The summary of subject disposition will be provided by treatment group and overall for all 
screened subjects. 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 never treated, 
subjects in the Safety Analysis Set, subjects in the FAS, subjects in the Open-Label Safety 
Analysis Set, subjects in the Open-Label FAS, subjects in the TFFU Safety Analysis Set, and 
subjects in the TFFU FAS.
In addition, the number and percentage of the subjects in the following categories will be 
summarized using the Safety Analysis Set:
Double-blind Study Drug Completion

Prematurely discontinued double-blind study treatment (with summary of reasons for 
discontinuing treatment)

Completed double-blind study treatment
Open-label Study Drug Completion

Willing to enter open-label phase

Prematurely discontinued open-label study treatment (with summary of reasons for 
discontinuing treatment)

Completed open-label study treatment
Study Completion

Entered 24-week treatment-free follow-up period

Prematurely discontinued study (with summary of reasons for discontinuing study)

Completed protocol-planned duration of the study

Started another HBV therapy


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No inferential statistics will be generated. A data listing of reasons for premature study 
drug/study discontinuation will be provided.
4.2.
Extent of Study Drug Exposure and Adherence
Exposure data described below will be summarized for double-blind phase and open-label phase 
separately.
4.2.1.
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).
Duration of exposure to blinded study drug will be summarized using descriptive statistics 
(sample size, mean, 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), ≥12 weeks (84 days), ≥24 weeks (168 days), ≥36 weeks (252 days), ≥48 weeks 
(336 days).
Summaries will be provided by treatment group for subjects in the Safety Analysis Set. 
No inferential statistics will be provided. 
4.2.2.
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:
prescribed
 tablets
of
Number 
 taken
 tablets
of
Number 
100
(%)
Adherence

           
1
[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 +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.


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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 48 visit for blinded study drug will be calculated using all data from 
the entire dosing period up to the date of permanent discontinuation of the blinded study drug for 
subjects who prematurely discontinued blinded study drug, or completed blinded study drug.
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 the 
blinded 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.
4.2.3.
Duration of Exposure to Open-Label Study Drug
Duration of exposure to open-label study drug will be defined as (last dose date of open-label 
study drug first dose date of open-label 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).
Duration of exposure to open-label study drug will be summarized using descriptive statistics 
(sample size, mean, SD, median, Q1, Q3, minimum, and maximum) and as the number and 
percentage of subjects exposed for specified periods, eg, ≥12 weeks (84 days), ≥24 weeks 
(168 days), ≥36 weeks (252 days), ≥48 weeks (336 days).
Summaries will be provided by treatment group for subjects in the Open-Label Safety Analysis 
Set. No inferential statistics will be provided. 
4.2.4.
Adherence with Open-Label Study Drug Regimen
Study drug regimen adherence will be computed based on tablet counts for open-label TAF. The 
numbers of tablets of study drug dispensed and returned are captured on study drug 
accountability forms.


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Adherence (%) of study drug regimen will be calculated as follows:
prescribed
 tablets
of
Number 
 taken
 tablets
of
Number 
100
(%)
Adherence

            
1
[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 +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 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 
subjects who prematurely discontinued open-label study drug, or completed open-label study 
drug.
The number and percentage of subjects who return at least 1 bottle and have calculable 
adherence during the study, descriptive statistics for adherence for the open-label 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.
Protocol Deviations 
A by-subject listing will be provided for those subjects in the Randomized Analysis Set who did 
not meet at least 1 eligibility (inclusion or exclusion) criterion. The listing will present the 
eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related 
comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the Randomized Analysis Set. A by-subject listing 
will be provided for subjects with important protocol deviations.
A separate by-subject listing of subjects who received the incorrect study drug will also be 
provided.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic data (eg, age, sex, race, and ethnicity) and baseline characteristics 
(eg, body weight, 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 Open-Label 
Safety Analysis Set.
In addition, the following baseline characteristics and medical history will be summarized:

Age group (< 50 years, ≥50 years
and further split into ≥ 50 to < 60 years and > 60 years)

Region (Asia, Europe or North America)

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 categories (< 20 IU/mL, 20 to < 69 IU/mL, ≥69 IU/mL)

HBsAg (log10 IU/mL)

ALT (U/L)

ALT level based on central laboratory normal range (≤ ULN, > ULN - 5 × ULN, > 5 × ULN)

ALT level based on 2018 AASLD normal range with the ULN as 25 U/L for females and 
35 U/L for males (≤ ULN, > ULN - 5 × ULN, > 5 × ULN) 

HBeAg and HBeAb status (HBeAg positive, HBeAg negative/HBeAb negative, 
HBeAg negative/HBeAb positive)

Years positive for HBV 

Cirrhosis history (yes, no, indeterminate/unknown)

FibroTest score

Fibrosis stage by FibroTest score (0 - 0.48, 0.49 - 0.74,  0.75 - 1)

Estimated GFR by CG, CKD-EPI creatinine, and CKD-EPI Cystatin C methods

Proteinuria by urinalysis (dipstick) (Grade 0, Grade 1, Grade 2, Grade 3)


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
Clinical BMD status for hip and spine (normal, osteopenia, osteoporosis)

Hip fracture and major osteoporotic fracture probabilities estimated using FRAX®
(see Section 7.3.4)

Previous experience with treatment other than TDF (yes, no)

Previous interferon experience (yes, no)

Medical history: diabetes mellitus (yes, no), hypertension (yes, no), cardiovascular disease 
(yes, no), and hyperlipidemia (yes, no) 
Diabetes mellitus, hypertension, cardiovascular disease, and hyperlipidemia above are 
determined by medical history, adverse events, and concomitant medication data, which will be 
reviewed by the Gilead medical monitor before to data finalization for the final analysis.
5.2.
Medical History
Medical history will be collected at screening for disease-specific and general conditions (ie, 
conditions not specific to the disease being studied). A listing of medical history data will be 
provided using the Randomized Analysis Set.


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6.
EFFICACY ANALYSES
For the final analysis, efficacy data will be summarized for (1) subjects in the FAS from baseline 
up to Week 96 and statistical comparisons will be performed, (2) subjects in the Open-Label 
FAS from open-label baseline up to Week 96 and no statistical comparisons will be performed, 
and (3) subjects in the TFFU FAS from TFFU baseline to the end of the study and no statistical 
comparisons will be performed. All efficacy data, including data collected during the 24-week 
TFFU period, will be listed.
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with HBV DNA ≥ 20 IU/mL 
(as determined by the modified US FDA-defined snapshot algorithm) at Week 48. The primary 
efficacy endpoint was analyzed in the Week 48 analysis and will not be re-analyzed in the final 
analysis. Details are provided in the Week 48 SAP.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

The proportion of subjects with HBV DNA ≥20 IU/mL (as determined by the modified 
US FDA-defined snapshot algorithm) at Week 96

The proportion of subjects with HBV DNA < 20 IU/mL and target detected/not detected 
(ie, < LLOD) at Weeks 48 and 96

The proportion of subjects with HBeAg loss and proportion with seroconversion to anti-HBe 
at Weeks 48 and 96

The proportion of subjects with HBsAg loss and proportion with seroconversion to anti-HBs 
at Weeks 48 and 96

The proportion of subjects with normal ALT and proportion with normalized ALT 
(by central laboratory and AASLD criteria) at Weeks 48 and 96

The change from baseline in fibrosis as assessed by FibroTest at Weeks 48 and 96


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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.

HBeAg loss is defined as HBeAg test result changes from HBeAg positive at baseline to 
HBeAg negative at a postbaseline visit with baseline HBeAb 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.

HBeAg seroconversion is defined as HBeAg loss and HBeAb test result changes from 
HBeAb negative or missing at baseline to HBeAb positive at a postbaseline visit.

ALT normalization is defined as ALT > ULN (by central laboratory normal range or 2018 
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 will be considered as HBsAg positive and HBeAg positive.

HBsAb and HBeAb borderline will be considered as HBsAb negative and HBeAb negative.
For the above definitions, baseline will be replaced with open-label baseline for the analyses of 
subjects in the Open-Label FAS, and with TFFU baseline for the analyses of subjects in the 
TFFU FAS.
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
The primary analysis of the proportion of subjects in the Full Analysis Set with HBV DNA 
≥20 IU/mL (as determined by the modified US FDA-defined snapshot algorithm {U. S. 
Department of Health and Human Services 2015}) will be repeated for the Week 96 endpoint
using the FAS. The Week 96 analysis window is defined as from Study Day 589 to Study 
Day 840, inclusive.
The analyses for the other secondary efficacy endpoints will be conducted using the FAS. All 
secondary efficacy endpoints involving proportions will be analyzed from baseline to Week 96 
using both the Missing  Failure (M
F) approach and the Missing  Excluded (M  E) 
approach, unless otherwise specified. In the M  E approach, all missing data will be excluded in 
the computation, and in the M  F approach, all missing data will be treated as failures and 
included in both the numerator and denominator. P-values will be calculated using the CMH test 
stratified by baseline HBeAg status (HBeAg-positive or HBeAg-negative) and age (< 50 or 
≥50 years), and the proportion difference between the 2 treatment groups and the associated 
95% CIs will be calculated based on the stratum-adjusted MH proportion.


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The change from baseline in log10 (HBsAg) (IU/mL), both overall and by baseline HBeAg status, 
and ALT will be summarized by visit using observed data (ie, missing data will be excluded). 
The p-value, differences in change from baseline in log10 (HBsAg) (IU/mL) and ALT between 
the 2 treatment groups and the associated 95% CI will be constructed using analysis of variance
(ANOVA) models, including treatment group, baseline HBeAg status (HBeAg-positive or 
HBeAg-negative), and age (< 50 or ≥50 years) as fixed effects in the model. For the analysis of 
change from baseline in log10 (HBsAg) (IU/mL) by baseline HBeAg status, only treatment group 
and age (< 50 or ≥50 years) will be included as fixed effects in the model.
In addition, the proportion of subjects in the FAS with HBV DNA < 20 IU/mL, the proportion of 
subjects with normal ALT by the central laboratory and 2018 AASLD criteria (ULN is 35 U/L 
for males and 25 U/L for females) using the M  E approach, and the mean change from baseline 
in log10 (HBsAg) (IU/mL) and ALT (U/L) will be plotted with 95% CI over time using observed 
data from baseline to Week 96.
Fibrosis assessed by FibroTest at Week 24, 48, and 96, 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 for subjects in the FAS. The p-value, 
differences in change from baseline in FibroTest score between the 2 treatment groups and the 
associated 95% CI will be constructed using ANOVA models, including treatment group, 
baseline HBeAg status (HBeAg-positive or HBeAg-negative) and age (< 50 or ≥50 years) as 
fixed effects in the model. A shift table of fibrosis stage from baseline based on the FibroTest score
at Week 24, 48, and 96 will be provided. Mean change from baseline in FibroTest score will be 
plotted with 95% CI over time using observed data from baseline to Week 96. A listing of 
fibrosis assessment by FibroTest will also be provided.
All the analyses of the secondary efficacy endpoints, using both the M  F and the M  E 
approach, and plots described above will be repeated for subjects in the Open-Label FAS from 
open-label baseline to Week 96. No statistical comparisons will be performed.
For subjects in the TFFU FAS, only HBV DNA, ALT, HBsAg, HBeAg loss/seroconversion, and 
HBsAg loss/seroconversion endpoints will be summarized by visit in the TFFU phase as 
described above only using the M  E approach. No statistical comparisons will be performed.
6.3.
Changes From Protocol-Specified Efficacy Analyses
FibroTest measurements were not specified to be collected at Week 24 in the study protocol but
were collected in the study. FibroTest analyses were updated to include the Week 24
measurement.


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7.
SAFETY ANALYSES
For the final analysis, cumulative safety data (treatment-emergent AEs, treatment-emergent 
laboratory abnormalities, etc.) will be summarized for (1) subjects in the FAS during the 
double-blind phase, (2) subjects in the Open-Label Safety Analysis Set during the open-label 
phase, and (3) subjects in the TFFU Safety Analysis Set during the TFFU phase. Exposure data 
will be summarized for (1) and (2).
By-visit summary tables of safety measurements will be presented for the entire study treatment 
period (double-blind and open-label phase combined) based on subjects in the Safety Analysis 
Set from baseline to Week 96, and open-label phase based on subjects in the Open-Label Safety 
Analysis Set from open-label baseline to Week 96. Statistical comparisons will only be 
performed for the analysis of the entire study treatment period, unless otherwise specified. No 
by-visit summaries for safety measurements will be generated for the TFFU phase.
All safety data including data collected during the 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
Adverse events are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe) or Grade 4 (life threatening) according to toxicity criteria specified in Appendix 4 of the 
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.


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7.1.5.
Serious AEs
Serious AEs (SAEs) are those identified as serious in the eCRF, where ‘Yes’ was marked for 
‘AE serious’. The clinical database will be reconciled with the SAE database (from the 
Pharmacovigilance and Epidemiology [PVE] Department) before database finalization.
7.1.6.
Treatment-Emergent AEs
7.1.6.1.
Definition of Treatment-Emergent
Treatment-emergent AEs will be separately defined for the double-blind phase and the open-
label phase. Post-treatment-emergent AEs will be defined only for the TFFU phase.
Treatment-emergent AEs occurring during the double-blind phase are defined as:

Any AE with onset date on or after the blinded study drug start date and no later than the 
minimum of the blinded study drug stop date + 3 days and the day prior to the first dose date 
of open-label study drug, if applicable, for those who discontinued blinded study drug 
permanently, or

Any AE with onset date on or after the blinded study drug start date for those who are still 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 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
permanently, or

Any AE with onset date on or after the open-label study drug start date for those who are still 
on open-label study drug, or

Any AE leading to open-label study drug discontinuation.
Post-treatment-emergent AEs occurring during the TFFU phase are defined as:

Any AE with onset date after the last dose of study drug + 3 days


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7.1.6.2.
Incomplete Dates
If an AE onset date is incomplete or completely missing, the following rules will be used to 
determine if the AE is considered treatment emergent during the double-blind and open-label 
phases, or post-treatment-emergent during the TFFU phase:
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 
minimum of the blinded study drug stop date + 3 days and the day prior to the first dose date 
of open-label study drug, if applicable, and

AE 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
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 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 open-label study drug + 3 days, and

AE 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


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The event is post-treatment-emergent during the TFFU 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 day after the last dose date + 3 days
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 
The event is post-treatment-emergent during the TFFU phase if the following criteria are met:

The (complete) end date is after the last dose date + 3 days, or

The month and year (or year) of end date is the same or after the month and year (or year) of 
the day after the last dose date + 3 days, or

End date is completely missing 
7.1.7.
Summaries of AEs and Deaths
AEs will be summarized for (1) subjects in the Safety Analysis Set during the double-blind 
phase, (2) subjects in the Open-Label Safety Analysis Set during the open-label phase, and 
(3) subjects in the TFFU Safety Analysis Set during the TFFU phase. The full set of AE 
summaries as described below will be generated for (1) and (2).
A brief summary of AEs (ie, the number and percentage of subjects) will be presented by 
treatment group for the following: any treatment-emergent AE, any Grade 3 or 4 
treatment-emergent AE, any Grade 2, 3 or 4 treatment-emergent AE, any treatment-emergent study 
drug-related AE, any Grade 3 or 4 treatment-emergent study drug-related AE, any Grade 2, 3 or 
4 treatment-emergent study drug-related AE, any treatment-emergent serious adverse event (SAE),


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any treatment-emergent study drug-related SAE, any treatment-emergent AE leading to 
premature study drug discontinuation, any treatment-emergent AE leading to dose modification 
or study drug interruption, and any death.
Summaries (number and percentage of subjects) of AEs (by SOC, HLT [if specified below], 
and PT) will be provided by treatment group and overall 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 AEs 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. 
For post-treatment AEs during the TFFU phase, the overall summary and individual summaries 
will be provided only for the following:

All post-treatment-emergent AEs

Any Grade 3 and 4 post-treatment-emergent AEs

All post-treatment-emergent SAEs
In addition to the by-treatment summaries, data listings will be provided for the following:

All AEs


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
Grade 3 and 4 AEs

SAEs

Study drug-related SAEs

Deaths

AEs leading to premature discontinuation of study drug

AEs leading to dose modification or study drug interruption
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for (1) the 
double-blind phase and open-label phase for subjects in the Safety Analysis Set from baseline to 
Week 96, and (2) summaries of laboratory data will be provided for the open-label phase only
for subjects in the Open-Label Safety Analysis Set from open-label baseline to Week 96. Only 
laboratory abnormalities will be summarized for subjects in the TFFU Safety Analysis Set from 
TFFU baseline to the end of study. 
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 3.5. 
A by-subject listing for laboratory test results will be provided by subject 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 double-blind phase and open-
label phase for subjects in the Safety Analysis Set from baseline to Week 96 as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window

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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of blinded study drug. Change from baseline to a postbaseline visit will be 
defined as the visit value minus the baseline value. 
Descriptive statistics (sample size, mean, SD, median, Q1, Q3, minimum, and maximum) will 
also be provided by treatment group for each laboratory test during the open-label phase only 
based on subjects in the Open-Label Safety Analysis Set from open-label baseline to Week 96, as 
follows:

Open-label baseline values

Values at each open-label postbaseline analysis window

Change from open-label postbaseline to each open-label postbaseline analysis window

Percentage change from open-label postbaseline to each open-label postbaseline analysis 
window (if specified) 
An open-label baseline laboratory value will be defined as the last measurement obtained on or 
prior to the date of first dose of open-label study drug. Change from open-label baseline to an
open-label postbaseline visit will be defined as the visit value minus the open-label baseline 
value.
Descriptive summaries for numeric laboratory results measured during the TFFU phase will not 
be provided.
Mean, median, Q1, Q3, minimum, and maximum values will be displayed to the reported 
number of digits; SD values will be displayed to the reported number of digits plus 1. In the case 
of multiple values in an analysis window, data will be selected for analysis as described in 
Section 3.6.2.
Median (Q1, Q3) change from baseline to Week 96 in selected safety endpoints over time, 
including the fasting lipid panel parameters and fasting glucose, for subjects in the Safety 
Analysis Set will be plotted by treatment group. This will be repeated for subjects in the 
Open-Label Safety Analysis Set from open-label baseline to Week 96.
7.2.1.1.
Metabolic Assessments
For the lipid panel and glucose measurements, only those under fasting status will be 
summarized for subjects in the Safety Analysis Set from baseline to Week 96. P-values for the 
difference between the 2 treatment groups in baseline values and the change from baseline in 
fasting lipid and glucose data (including total cholesterol, triglycerides, LDL, HDL, total 
cholesterol to HDL ratio, and glucose) will be estimated from the 2-sided Wilcoxon rank sum 
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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.
The summaries described above will be repeated for the subjects in the Open-Label Safety 
Analysis from open-label baseline to Week 96 using open-label baseline instead of baseline, and 
no statistical comparisons will be made.
7.2.1.2.
Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized by-visit for subjects in the 
Safety Analysis Set from baseline to Week 96, and separately for subjects in the Open-Label 
Analysis Set from open-label baseline to Week 96. 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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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 minimum of the blinded study drug stop date + 3 days and the first dose date of 
open-label study drug, if applicable, 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 double-blind study drug. If the relevant baseline laboratory value is 
missing, any laboratory abnormality of at least Grade 1 observed within the double-blind phase 
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 open-label baseline at any open-label 
postbaseline visit up to and including the last dose date of the open-label study drug + 3 days for 
those who discontinued open-label study drug permanently, or values that increase by at least 
1 toxicity grade from open-label baseline at any open-label postbaseline visit for those who are 
still on open-label study drug. For the analyses of abnormalities occurring during open-label 
treatment, open-label baseline will be the last available record on or prior to Open-Label Study 
Day 1.
Post-treatment-emergent laboratory abnormalities occurring in the TFFU phase are defined as 
values that increase by at least 1 toxicity grade from TFFU baseline. For the analyses of 
abnormalities occurring during the TFFU phase, TFFU baseline will be the last available record 
on or prior to last dose date + 3 days.
Fasting glucose and nonfasting glucose (including glucose results without a known fasting 
status) are graded based on different grading scales as specified in the protocol.
Treatment-emergent and post-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 minimum of the blinded study drug stop date + 3 days and the first dose date of 
open-label study drug, if applicable, for those who discontinued blinded study drug permanently, 
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 observed within the double-blind time frame specified 
above will be considered as treatment-emergent marked laboratory abnormalities during the 
double-blind phase.
Treatment-emergent marked laboratory abnormalities occurring in the open-label phase are 
defined as values that worsen by at least 3 grades from open-label baseline at any open-label 
postbaseline visit up to and including the date of last dose of open-label study drug + 3 days for 
those who discontinued open-label study drug permanently, or values that worsen by at least 


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3 grades from open-label baseline at any open-label postbaseline visit for those who are still on 
open-label study drug.
Post-treatment-emergent marked laboratory abnormalities will not be summarized for the TFFU 
phase.
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) for (1) subjects in the Safety Analysis Set during the double-blind phase, (2) subjects in 
the Open-Label Safety Analysis Set during the open-label phase, and (3) subjects in the TFFU 
Safety Analysis Set during the TFFU phase:

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 and 4 laboratory abnormalities

Treatment-emergent marked laboratory abnormalities (this will not be summarized for (3))
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
any nonmissing postbaseline (or open-label postbaseline, or post-TFFU baseline) value in the 
given study period. By-subject listings of Grade 3 or 4 and graded laboratory abnormalities will 
be provided by subject ID number and visit in chronological order.
7.2.3.
ALT Elevation
An ALT elevation is defined as serum ALT > 2 × open-label baseline value and > 10 × ULN, 
with or without associated symptoms. Confirmed ALT elevation (ALT flare) is defined as ALT 
elevations at 2 consecutive open-label postbaseline visits. All treatment-emergent ALT 
elevations including confirmed ALT elevations will be summarized for the open-label phase
only. 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)
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 subjects in 
the Hip and Spine DXA Analysis Sets. Percentage change from open-label baseline in hip BMD 
and spine BMD during the open-label phase will be summarized by treatment group and visit 
using descriptive statistics for subjects in the Open-Label Hip and Spine DXA Analysis Sets.
For each subject and visit, the clinical BMD status will be defined for hip and spine BMD based 
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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 subjects in each clinical BMD status (normal, osteopenia, and 
osteoporosis) will be summarized by visit and by baseline (or open-label baseline) clinical status
for both hip and spine using observed data. Only for the entire study treatment period summary, 
the distribution of the clinical BMD status will be compared between the 2 treatment groups, 
adjusting for baseline status using rank analysis of covariance (ANCOVA) {LaVange 2008}.
The number and percentage of subjects in each category based on percentage change from 
baseline (or open-label 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 using observed data. Only for the entire study 
treatment period summary, the distribution difference in these categories between the 2 treatment 
groups will be compared using the CMH test (row mean scores differ statistic).
Median (Q1, Q3) and mean (95% CIs) of percentage change from baseline to Week 96 in 
observed hip BMD and spine BMD over time will be plotted by treatment group for subjects in 
the corresponding Hip and Spine DXA Analysis Sets. This will be repeated using subjects in the 
Open-Label Hip and Spine DXA Analysis Sets from open-label baseline to Week 96.
7.3.2.
Bone Biomarkers
Bone biomarkers include serum CTX, P1NP, and PTH.
Baseline, postbaseline, change from baseline, and percentage change from baseline in bone 
biomarkers will be summarized by treatment group and visit using descriptive statistics for 
subjects in the Safety Analysis Set from baseline to Week 96. Percentage change from baseline 
will be compared between the 2 treatment groups using the Wilcoxon rank sum test.
Open-label baseline, open-label postbaseline, change from open-label baseline, and percentage 
change from open-label baseline in bone biomarkers will be summarized by treatment group and 
visit using descriptive statistics for subjects in the Open-Label Safety Analysis Set from open-
label baseline to Week 96. No statistical comparisons will be performed.
Median (Q1, Q3) percentage change from the baseline to Week 96 in each bone biomarker over 
time will be plotted by treatment group for subjects in the Safety Analysis Set. This will be 
repeated using subjects in the Open-Label Safety Analysis Set from open-label baseline to 
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7.3.3.
Fracture Events
The PTs for fracture events were defined based on HLGT of Fractures from the most current 
version of MedDRA at the time of the analysis (see Appendix 3). The number and percentage of 
subjects in the Open-Label Safety Analysis Set who experienced fracture events will be 
summarized by treatment group for the open-label phase. 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 to Week 96 in the 
10-year probabilities of hip fracture, as well as major osteoporotic fracture, will be presented by 
treatment group and visit for subjects in the Safety Analysis Set aged between 40 and 90 years. 
Change from baseline in the 10-year fracture probabilities at each analysis visit will be compared 
between the 2 treatment groups using ANOVA, which includes treatment as a fixed effect.
In the second set of analysis, the above-specified analysis will be performed to include all 
subjects, where subjects in the Safety Analysis Set 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.
The analyses described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed.
Only 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 based a search for bone disorder related adverse events
reviewed by PVE using the most current version of MedDRA at the time of the analysis (see 
Appendix 2). The number and percentage of subjects in the Open-Label Safety Analysis Set who 


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experienced treatment-emergent bone events will be summarized by treatment group for the 
open-label phase. 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 open-label baseline in creatinine of at least 0.5 mg/dL or

Confirmed creatinine clearance CLcr by CG below 50 mL/min or

Confirmed phosphorous < 2 mg/dL
Confirmed renal abnormalities are defined as renal abnormalities at 2 consecutive open-label 
postbaseline visits. Treatment-emergent confirmed renal abnormalities during the open-label 
phase will be summarized, where open-label baseline will be defined as the last available record 
on or prior to Open-Label Study Day 1. All confirmed renal abnormalities including those that 
occur during the open-label phase will be listed.
7.4.2.
Serum Creatinine
For the renal safety analyses, observed creatinine values will be used.
For subjects in the Safety Analysis Set, the baseline and change from baseline in serum 
creatinine during the entire study period will be summarized using descriptive statistics. The 
baseline serum creatinine and change from baseline in serum creatinine will be compared 
between the 2 treatment groups using the two-sided Wilcoxon rank sum test.
For subjects in the Open-Label Safety Analysis Set, the open-label baseline and change from 
open-label baseline in serum creatinine during the open-label phase will be summarized 
using descriptive statistics. No statistical comparisons will be performed. 
Median (Q1, Q3) and mean (95% CIs) of change from baseline to Week 96 in serum creatinine 
over time will be plotted by treatment group for subjects in the Safety Analysis Set. This will be 
repeated using subjects in the Open-Label Safety Analysis Set from open-label baseline to 
Week 96.
7.4.3.
Estimated Glomerular Filtration Rate
Estimated glomerular filtration rate will be summarized for subjects in the Safety Analysis Set 
from baseline to Week 96.


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The following formulae will be used to calculate eGFR: 

CG based:
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}.

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.
P-values for the baseline, the change from baseline in eGFRCG and eGFRCKD EPI, creatinine will be 
estimated from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups. For 
eGFRCKD EPI, cysC, only the baseline value will be summarized as the postbaseline tests were only 
performed as reflex tests.
The number and proportion of subjects with decrease from baseline of ≥ 25% and ≥ 50% in 
eGFRCG and eGFR CKD EPI, creatinine will be summarized by treatment groups for subjects in the 
Safety Analysis Set from baseline to Week 96. Statistical comparisons of the subject incidence 
rates between the 2 treatment groups during the entire study period will be performed using 
Fisher’s exact test. 
The number and proportion of subjects in each stage of chronic kidney disease (CKD) will be 
summarized by baseline stages of CKD at Weeks 12, 24, 36, 48, 60, 72, and 96 for the entire 
study treatment period based on subjects in the Safety Analysis Set. The distribution of the stages 
of CKD at these visits will be compared between the 2 treatment groups adjusting for entire 
study treatment period using rank ANCOVA {LaVange 2008}.
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

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The summaries described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed.
Median (Q1, Q3) change from baseline in eGFR by CG and by CKD-EPI Creatinine over time 
will be plotted by treatment group for subjects in the Safety Analysis Set from baseline to 
Week 96. This will be repeated for subjects in the Open-Label Safety Analysis Set from 
open-label baseline to Week 96.
7.4.4.
Treatment-Emergent Proteinuria (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) will be summarized by treatment group 
for the subjects in the Open-Label Safety Analysis Set during the open-label phase. 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 during the double-blind and 
open-label phase. The difference in percentage change from baseline in these ratios between the 
2 treatment groups will be tested using the Wilcoxon rank sum test only for the entire study 
period summary.
The summary described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed.
Median (Q1, Q3) percentage change from the baseline in the urine RBP to creatinine ratio, and 
beta-2-microglobulin to creatinine ratio over time will be plotted by treatment group for subjects 
in the Safety Analysis Set from baseline to Week 96. This will be repeated for subjects in the 
Open-Label Safety Analysis Set from open-label baseline to Week 96.
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 
subjects in the Safety Analysis Set from baseline to Week 96. Percentage change from baseline 
will be compared between the 2 treatment groups using the Wilcoxon rank sum test only for the 
entire study period summary.
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 during the entire study treatment 
period {KDIGO Guideline Development Staff 2013}.


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The number and proportion of subjects 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}.
The distribution of the UPCR and UACR categories during the entire study period will be 
compared between the 2 treatment groups adjusting for baseline categories using rank ANCOVA 
{LaVange 2008}, respectively.
The summaries described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed. 
Median (Q1, Q3) percentage change from baseline in the 2 ratios over time will be plotted by 
treatment group for subjects in the Safety Analysis Set from baseline to Week 96. This will be 
repeated for subjects in the Open-Label Safety Analysis Set from open-label baseline to 
Week 96.
7.4.7.
Other Renal Biomarkers
Other renal biomarkers include TmP/GFR and FEPO4.
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 (%)


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The baseline, postbaseline, and change from baseline in TmP/GFR and FEPO4 will be 
summarized by treatment group and visit using descriptive statistics during the double-blind and
open-label phase using the subjects in the Safety Analysis Set. Baseline and change from 
baseline will be compared between the 2 treatment groups using the Wilcoxon rank sum test only 
for the entire study period. 
The summaries described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed. 
Median (Q1, Q3) change from the baseline in TmP/GFR and FEPO4 over time will be plotted by 
treatment group for subjects in the Safety Analysis Set from baseline to Week 96. This will be 
repeated for subjects in the Open-Label Safety Analysis Set from open-label baseline to 
Week 96.
7.5.
Child-Pugh-Turcotte Score
The Child-Pugh-Turcotte (CPT) score is calculated as: the sum of the scores related to the 
5 items in the table below (if any of the components are missing, the score is not calculated):
Measure
1 point
2 points
3 points
Total Bilirubin (mg/dL)
< 2
2 - 3
> 3
Serum Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Slight/Moderate 
(medically controlled)
Severe (medically 
uncontrolled)
Hepatic Encephalopathy
None
Slight/Moderate 
(medically controlled)
Severe (medically 
uncontrolled)
For summary purposes, the score will be further classified into classes: Class A (5-6 points), 
Class B (7-9 points), and Class C (10-15 points). The number and proportion of subjects in each 
class of CPT score will be summarized in a shift table with baseline, Week 48, and Week 96
CPT class based on subjects in the Safety Analysis Set during the entire study treatment period.
The distribution of the CPT class at these visits will be compared between the 2 treatment groups 
adjusting for baseline class using rank ANCOVA {LaVange 2008}.
The summaries described above will be repeated for subjects in the Open-Label Safety Analysis 
Set from open-label baseline to Week 96, using open-label baseline in place of baseline, and no 
statistical comparisons will be performed. 
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, using subjects in the Safety Analysis Set 


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from baseline to Week 96. In the case of multiple values in an analysis window, data will be 
selected for analysis as described in Section 3.6.2.
This summary will be repeated for subjects in the Open-Label Safety Analysis Set from open-
label baseline to Week 96. 
7.7.
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. Use of concomitant medications for 
the open-label phase will be summarized (number and percentage of subjects) by treatment 
group and preferred name. Multiple drug use (by preferred name) will be counted only once per 
subject. The summary will be sorted by decreasing total frequency.
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 


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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 open-label phase using the 
Safety Analysis Set. No inferential statistics will be provided. Subjects with any concomitant 
medication use will also be listed.
7.8.
Electrocardiogram (ECG) Results
The number and percentage of subjects with an investigator’s ECG assessment of normal, 
abnormal but not clinically significant, or abnormal and clinically significant will be summarized 
by treatment group for subjects in the Safety Analysis Set from baseline to Week 96. This 
summary will be repeated for subjects in the Open-Label Safety Analysis Set from open-label 
baseline to Week 96. No inferential statistics will be provided. 
A by-subject listing of safety ECG results will be provided including treatment, assessment date 
and time, and ECG results.
7.9.
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.
7.10.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PATIENT REPORTED OUTCOMES
The effect of treatment on health related quality of life questionnaires (via SF-36, CLDQ, and 
WPAI questionnaires) will be analyzed by visit for subjects in the Safety Analysis Set for the 
entire study treatment period (ie, from baseline up to Week 96), and separately for subjects in the 
Open-Label Safety Analysis Set for the open-label phase only (ie, from open-label baseline up to 
Week 96).
8.1.
Definition of Patient Reported Outcomes
8.1.1.
SF-36
The Short Form-36 (SF-36) includes 11 questions with multiple sub-questions that yield a total 
of 36 questions. The responses are rated on a 3-point, 5-point, or 6-point scale, and scoring are 
performed on 8 domains: Physical function (PF), Role physical (RP), Bodily Pain (BP), General 
health perceptions (GH), Vitality (VT), Social functioning (SF), Role emotional (RE), Mental 
health (MH).
Scale
Item
Abbreviated Item Content
Physical Functioning (PF)
3a
Vigorous activities, such as running, lifting heavy objects, or 
participating in strenuous sports
3b
Moderate activities, such as moving a table, pushing a vacuum cleaner, 
bowling, or playing golf
3c
Lifting or carrying groceries
3d
Climbing several flights of stairs
3e
Climbing one flight of stairs
3f
Bending, kneeling, or stooping
3g
Walking more than a mile
3h
Walking several hundred yards
3i
Walking one hundred yards
3j
Bathing or dressing oneself
Role-Physical (RP)
4a
Cut down the amount of time one spent on work or other activities
4b
Accomplished less than you would like
4c
Limited in kind of work or other activities
4d
Had difficulty performing work or other activities (e.g., it took extra 
effort)
Bodily Pain (BP)
7
Intensity of bodily pain
8
Extent pain interfered with normal work


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Scale
Item
Abbreviated Item Content
General Health (GH)
1
Is your health: excellent, very good, good, fair, poor 
11a
Seem to get sick a little easier than other people 
11b
As healthy as anybody I know 
11c
Expect my health to get worse 
11d
Health is excellent
Vitality (VT)
9a
Feel full of life 
9e
Have a lot of energy 
9g
Feel worn out 
9i
Feel tired
Social Functioning (SF)
6
Extent health problems interfered with normal social activities 
10
Frequency health problems interfered with social activities
Role-Emotional (RE)
5a
Cut down the amount of time spent on work or other activities
5b
Accomplished less than you would like
5c
Did work or other activities less carefully than usual
Mental Health (MH)
9b
Been very nervous
9c
Felt so down in the dumps that nothing could cheer you up
9d
Felt calm and peaceful
9f
Felt downhearted and depressed
9h
Been happy
Health Transition (HT)
2
How health is now compared to before
Two summary scales will be presented based on the domain scores: 

Physical component summary (PCS): combines PF, RP, BP, and GH

Mental component summary (MCS): combines VT, SF, RE, and MH
The summary scores aggregate information from the 8 SF-36 domains in a way that captures 
80% to 85% of the variance in the 8 domains.
The SF-36 physical component and the mental component scores will be calculated based on the 
8 domain scores using the SF-36v2 scoring method (http://www.sf-36.org/demos/SF-36v2.html).
8.1.2.
CLDQ
The Chronic Liver Disease Questionnaire (CLDQ) includes 29 questions which aim to survey 
how subjects felt during the last two weeks. The responses are rated on a 7-point scale, and 


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translated into 6 domain scores: fatigue, activity, emotional function, abdominal symptoms, 
systemic symptoms, and worry, and an overall CLDQ score. Specifically, 

Abdominal symptoms (AB)  Mean of {R1, R5, R17}

Fatigue (FA)  Mean of {R2, R4, R8, R11, R13}

Systemic (SY)  Mean of {R3, R6, R21, R23, R27}

Activity (AC)  Mean of {R7, R9, R14}

Emotion (EM)  Mean of {R10, R12, R15, R16, R19, R20, R24, R26}

Worry (WO)  Mean of {R18, R22, R25, R28, R29}
where R# is the response to question number # (eg, R1 is the response to question 1).
The overall CLDQ score will then be calculated by taking the mean of 6 domain scores.
8.1.3.
WPAI:SHP
The Work Productivity and Activity Impairment Questionnaire: Specific Health Hepatitis 
(WPAI:SHP) includes 6 questions that are summarized into a four WPAI:SHP scores. The first 
question is to determine the employment status. Questions 2 through 5 are applicable to 
employed patients only. Using subject responses to six questions, four scores are derived: 

percentage of absenteeism, 

percentage of presenteeism (reduced productivity while at work), 

an overall work impairment score that combines absenteeism and presenteeism and 

percentage of impairment in activities performed outside of work. 
Greater scores indicate greater impairment 
(http://www.reillyassociates.net/WPAI_Scoring.html).


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Score
Source
Formula
Absenteeism
Question 2: During the past seven days, how many 
hours did you miss from work because of {your health 
problems}?
100 x [Q2/(Q2+Q4)]
Question 4: During the past seven days, how many 
hours did you actually work?
Presenteesism
Question 5: During the past seven days, how much did 
{your health problems} affect your productivity while 
you were working?
100 x [(Q5)/10]
Work 
Productivity 
Loss
Question 2: During the past seven days, how many 
hours did you miss from work because of {your health 
problems}?
100 x [Q2/(Q2+Q4) +
{1 – Q2/(Q2+Q4)}x(Q5)/10]
Question 4: During the past seven days, how many 
hours did you actually work?
Question 5: During the past seven days, how much did 
{your health problems} affect your productivity while 
you were working?
Activity 
Impairment
Question 6: During the past seven days, how much did 
{your health problems} affect your ability to do your 
regular daily activities, other than work at a job?
100 x [(Q6)/10]
For the WPAI:SHP, four scores will be calculated based on the results.
8.2.
Analysis Methods for Patient Reported Outcomes
Descriptive statistics for each of the SF-36 domains, and physical and component scores, CLDQ 
domain and overall scores, and the WPAI:SHP scores at baseline, Week 24, Week 48, Week 96,
and change from baseline at Week 24, Week 48, and Week 96, will be presented by treatment 
group for subjects in the Safety Analysis Set from baseline to Week 96. Change from baseline 
for each score will be compared between treatment groups using a 2-sided Wilcoxon rank-sum 
test. 
This will be repeated for subjects in the Open-Label Safety Analysis Set from open-label 
baseline to Week 96, using open-label baseline in place of baseline, and no statistical 
comparisons will be performed.
A by-subject listing for the scores from each of the questionnaires will be provided by subject ID 
number and visits in chronological order.
8.3.
Changes From Protocol-Specified Patient Reported Outcomes Analyses
There are no deviations from the protocol-specified patient reported outcomes analyses.


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9.
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.
LaVange LM, Koch GG. Randomization-Based Nonparametric (ANCOVA). In: D'Agostino Sr. 
RB, Sullivan LM, Massaro JM, eds.  Wiley Encyclopedia of Clinical Trials. John 
Wiley & Sons, Inc.; 2008: 31-8. vol 4).
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.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Silver Spring, MD.  November, 2015.


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10.
SOFTWARE
SAS® (SAS Institute Inc., Version 9.2, 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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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Study Procedures Table
Appendix 2.
Bone Events
Appendix 3.
Fracture Events


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Appendix 1.
Study Procedures Table
Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
Informed Consent
x
Inclusion/Exclusion Criteria
x
x
Medical History (including HBV disease and treatment history)
x
x
Concomitant Medications
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
Complete Physical Examination with weight and vital signs
x
x
x
x
x
x
x
Height 
x
Body Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom driven Physical Examination
x
x
x
x
x
x
x
Health Related Quality of Life (CLDQ, SF 36, WPAI)m
x
x
x
x
x
Serum Chemistry and Liver Testsb
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
Fasting metabolic panelc
x
x
x
x
x
x
x
x
x
Pregnancy testing (women of child bearing potential only)
serum
urine (+ve test to be confirmed with serum)
x
x
x
x
x
x
x
x
x
x
x
x
Estimated Creatinine Clearance by Cockcroft Gault method 
(eGFRCG)
x
x
x
x
x
x
x
x
x
x
x
x
x
HBV serology (qualitative HBsAg and HBeAg) and 
quantitative HBsAgi
x
x
x
x
x
x
x
x
x
x
x


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Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
HCV, HDV, HIV Testing
x
α fetoprotein (AFP)
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine drug screen
x
DXA scans (Hip & Spine)d
x
x
x
x
x
x
ECGe
x
x
x
x
Plasma HBV DNA levels
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomization
x
Study Drug Accountability
x
x
x
x
x
x
x
x
x
Study Drug Dispensation
x
x
x
x
x
x
x
x
x
FibroTest®
x
x
x
x
Child Pugh Scoren
x
x
x
x
Serum Cystatin Cl
x
Fasting Blood for Bone Biomarkerf
x
x
x
x
x
x
x
x
Fasting Urine for Renal Biomarkerf
x
x
x
x
x
x
x
x
Fracture Risk Assessment (FRAX)
x
Virology (Sequence analysis of HBV pol/RT for 
resistance surveillance)j
x
x
x
x
x
x
x
x
x
x
x
Vitamin D
x


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Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
Serum, plasma and urine for storage
x
x
x
x
x
x
x
x
x
x
x
x (serum only)
a
Vital signs include blood pressure, pulse, respiration rate and temperature
b
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. At Baseline, Weeks 24, 48, 72, 96, and 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: PT/INR will be done at Screening, Week 48, 96 and ED and then as a reflex only test for ALT flares.
c
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). At Baseline, Weeks 12, 24, 36, 48, 60, 72, and 96/ED analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry panel.
d
The Baseline DXA can be performed at any time during the Screening period, but should be completed at least 14 days prior to the Baseline visit to ensure results are received prior to 
the first dose of study drug. The Week 24 DXA window is ± 14 days. The Week48 DXA window is 14 days only. DXA required for Early Discontinuation (ED) visit if not done 
within the last 12 weeks and should be done within ±14 days of the expected ED visit date
e
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
f
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
g
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
h
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti HBs on or after the Week 24 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the original study visit schedule through Week 96/ED. 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 appropriate, alternative HBV 
therapy, whichever occurs first. Initiation of appropriate, alternative HBV therapy is highly encouraged.
i
HBeAb and HBsAb reflex testing will be performed as needed.
j
Resistance sequence analysis may be performed at BL for subjects with HBV DNA ≥ 69 IU/mL and may be attempted for viremic subjects (HBV DNA ≥ 69 IU/mL) at 
Wks 48 and 96/ED. Phenotypic analysis will be performed for subjects that are subjected to sequence analysis. As it may not be known at the time of the visit whether a subject is 
viremic or if it will be their last study visit, a virology sample will be collected as each visit. In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be 
asked to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound occurring within the first 12 weeks of the study, the next scheduled visit will used for 
follow up. For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 2 3 weeks after the date of the original test that resulted with HBV DNA
virologic rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for resistance testing will be obtained. For unscheduled visits, the subject will be 
required to bring their supply of study drug with them and be assessed for adherence by pill count, and if necessary, the subject will be re counseled on adherence to study medication.
k
The visit window for Week 48 visit is 14 days only.
l
Serum Cystatin C will be done when eGFRCG falls < 50 ml/min during blinded period of study.
m
Health Related Quality of Life surveys required for Early Discontinuation (ED) visit if not done within the last 24 weeks of the expected ED visit date
n
Child Pugh Score will be assessed at Baseline (Day 1), Weeks 48 and 96. Assessment requires: total bilirubin, albumin, PT/INR, Ascites assessment, and Hepatic encephalopathy 
assessment     
CCI


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Appendix 2.
Bone Events
The selected Preferred Terms of bone events based on MedDRA 22.1 are listed as follows:
Selected Preferred Terms
Abscess oral
Acetabulum fracture
Aneurysmal bone cyst
Ankle fracture
Arm amputation
Arthrogram
Arthrogram abnormal
Arthrogram normal
Arthroscopy
Arthroscopy abnormal
Arthroscopy normal
Aspiration bursa
Aspiration bursa abnormal
Aspiration bursa normal
Aspiration joint
Aspiration joint abnormal
Aspiration joint normal
Biopsy abdominal wall
Biopsy abdominal wall abnormal
Biopsy abdominal wall normal
Biopsy bone
Biopsy bone abnormal
Biopsy bone normal
Biopsy cartilage
Biopsy cartilage abnormal
Biopsy cartilage normal
Biopsy muscle
Biopsy muscle abnormal
Biopsy muscle normal
Bone cyst
Bone development abnormal
Bone disorder


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Selected Preferred Terms
Bone formation increased
Bone graft
Bone hypertrophy
Bone lesion excision
Bone pain
Bone scan
Bone trimming
Bunion operation
Calcification metastatic
Calcium deficiency
Calcium intoxication
Calcium metabolism disorder
Callus formation delayed
Chondrocalcinosis pyrophosphate
Clavicle fracture
Closed fracture manipulation
Coccydynia
Complicated fracture
Compression fracture
Dental alveolar anomaly
Dental necrosis
Dislocation of vertebra
Dwarfism
Epiphyses delayed fusion
Epiphyses premature fusion
Epiphysiolysis
Epiphysitis
Exostosis
Exostosis of external ear canal
Exostosis of jaw
External fixation of fracture
Face and mouth X-ray
Face and mouth X-ray abnormal
Face and mouth X-ray normal
Facial bones fracture


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Selected Preferred Terms
Femoral neck fracture
Femur fracture
Fibula fracture
Finger amputation
Finger repair operation
Flail chest
Foot amputation
Foot fracture
Forearm fracture
Fracture
Fracture delayed union
Fracture malunion
Fracture nonunion
Fracture of clavicle due to birth trauma
Fractured ischium
Fractured maxilla elevation
Fractured sacrum
Fractured skull depressed
Greenstick fracture
Groin pain
Hand amputation
Hand fracture
Hand repair operation
Hip arthroplasty
Hip disarticulation
Hip fracture
Humerus fracture
Hypercalcaemia
Hypercalcaemia of malignancy
Hypercalcaemic nephropathy
Hypercalciuria
Hyperparathyroidism
Hyperparathyroidism primary
Hyperparathyroidism secondary
Hyperparathyroidism tertiary


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Selected Preferred Terms
Hyperphosphataemia
Hypertrophic osteoarthropathy
Hypocalcaemia
Hypochondroplasia
Hypoparathyroidism
Hypophosphataemia
Ilium fracture
Internal fixation of fracture
Jaw cyst
Jaw fracture
Jaw lesion excision
Knee arthroplasty
Kyphoscoliosis
Kyphosis
Leg amputation
Metacarpal excision
Metatarsal excision
Metatarsalgia
Microsurgery to hand
Multiple fractures
Open fracture
Open reduction of fracture
Open reduction of spinal fracture
Osteitis
Osteitis condensans
Osteitis deformans
Osteoarthropathy
Osteodystrophy
Osteolysis
Osteomalacia
Osteomyelitis
Osteomyelitis acute
Osteomyelitis blastomyces
Osteomyelitis chronic
Osteomyelitis drainage


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Selected Preferred Terms
Osteomyelitis salmonella
Osteonecrosis
Osteoporosis
Osteoporosis postmenopausal
Osteoporotic fracture
Osteosclerosis
Osteosis
Osteotomy
Pain in jaw
Patella fracture
Patellectomy
Pathological fracture
Periodontal destruction
Periostitis
Periostitis hypertrophic
Perthes disease
Post-traumatic osteoporosis
Pseudohypoparathyroidism
Radius fracture
Removal of epiphyseal fixation
Removal of foreign body from joint
Removal of internal fixation
Renal rickets
Resorption bone increased
Rib fracture
Rickets
Scapula fracture
Senile osteoporosis
Skeletal survey
Skeletal survey abnormal
Skeletal survey normal
Skeletal traction
Skull fractured base
Skull X-ray
Skull X-ray abnormal


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Selected Preferred Terms
Skull X-ray normal
Spinal compression fracture
Spinal fracture
Spinal X-ray
Spinal X-ray abnormal
Spinal X-ray normal
Sternal fracture
Stress fracture
Synovectomy
Tetany
Tibia fracture
Toe amputation
Toe operation
Tooth abscess
Ulna fracture
Wrist fracture
X-ray of pelvis and hip
X-ray of pelvis and hip abnormal
X-ray of pelvis and hip normal
Pseudarthrosis
Tooth infection
Synoviorthesis
Vertebral lesion
Osteopathic treatment
Ankle operation
Osteopenia
Fractured coccyx
Arthrectomy
Bone density decreased
Traumatic fracture
Knee operation
Shoulder arthroplasty
Williams syndrome
Pubic pain
Extraskeletal ossification


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Selected Preferred Terms
Bone infarction
Osteoporosis prophylaxis
Cervical vertebral fracture
Lumbar vertebral fracture
Thoracic vertebral fracture
Temporomandibular joint surgery
Ankle arthroplasty
Melorheostosis
Rotator cuff repair
Synovial fluid white blood cells positive
Joint prosthesis user
Osteocalcin
Osteocalcin increased
Osteocalcin decreased
Bone densitometry
Hypocalciuria
Oral surgery
Hip surgery
Wrist surgery
Hyperphosphaturia
Biopsy chest wall
Biopsy ligament
Biopsy tendon
Chvostek's sign
Bone fistula
Calciphylaxis
Bone erosion
Bone marrow oedema
Osteorrhagia
Latent tetany
Baker's cyst excision
Bone cyst excision
Periprosthetic osteolysis
Osteoporosis circumscripta cranii
Comminuted fracture


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Selected Preferred Terms
Epiphyseal surgery
Fracture displacement
Discogram
Ostectomy
Rheumatoid nodule removal
Sequestrectomy
Abscess jaw
Bone swelling
N-telopeptide urine
N-telopeptide urine normal
N-telopeptide urine abnormal
N-telopeptide urine increased
N-telopeptide urine decreased
Epiphyseal fracture
Congenital syphilitic osteochondritis
Maxillofacial operation
Vertebral column mass
Meniscus operation
Intervertebral disc injury
Sternal injury
Limb reattachment surgery
Meniscus removal
Bone formation decreased
Body height below normal
Body height decreased
Body height abnormal
Synovial fluid red blood cells positive
Synovial fluid crystal present
Fracture debridement
Bone electrostimulation therapy
Fracture reduction
Bone debridement
Joint arthroplasty
Biopsy chest wall abnormal
Biopsy chest wall normal


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Selected Preferred Terms
Bone density increased
Bone callus excessive
Biopsy ligament abnormal
Biopsy tendon abnormal
Biopsy ligament normal
Biopsy tendon normal
Arthroscopic surgery
Spinal deformity
Bankart lesion
Bone metabolism disorder
Jaw operation
Fractured zygomatic arch elevation
Pyridinoline urine
Pyridinoline urine increased
Pyridinoline urine decreased
Erdheim-Chester disease
Epiphyseal disorder
Hyperphosphatasaemia
Foot operation
Pelvic fracture
Limb operation
Jaw disorder
Phosphorus metabolism disorder
Skeletal injury
Skull fracture
Spinal disorder
Upper limb fracture
X-ray limb
X-ray limb abnormal
X-ray limb normal
Lower limb fracture
Amputation
Arthrodesis
Bone lesion
Bone operation


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Selected Preferred Terms
Bone scan abnormal
Bone scan normal
Fracture treatment
Shoulder operation
Osteoprotegerin
Osteoprotegerin decreased
Osteoprotegerin increased
Osteoprotegerin ligand
Osteoprotegerin ligand decreased
Talipes correction
Limb immobilisation
Hungry bone syndrome
High turnover osteopathy
Carpal collapse
Low turnover osteopathy
Synovial fluid white blood cells
Synovial fluid red blood cells
Synovial fluid cell count
Synovial fluid crystal
Vertebroplasty
Ultrasound joint
Bone fissure
Bone fragmentation
Staphylococcal osteomyelitis
Bone marrow oedema syndrome
Osteonecrosis of jaw
Candida osteomyelitis
Periarthritis calcarea
Joint resurfacing surgery
Epiphyseal injury
Discogram abnormal
Discogram normal
Oroantral fistula
Ligament operation
Interscapulothoracic amputation


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Selected Preferred Terms
Osteomyelitis bacterial
Osteomyelitis viral
Osteomyelitis fungal
Deoxypyridinoline urine increased
Medial tibial stress syndrome
Vertebral wedging
Capsulorrhaphy
Craniotabes
Bone loss
Torus fracture
Avulsion fracture
Bone contusion
Impacted fracture
Hypoparathyroidism secondary
N-telopeptide
C-telopeptide
Eagle's syndrome
Patella replacement
Alveolar osteitis
Elbow operation
Radiation osteitis
Osteoradionecrosis
Tophus removal operation
Bone groove deepening
Inadequate osteointegration
Post transplant distal limb syndrome
Bone resorption test
Calcanectomy
Bone abscess
Familial hypocalciuric hypercalcaemia
Tartrate-resistant acid phosphatase
Pseudohyperphosphataemia
Bone density abnormal
Limb reconstructive surgery
Radiotherapy to joint


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Selected Preferred Terms
Bone atrophy
Arthrolysis
C-telopeptide increased
Bone resorption test abnormal
Deoxypyridinoline urine
Bone formation test
Bone formation test abnormal
Intramedullary rod insertion
Periprosthetic fracture
Dent's disease
Bone graft removal
Acute phosphate nephropathy
Spinal column injury
Biopsy soft tissue
Os trigonum syndrome
Scapulothoracic dissociation
Pubis fracture
Cemento osseous dysplasia
Arthrotomy
Brown tumour
Bone hyperpigmentation
Cementoplasty
Bone decalcification
Atypical femur fracture
Exposed bone in jaw
Enostosis
Gorham's disease
Trousseau's sign
Chronic recurrent multifocal osteomyelitis
Limb amputation
Hypercalcitoninaemia
Spinal pain
Atypical fracture
Hypocalcaemic seizure
Orthopaedic procedure


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Selected Preferred Terms
Tooth demineralisation
Chance fracture
Bone prosthesis insertion
Synovial biopsy
Intervertebral disc biopsy
Radial head dislocation
Osteochondral fracture
Sacroiliac fracture
Limb fracture
Spinal fusion fracture
Delayed spinal fusion
Radiolucency around implant
Alveolar bone resorption
Subperiosteal abscess
Epiphysiodesis
Maxillonasal dysplasia
Primary hypoparathyroidism
Dental cyst
Vertebral body replacement
Synovial biopsy abnormal
Incomplete spinal fusion
Tartrate-resistant acid phosphatase decreased
Resorption bone decreased
Osteonecrosis of external auditory canal
Surgical fixation of rib fracture
Pseudohypercalcaemia
Periosteal haematoma
Rachitic rosary
Periostosis
Craniofacial fracture
Hereditary hypophosphataemic rickets
Chronic kidney disease-mineral and bone disorder
Orthoroentgenogram
Gluteoplasty
Rotationplasty


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Selected Preferred Terms
Costal cartilage fracture
Astragalectomy
Lisfranc fracture
Primary familial brain calcification
Bone metabolism biochemical marker increased
Jaw fistula
Neonatal hypocalcaemia
Cystic angiomatosis
Fracture blisters
Trapeziectomy
Serum procollagen type I N-terminal propeptide decreased
Parathyroid hyperplasia
Metaphyseal corner fracture
Fracture infection
Subchondral insufficiency fracture
Gastric mucosal calcinosis
Itai-itai disease
X-ray dental abnormal
Peri-spinal heterotopic ossification
Pseudofracture
Idiopathic condylar resorption
Removal of external fixation
Osteophyte fracture
Femoral derotation osteotomy
Familial isolated hyperparathyroidism
Malacoplakia of bone
Post procedural hypoparathyroidism
Tartrate-resistant acid phosphatase increased
Distraction osteogenesis
Cheilectomy
Bone sequestrum
Maisonneuve fracture
Hypophosphataemic osteomalacia
Stapes fracture
Scapholunate dissociation


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Selected Preferred Terms
Anterior labroligamentous periosteal sleeve avulsion lesion
Degenerative bone disease
Sesamoidectomy
Computerised tomogram spine
Os odontoideum
Iliocostal friction syndrome
Mueller-Weiss syndrome
Metastatic bone disease prophylaxis
Pathological fracture prophylaxis
Musculoskeletal toxicity
Vertebral end plate inflammation
Kohler's disease
Computerised tomogram neck
Magnetic resonance imaging joint
Magnetic resonance imaging neck


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Appendix 3.
Fracture Events
The selected Preferred Terms of fracture events from HLGT of Fractures based on MedDRA 22.1 are listed as 
follows:
Selected Preferred Term
Acetabulum fracture
Ankle fracture
Clavicle fracture
Complicated fracture
Compression fracture
Facial bones fracture
Femoral neck fracture
Femur fracture
Fibula fracture
Flail chest
Foot fracture
Forearm fracture
Fracture
Fracture delayed union
Fracture malunion
Fracture nonunion
Fracture of clavicle due to birth trauma
Fractured ischium
Fractured sacrum
Fractured skull depressed
Greenstick fracture
Hand fracture
Hip fracture
Humerus fracture
Ilium fracture
Jaw fracture
Multiple fractures
Open fracture
Osteoporotic fracture
Patella fracture
Pathological fracture
Radius fracture


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Selected Preferred Term
Rib fracture
Scapula fracture
Skull fractured base
Spinal compression fracture
Spinal fracture
Sternal fracture
Stress fracture
Tibia fracture
Ulna fracture
Wrist fracture
Pseudarthrosis
Fractured coccyx
Traumatic fracture
Cervical vertebral fracture
Lumbar vertebral fracture
Thoracic vertebral fracture
Comminuted fracture
Fracture displacement
Epiphyseal fracture
Pelvic fracture
Skull fracture
Upper limb fracture
Lower limb fracture
Bone fissure
Bone fragmentation
Torus fracture
Avulsion fracture
Impacted fracture
Periprosthetic fracture
Scapulothoracic dissociation
Pubis fracture
Atypical femur fracture
Atypical fracture
Chance fracture
Osteochondral fracture


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Selected Preferred Term
Sacroiliac fracture
Limb fracture
Spinal fusion fracture
Craniofacial fracture
Costal cartilage fracture
Lisfranc fracture
Fracture blisters
Metaphyseal corner fracture
Fracture infection
Subchondral insufficiency fracture
Pseudofracture
Osteophyte fracture
Maisonneuve fracture


SAP GS-US-320-4018 Final v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
11-Mar-2020
23:29:44
PPD-

Prot_001.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Switching from Tenofovir Disoproxil 
Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 
25mg QD in Subjects with Chronic Hepatitis B who are 
Virologically Suppressed
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
115561
2016-003632-20
Indication:
Chronic Hepatitis B
Protocol ID:
GS-US-320-4018
Gilead Sciences 
Study Director:
Name:
Telephone:
Fax:
Mobile:
Email:
Gilead Sciences 
Medical Monitor:
Name:
Telephone:
Fax:
Mobile:
Email: 
Protocol Version/Date:
Original:
30 September 2016
Amendment 1:
21 December 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................22
1.1.
Background ............................................................................................................................................22
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................24
1.2.1.
General Information .............................................................................................................24
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................25
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................27
1.3.
Information about Tenofovir Disoproxil Fumarate (TDF).....................................................................44
1.4.
Rationale for This Study ........................................................................................................................44
1.5.
Risk/Benefit Assessment for the Study..................................................................................................44
1.6.
Compliance ............................................................................................................................................45
2.
OBJECTIVES.....................................................................................................................................................46
3.
STUDY DESIGN................................................................................................................................................48
3.1.
Study Treatment Plan and Regimen.......................................................................................................48
3.2.
Biomarker Testing..................................................................................................................................49
3.2.1.
Biomarker Samples to Address the Study Objectives ..........................................................49
3.2.2.
Biomarker Samples for Optional Future Research...............................................................50
3.2.3.
............................................50
3.3.
End of Study...........................................................................................................................................50
3.4.
Post Study Care......................................................................................................................................50
4.
SUBJECT POPULATION..................................................................................................................................51
4.1.
Number of Subjects and Subject Selection ............................................................................................51
4.2.
Inclusion Criteria....................................................................................................................................51
4.3.
Exclusion Criteria...................................................................................................................................51
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................53
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................53
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................53
5.2.
Description and Handling of Tenofovir Alafenamide (TAF) and TDF..................................................53
5.2.1.
Formulation..........................................................................................................................53
5.2.2.
Packaging and Labeling .......................................................................................................54
5.2.3.
Storage and Handling...........................................................................................................54
5.3.
Dosage and Administration of Tenofovir Alafenamide (TAF) and TDF...............................................55
5.4.
Prior and Concomitant Medications.......................................................................................................55
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos...................................................................................................................................56
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................57
6.
STUDY PROCEDURES ....................................................................................................................................58
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................58
6.2.
Pretreatment Assessments......................................................................................................................58
6.2.1.
Screening Visit .....................................................................................................................58
6.2.2.
Baseline Assessments...........................................................................................................59
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6.3.
Treatment Assessments..........................................................................................................................60
6.3.1.
Double Blind Visits (Visit Window ± 3 days) .....................................................................60
6.3.2.
Open Label Visits (Visit Window ± 7 days) ........................................................................65
6.4.
Post-Treatment Assessments..................................................................................................................67
6.4.1.
HBsAg Loss and Seroconversion Subjects ..........................................................................67
6.4.2.
All Other Subjects Who Discontinue Study Drug................................................................67
6.4.3.
Treatment-Free Follow Up Visit Assessments (All Subjects)..............................................67
6.5.
Assessments for Premature Discontinuation from Study.......................................................................68
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................69
6.7.
Other Evaluations...................................................................................................................................69
6.7.1.
Bone and Renal Markers ......................................................................................................69
6.8.
Resistance Surveillance and Virologic Rebound Management..............................................................70
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................71
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................71
7.1.1.
Adverse Events.....................................................................................................................71
7.1.2.
Serious Adverse Events........................................................................................................71
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................72
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................72
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................72
7.2.2.
Assessment of Severity ........................................................................................................73
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................73
7.4.
Gilead Reporting Requirements.............................................................................................................75
7.5.
Toxicity Management ............................................................................................................................75
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................76
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................76
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................76
7.5.4.
Management of Bone Evaluation.........................................................................................76
7.5.5.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................77
7.5.6.
Management of Ocular Safety..............................................................................................78
7.5.7.
Management of Potential Nephrotoxicity.............................................................................79
7.6.
Special Situations Reports......................................................................................................................80
7.6.1.
Definitions of Special Situations..........................................................................................80
7.6.2.
Instructions for Reporting Special Situations.......................................................................80
8.
STATISTICAL CONSIDERATIONS................................................................................................................82
8.1.
Analysis Objectives and Endpoints........................................................................................................82
8.1.1.
Analysis Objectives..............................................................................................................82
8.1.2.
Primary Endpoint .................................................................................................................83
8.1.3.
Secondary Endpoint .............................................................................................................83
8.1.4.
Other Endpoints of Interest ..................................................................................................84
8.2.
Analysis Conventions.............................................................................................................................84
8.2.1.
Analysis Sets ........................................................................................................................84
8.3.
Data Handling Conventions ...................................................................................................................85
8.4.
Multiplicity Adjustments........................................................................................................................85
8.5.
Demographic Data and Baseline Characteristics ...................................................................................86
8.6.
Efficacy Analysis ...................................................................................................................................87
8.6.1.
Primary Analysis..................................................................................................................87
8.6.2.
Analyses of Secondary Endpoints........................................................................................88
8.7.
Safety Analysis.......................................................................................................................................88
8.7.1.
Key Secondary Safety Analyses...........................................................................................88


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8.7.2.
Extent of Exposure...............................................................................................................88
8.7.3.
Adverse Events.....................................................................................................................88
8.7.4.
Laboratory Evaluations ........................................................................................................89
8.8.
Biomarker Analysis................................................................................................................................89
8.9.
Sample Size............................................................................................................................................90
8.10.
Data Monitoring Committee ..................................................................................................................90
9.
RESPONSIBILITIES..........................................................................................................................................91
9.1.
Investigator Responsibilities ..................................................................................................................91
9.1.1.
Good Clinical Practice..........................................................................................................91
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ..........................................................91
9.1.3.
Informed Consent.................................................................................................................91
9.1.4.
Confidentiality......................................................................................................................92
9.1.5.
Study Files and Retention of Records ..................................................................................92
9.1.6.
Case Report Forms...............................................................................................................93
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................94
9.1.8.
Inspections............................................................................................................................94
9.1.9.
Protocol Compliance............................................................................................................94
9.2.
Sponsor Responsibilities ........................................................................................................................94
9.2.1.
Protocol Modifications.........................................................................................................94
9.2.2.
Study Report and Publications .............................................................................................95
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................95
9.3.1.
Payment Reporting...............................................................................................................95
9.3.2.
Access to Information for Monitoring..................................................................................95
9.3.3.
Access to Information for Auditing or Inspections ..............................................................96
9.3.4.
Study Discontinuation..........................................................................................................96
10.
REFERENCES ...................................................................................................................................................97
11.
APPENDICES ..................................................................................................................................................100
Appendix 1.
Investigator Signature Page..................................................................................................101
Appendix 2.
Study Procedures Table........................................................................................................102
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................105
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............106
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................128


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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................29
Table 1-2.
GS US 320 0108 and GS US 320 0110: HBV DNA Outcome at Week 48 Using 
HBV DNA of < 29 IU/mL, Missing = Failure (Full Analysis Set) ........................................30
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with ALT 
Normalization at Week 48, Missing = Failure (Full Analysis Set with Baseline ALT 
> ULN) ...................................................................................................................................31
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or Seroconversion at 
Week 48, Missing = Failure (Serologically Evaluable Full Analysis Set) .............................32
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set) ...........................................................34
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................35
Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for ≥5% of 
Subjects in Either Treatment Group in the TAF Phase 3 Safety Population (Safety 
Analysis Set)...........................................................................................................................36
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by Treatment 
Regimen in > 1 Subject in the TAF Phase 3 Safety Population (Safety Analysis Set)...........37
Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral Density at 
Week 48 (Hip DXA Analysis Set and Spine DXA Analysis Set) ..........................................39
Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine Creatinine 
Ratios at Week 48 in the TAF Phase 3 Safety Population (Safety Analysis Set)...................40
Table 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent Grade 3 or 4 
Laboratory Abnormalities Reported for at Least 1% of Subjects in Either Treatment 
Group in the Overall TAF Phase 3 Safety Population (Safety Analysis Set) .........................42
Table 5-1.
Disallowed Concomitant Medications....................................................................................56


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Amendment 1
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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Switching from Tenofovir Disoproxil 
Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 
25mg QD in Subjects with Chronic Hepatitis B who are 
Virologically Suppressed
IND Number:
EudraCT Number:
115561
2016-003632-20
Study Centers Planned:
Approximately 50 centers in North America, Europe, and 
Asia Pacific regions
Objectives:
The primary objectives of this study are as follows:

To evaluate the efficacy of switching to TAF 25 mg QD versus 
continued TDF 300 mg QD in virologically suppressed subjects 
with chronic HBV as determined by the proportion of subjects 
with HBV DNA ≥20 IU/mL (as defined by the modified US 
FDA-defined snapshot algorithm) at Week 48

To compare the safety and tolerability of switching to TAF
25 mg QD versus continuing TDF 300 mg QD in virologically 
suppressed subjects with chronic HBV at Week 48
The key secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus 
continued 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 switching to TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the change from 
baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 48


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Other secondary objectives of this study are as follows: 

To evaluate the proportion of subjects with HBV DNA 
< 20 IU/mL and target detected/not detected (i.e. < LLOD) at 
Week 48 in subjects switched to TAF 25 mg QD versus 
continued TDF 300 mg QD

To compare the safety of switching to TAF 25 mg QD for 
96 weeks versus continued TDF 300 mg QD for 48 weeks 
followed by open-label TAF for 48 weeks as determined by the 
percent change from baseline in hip and spine bone mineral 
density (BMD) at Week 96

To compare the safety of switching to TAF 25 mg QD for 
96 weeks versus continued TDF 300 mg QD for 48 weeks 
followed by open-label TAF for 48 weeks as determined by the 
change from baseline in estimated creatinine clearance by 
Cockcroft-Gault method (eGFRCG) at Week 96

To compare the serological response (loss of HBsAg and 
seroconversion to anti-HBs, and loss of HBeAg and 
seroconversion to anti-HBe in HBeAg-positive subjects) of 
switching to TAF 25 mg QD versus continued TDF 300 mg QD 
at Week 48

To compare biochemical response (normal ALT and normalized 
ALT) of switching to TAF 25 mg QD versus continued TDF 
300 mg QD at Week 48

To compare the change in fibrosis as assessed by FibroTest®
after switching to TAF 25 mg QD versus continued TDF 
300 mg QD at Week 48

To evaluate the comparative open-label efficacy (virologic, 
serological, and biochemical) and safety of switching to 
TAF 25 mg QD from Week 48 through Week 96 in subjects
initially randomized to TAF 25 mg QD and in subjects
sequentially treated with continued TDF 300 mg QD for 
48 weeks and then switched to open-label TAF 25 mg QD at 
Week 96
The exploratory objectives of this study are as follows:
 
 
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Study Design:
This is a randomized, double-blind, multicenter, active-controlled 
study to evaluate the safety and efficacy of TAF 25 mg QD in 
virologically suppressed subjects who switch from TDF to TAF
compared to continued TDF treatment.
Approximately 460 subjects (with approximately 50% of subjects 
being ≥50 years old) who are virologically suppressed and actively 
taking TDF 300 mg QD, will be randomized in a 1:1 ratio (A:B) to 
receive either TAF 25 mg QD and matched placebo of TDF 300 mg 
QD, or Gilead-provided TDF 300 mg QD and matched placebo of
TAF 25 mg QD. At randomization, subjects will be stratified by 
screening HBeAg status (HBeAg-negative vs. HBeAg-positive) and 
age (≥50 or < 50 years).

Treatment Arm A: approximately 230 subjects administered 
TAF 25 mg QD and matched placebo of TDF 300 mg QD

Treatment Arm B: approximately 230 subjects administered 
Gilead-provided TDF 300 mg QD and matched placebo of TAF 
25 mg QD
The duration of double blind treatment is 48 weeks. All subjects 
who complete 48 weeks of treatment are eligible for participation in 
the open label TAF 25 mg extension period for an additional 
48 weeks (through Week 96). During the double-blind period only, 
subjects with a confirmed creatinine clearance by Cockcroft Gault 
Method (eGFRCG) < 50 ml/min, and > 20% decline in estimated 
glomerular filtration rate (eGFRCysC) by CKD-EPI (cystatin C) 
compared to baseline 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 during the 
double-blind period of the study will have the study drug 
discontinued.
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Subjects who permanently discontinue study drug (either 
prematurely or at the end of study [Week 96]) 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 appropriate alternative, HBV therapy, whichever 
occurs first. Use of appropriate, alternative HBV therapy is strongly 
encouraged.
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 prior to Week 48
are not permitted to discontinue study drug prior to the Week 48
visit. Subjects with HBsAg loss with confirmed seroconversion will 
be followed off treatment every 4 weeks for 12 weeks and then per 
the study visit schedule (Appendix 2) through Week 96/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.
The primary analysis will occur at Week 48 with the primary 
efficacy endpoint being the proportion of subjects with HBV DNA
≥20 IU/mL, as determined by the modified US FDA-defined 
snapshot algorithm.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will convene and review the progress and safety 
of this study after the last subject enrolled completes 24 weeks of 
the study. However, Gilead will defer to the DMC for any decision 
to convene earlier or more frequently. 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:
Approximately 460 subjects (approximately 230 subjects will 
receive TAF 25 mg QD and matched placebo of TDF 300 mg QD, 
and 230 subjects will receive Gilead-provided TDF 300 mg QD and 
matched placebo of TAF 25 mg QD)
Target Population:
Adult subjects with CHB who are currently (≥12 weeks) 
virologically suppressed (HBV DNA < LLOQ) while receiving 
therapy with TDF 300 mg QD for ≥48 weeks, and as monotherapy 
for ≥24 weeks prior to Screening.


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Amendment 1
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Duration of Treatment:
The duration of the double-blind treatment is 48 weeks. After 
completing the double-blind period, all subjects will be eligible to 
receive open label TAF 25 mg QD for an additional 48 weeks until 
Week 96. 
Diagnosis and Main 
Eligibility Criteria:
Inclusion 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; consent must be obtained prior to initiation of 
study procedures
2) Adult male and non-pregnant, non-lactating female subjects, 
≥18 years of age 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 5).
3) Documented evidence of chronic HBV infection previously 
(e.g., documented HBsAg positive for more than 6 months)
4) Maintained on TDF 300 mg QD for at least 48 weeks, and as 
monotherapy for CHB for at least 24 weeks prior to screening
and with viral suppression (HBV DNA < LLOQ by local 
laboratory assessment) for a minimum of 12 weeks prior to 
Screening, and including a Screening HBV DNA value of 
< 20 IU/mL (by central laboratory). The assay that will be used 
to quantify HBV DNA in Study GS-US-320-4018 is the 
Roche COBAS Ampliprep-COBAS TaqMan Hepatitis B Test 
v2.0 {Berger 2010}.
5) Estimated creatinine clearance ≥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)
6) Normal ECG (or if abnormal, determined by the Investigator
not to be clinically significant)
7) Must be willing and able to comply with all study requirements


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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 5.
3) Co-infection with HCV, HDV, HIV

Subjects who are HCV positive, but have a documented 
negative HCV RNA, are eligible
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by 
recent imaging)
5) Current evidence of, or recent (≤5 year) history 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 > 5 × ULN
e) Albumin < 3.0 mg/ dL
f)
INR > 1.5 × ULN (unless stable on anticoagulant regimen)
g) Total bilirubin > 2.5 × ULN
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator
9) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g. basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible.
10) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), nephrotoxic agents, or agents capable of 
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11) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
12) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
13) 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.
14) Use of investigational agents within 3 months of Screening, 
unless allowed by the Sponsor
15) Use of any prohibited medications as described in Section 5.4. 
Subjects on prohibited medications, who are otherwise eligible, 
will need a wash out period of at least 30 days prior to the 
Baseline visit.
Study Procedures/
Frequency:

Screening Visit

Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 24, 36 
and 48, and open label Weeks 60, 72, and 96/Early 
Discontinuation (ED)

Subjects who permanently discontinue study drug (either 
prematurely or at the end of study [Week 96]) 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 appropriate, alternative, HBV therapy, 
whichever occurs first. Use of appropriate, alternative HBV 
therapy is strongly encouraged.

Review of concomitant medications and assessment for adverse 
events and vital signs, and weight measurement will be 
conducted at all study visits. 

Laboratory analyses (serum chemistry, hematology, eGFRCG, 
urinalysis, plasma HBV DNA levels, pregnancy testing 
[for females of childbearing potential]) will be conducted at all 
study visits. 
Screening Visit assessments include:

Complete physical examination with height, body weight, and 
vital signs and medical history (including HBV disease and 
treatment history)

INR and Alpha-fetoprotein (AFP); 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.


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
Plasma HBV DNA levels (must be < 20 IU/mL at time of 
Screening to be eligible)

HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed)
and quantitative HBsAg

HCV, HDV and HIV testing

Urinalysis and urine drug screen

Baseline DXA scans of the hip and spine can be conducted 
anytime during the Screening period, but should be conducted 
at least 14 days prior to the Baseline visit to ensure results are 
received prior to the first dose of study drug

ECG
Baseline and On-treatment assessments include:

Complete physical examinations with body weight and vital 
signs will be performed at Baseline, Weeks 24, 48, 72, and 
96/ED. A symptom driven physical exam will be performed at 
all other visits.

HBV serology (qualitative HBsAg and HBeAg) and 
quantitative HBsAg will be performed at Baseline and 
Weeks 12, 24, 36, 48, 60, 72, and 96/ED. HBeAb and HBsAb 
reflex testing will be performed as needed.

Fasting blood sample for metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and 
triglycerides] at Baseline and Weeks 12, 24, 36, 48, 60, 72, and 
96/ED.

FibroTest® at Baseline and at Weeks 48, and 96/ED.

Child-Pugh Score at Baseline, Weeks 48, 96/ED.

Serum Cystatin C (CysC) will be assessed at baseline and 
repeated if eGFRCG is confirmed to be < 50 ml/min during the 
double blind period of the study (to estimate eGFR by 
CKD-EPICysC)

Fasting blood and urine for bone and renal biomarker testing 
will be collected at Baseline and Weeks 4, 12, 24, 48, 72, and 
96/ED

Vitamin D assessment 

Fracture Risk Assessment will be evaluated at Baseline

DXA scans of the hip and spine will be conducted at 
Weeks 24, 48, 72, and 96/ED visit. The ED visit DXA should 
be done if not done within the last 12 weeks of this visit.


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
ECG will be performed at Weeks 48 and 96/ED.
 
 
 
 
 
 
 
 

Sequence analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance may be performed at
Baseline for subjects with HBV DNA ≥69 IU/mL and may be 
attempted for viremic subjects (HBV DNA ≥69 IU/mL) at 
Weeks 48 and 96/ED. Phenotypic analysis will be performed 
for subjects that are subjected to sequence analysis. As it may 
not be known at the time of the visit whether a subject 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. In the event of unconfirmed virologic rebound 
(HBV DNA ≥20 IU/mL), subjects will be asked to return to the 
clinic for a scheduled or unscheduled blood draw. For virologic 
rebound occurring within the first 12 weeks of the study, the 
next scheduled visit will be used for follow up. For virologic 
rebound occurring after Week 12, the subject will return for an 
unscheduled visit 2-3 weeks after the date of the original test 
that resulted with HBV DNA virologic rebound for 
confirmation of virologic rebound. At this follow up visit, a 
serum blood sample for resistance testing will be obtained. For 
unscheduled visits, the subject will be required to bring their 
supply of study drug with them and be assessed for adherence 
by pill count, and if necessary, the subject will be re-counseled 
on adherence to study medication.
 

Health Related Quality of Life (HRQoL) Surveys (SF-36, 
WPAI and CLDQ) at Baseline, Weeks 24, 48, and 96/ED. The 
ED visit HRQoLs should be done if not done within the last 
24 weeks of this visit.
See Section 6 (Study Procedures) for further information.
PPD
PPD


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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 (TDF) 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 the change from 
baseline at Week 48 in eGFRCG. During the double-blind period of 
the study if a subject has a confirmed creatinine clearance 
(eGFRCG) < 50 ml/min with a > 20% decline from baseline in 
eGFR by CKD-EPICysC, the subject will be required to undergo 
dose modification to every other day dosing of study drug. During 
the double-blind period, subjects with confirmed eGFRCG
< 30 mL/min will have the study drug 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 Week 48 will be summarized. 
Percent change from baseline in BMD by DXA of the hip and spine 
hip will be assessed at Weeks48 and 96. Change from eGFRCG will 
be assessed at every visit and summarized through Week 48. 
Adverse events and clinical laboratory tests will be collected at 
every visit and summarized through Week 48. Additionally, 
summaries of AEs, discontinuations due to AEs, and laboratory 
data including BMD measurements (via DXA scans and eGFRCG) 
by original treatment arms (TAF versus TDF) will continue on an 
annual basis through Week 96.


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Efficacy:
The primary efficacy endpoint is:

Proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot
algorithm) at Week 48
The secondary efficacy endpoints are:

Proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot
algorithm) at Week 96

Proportion of subjects with serological response (loss of 
Hepatitis B s antigen [HBsAg] and seroconversion to anti-HBs, 
and loss of Hepatitis B e antigen [HBeAg] and seroconversion 
to anti-HBe in HBeAg-positive subjects) at Weeks 48 and 96

Proportion of subjects with biochemical response (normal ALT 
and normalized ALT) at Weeks 48 and 96

Change from baseline in fibrosis as assessed by FibroTest® at 
Weeks 48 and 96

Proportion of subjects with HBV DNA < 20 IU/mL and target 
detected/not detected (i.e. < LLOD) at Weeks 48 and 96
Statistical Methods:
The primary analysis will be performed when the last subject has 
completed Week 48 assessments or discontinued prematurely. 
The analysis will compare the TAF arm to the TDF arm.
Analysis Methods:
The primary analysis will consist of a non-inferiority evaluation of 
efficacy of TAF versus TDF, with respect to the proportion of 
subjects with HBV DNA ≥20 IU/mL (as determined by the 
modified US FDA-defined snapshot algorithm) at Week 48. It will 
be concluded that TAF is not inferior to TDF if the upper bound of 
the two-sided 95% confidence interval of the difference between 
treatment arms (TAF arm – TDF arm) in the response rate is less 
than 4% (ie, a margin of 4% is applied to non-inferiority 
assessment). The 95% confidence interval will be constructed using 
the normal approximation method based on stratified 
Mantel-Haenszel proportions, where stratification factors are 
screening HBeAg status and age (≥ 50 or < 50 years).
The percent change from baseline in hip and spine BMD at 
Week 48 will be summarized and compared between the 
two treatment groups using an ANOVA model with treatment as a 
fixed effect.
The change from baseline in eGFRCG at Week 48 will be 
summarized and compared between the two treatment groups using 
the Wilcoxon Rank-Sum test.


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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 HBV DNA ≥20 IU/mL (as determined by the 
modified US FDA-defined snapshot algorithm {U. S. Department 
of Health and Human Services 2015}) at Week 48, when the 
sample sizes are 230 (TAF 25 mg arm) and 230 (TDF 300 mg arm), 
a two-group, large-sample normal approximation test of proportions 
with a one-sided 0.025 significance level will have 80% power to 
establish non-inferiority. It is assumed that both treatment arms will 
have subjects who have HBV DNA ≥ 20 IU/mL (as determined by 
the modified US FDA-defined snapshot algorithm) at a rate of 2.4% 
at Week 48 based on combined data of suppressed subjects from 
studies GS-US-174-0102 and GS-US-174-0103 with 
HBeAg-negative:HBeAg-positive = 2:1), with a non-inferiority 
margin of 4%.
This sample size also provides > 99% power to detect a 1.81% 
difference in the percentage change from baseline in hip BMD at 
Week 48 (assuming a 1.47% [SD 2.71%] change from baseline in 
TAF 25 mg arm and −0.34% [SD 2.83%] change from baseline in 
the TDF 300 mg arm, with a two-sided α = 0.05); and > 99% power 
to detect a 2.00% difference in the percentage change from baseline 
in spine BMD at Week 48 (assuming a 1.56% [SD 3.84%] change 
from baseline in the TAF 25 mg arm and −0.44% [SD 4.14%] 
change in the TDF 300 mg arm, with a two-sided α = 0.05); and 
97% power to detect a 4.9 mL/min difference in the change from 
baseline in eGFRCG at Week 48 (assuming a 1.3 mL/min [SD 13.2] 
change from baseline in the TAF 25 mg arm and −3.6 mL/min 
[SD 13.0] change from baseline in the TDF 300 mg arm, with a 
two-sided α = 0.05). These assumptions were derived from an HIV 
switch study, GS-US-292-0109, due to the unavailability of switch 
data from TAF HBV studies.
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
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil counts
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
Anti-HBe
Anti-Hepatitis B e-antigen
AR
Adverse reaction
ARV
Antiretroviral
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)
BMD
Bone mineral density
CatA
Cathepsin A
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CLCr
Creatinine clearance
CLDQ
Chronic Liver Disease Questionarie
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
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
EC
Ethics committee
EC50
50% Effective Concentration
EudraCT
European clinical trials database


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E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
eGFRCG
Estimated glomerular filtration rate by the Cockcroft-Gault formula
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B s antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
IC20
20% inhibitory concentration
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
IMP
Investigational Medicinal Product
IRB
Institutional review board
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LDL
Low-density lipoprotein
LdT
Telbivudine
LAM
Lamivudine


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LLOD
Lower Limit of Detection
LLOQ
Lower Limit of Quantitation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MT-2
Human T-lymphotrophic virus-1 transformed cells
M = F
Missing = Failure
NDA
New Drug Application
NOAEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OAV
Oral antivirals
OL
Open-label
PD
Pharmacodynamic
P1NP
Procollagen type 1 amino-terminal propeptide
RBP
Retinol binding protein
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT/INR
Prothrombin time/International normalized ratio
QD
Once daily (use only in tables)
RPV
Rilpivirine
RT
Reverse transcriptase
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Set
sCr
Serum creatinine
SD
Standard deviation
SF-36
Short Form (36)
SOP
Standard Operating Procedure
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
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
UACR
Urine albumin-to-creatinine ratio


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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
WPAI
Work Productivity and Activity Impairment


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a major public health care issue worldwide and one of the principal 
causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The hepatitis B 
virus (HBV) is easily transmissible through perinatal, percutaneous, and sexual exposure 
{Lok 2009}. Following acute HBV infection, 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}. Individuals who develop CHB are at substantial risk of 
cirrhosis, hepatic decompensation, and HCC, which will afflict 15% to 40% of subjects with 
CHB in the absence of effective treatment {World Health Organization (WHO) 2015a, 
Wright 2006}. Liver cancer is the third leading cause of cancer deaths globally, with the highest 
burden of disease found in regions where HBV is endemic {Global Burden of Disease Cancer 
Collaboration 2015}. Recent reports estimated that 250 to 350 million individuals were living 
with HBV (i.e., are hepatitis B surface antigen [HBsAg] positive) in 2010, representing a 
worldwide prevalence of 3.6%, with considerable geographic variability {Schweitzer 2015, 
World Health Organization (WHO) 2015b}. For example, HBV prevalence rates of 0.01%, 
0.76%, 4.0%, 5.5%, and 22.4% have been reported for the United Kingdom, Canada, Turkey, 
China, and South Sudan, respectively. In 2013, an estimated 686,000 deaths were due to HBV 
infection, placing it among the top 20 causes of mortality worldwide {G. B. D. Mortality Causes 
of Death Collaborators 2015, Ott 2012}.
Worldwide universal vaccination remains the goal for eliminating HBV infection and its
complications, yet despite the availability of HBV vaccine programs in many countries, new 
HBV infections are still common even in areas of low prevalence. The World Health 
Organization estimates that each year there are over 4 million acute clinical cases of HBV 
infection globally {World Health Organization (WHO) 2015b}. In the United States (US), 
approximately 20,000 people become acutely infected each year according to an estimate from 
the Centers for Disease Control and Prevention {Centers for Disease Control (CDC) 2013}.
The natural history of chronic hepatitis B virus infection and disease is complex and highly 
variable. Following acute hepatitis B infection, up to 90% of newborns who are vertically 
infected, and 25-50% of children who acquire HBV within the first 6 years of life, will become 
chronic carriers of the virus when the immune system is thought to be immature, compared to 
immunocompetent individuals who become infected during adulthood (< 1%) {Fattovich 2008, 
Sarin 2015}. CHB has traditionally been characterized by four distinct phases of variable 
duration that reflect the dynamics of viral replication and the evolving host immune response 
{Fattovich 2008, Sokal 2013}. In the first, or the immune tolerant phase, individuals have high 
plasma levels of HBV DNA, detectable hepatitis B surface antigen (HBsAg) and hepatitis B e 
antigen (HBeAg), with normal or slightly elevated serum alanine transaminase (ALT) levels 
reflective of minimal inflammation and fibrosis. This phase typically extends into late childhood 
or adolescence, and is followed by an HBeAg-positive, immune-active phase wherein ALT 
levels are persistently elevated along with fluctuating levels of HBV DNA, reflective of 


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moderate to severe inflammation or fibrosis. This phase may be followed by loss of HBeAg with 
seroconversion to anti-HBe. In the inactive CHB phase, subjects have undetectable or low levels 
of HBV DNA (< 2000 IU/mL), the presence of anti-HBe antibody, and normal or minimal 
elevation in serum ALT, which reflects minimal inflammation but with variable fibrosis. This 
third phase can evolve in a subgroup of individuals to an HBeAg-negative, immune reactivation 
phase, in which ALT levels and HBV DNA levels are increased. Subjects develop 
HBeAg-negative CHB as a result of variants that arise in the precore or core promoter region of 
the virus {Sarin 2015}. The goal of anti-HBV therapy is to improve long-term survival and 
quality of life by reducing disease progression to cirrhosis, decompensated liver disease, and 
HCC {Sarin 2015, Terrault 2015}. As seroclearance of HBsAg is a rare spontaneous occurrence 
in patients with CHB, durable anti-HBe seroconversion in HBeAg-positive subjects is sometimes 
considered a reasonable endpoint, associated with improved prognosis, including a reduced risk 
of HCC. However, in many subjects who discontinue treatment following anti-HBe 
seroconversion, disease relapse with increased levels of viremia can occur {Sarin 2015}. 
Successful reduction of viremia to levels below assay detection leads to reduced inflammation 
and slowing or reversal of fibrosis {Marcellin 2013}.
Currently, there are 2 approved options for treatment of CHB: injectable interferons and oral 
antiviral (OAV) agents. Of these, treatment with OAV agents has been more successful in 
achieving and maintaining a high degree of viral suppression in subjects with CHB. The 
development of nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) was a major 
breakthrough for the treatment of CHB, providing effective suppression of viral replication and 
reducing the risk of long-term complications {Marcellin 2013, World Health Organization 
(WHO) 2015a}. However, several N[t]RTIs possess a low barrier for viral resistance 
development, including lamivudine (LAM), telbivudine, (TBV) and adefovir dipivoxil (ADV) 
{European Association for the Study of the Liver (EASL) 2012, Liaw 2012}. Additionally, while 
development of resistance to entecavir (ETV) is low in treatment-naïve subjects, the cumulative 
probability of ETV resistance increases substantially with long-term use in subjects, particularly 
in subjects who are refractory to lamivudine, and those with lamivudine resistance (up to 57% 
through 6 years of treatment) {Tenney 2009}. In contrast, resistance to tenofovir disoproxil 
fumarate (TDF; Viread®) has not been documented through 8 years of use {Liu 2016}.
Tenofovir (TFV) is a nucleotide analog with limited oral bioavailability that inhibits reverse 
transcription in HIV-1 and HBV. TDF, an oral prodrug of TFV, was first approved for the 
treatment of HIV infection in 2001 to be given in combination with other antiretroviral (ARV) 
agents and was approved for treatment of CHB as monotherapy in 2008. TDF is currently 
approved in over 165 countries, including the US, Canada, Europe, Japan, Taiwan, South Korea, 
and China, with more than 3,393,649 patient-years of use worldwide for both HIV and HBV 
infections since first marketing approval. TDF is a first-line treatment for CHB in all major 
treatment guidelines {European Association for the Study of the Liver (EASL) 2012, Sarin 2015, 
Terrault 2015}. Although highly effective, use of TDF is associated with nephrotoxicity and 
bone-related toxicity in some subjects. 


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Vemlidy® (Tenofovir alafenamide [TAF]) is a phosphonamide prodrug of TFV that is more 
stable in plasma than TDF, and provides higher intracellular levels of the active phosphorylated 
metabolite TFV-DP to target cells (eg, HBV-infected hepatocytes and HIV-infected lymphoid 
cells) with approximately 90% lower circulating levels of TFV relative to TDF at therapeutically 
active doses {Agarwal 2015, Babusis 2013, Murakami 2015, Ruane 2013}. The distinct 
metabolism of TAF offers the potential for an improved safety profile when compared with TDF. 
In support of this concept are recent results from a large dataset of 1733 HIV-infected, treatment 
naive subjects randomized to receive treatment with the fixed-dose combination [FDC] of 
elvitegravir (E), cobicistat (C), emtricitabine (F), TAF [E/C/F/TAF; Genvoya®] or E/C/F/TDF 
[STB; Stribild®]). Renal and bone parameters were significantly less affected in subjects who 
received E/C/F/TAF compared with E/C/F/TDF {Sax 2015}. In a recent open-label Phase 3 
study, HIV-1-infected patients were switched from a TDF-based regimen to a TAF-based 
regimen with data supporting the efficacy and safety of switching regimens. In adult subjects 
with CHB, a global Phase 3 program for TAF consisting of 2 prospective, randomized, 
active-controlled studies with 1 each in HBeAg-negative (Study GS-US-320-0108) and 
HBeAg-positive (Study GS-US-320-0110) subjects is currently ongoing as described below.
Efficacy and safety results at Week 48 from Studies GS-US-320-0108 and GS-US-320-0110 are 
summarized below in Section 1.2.3. Based on Week 48 results, TAF was approved for treatment 
of CHB in adults with compensated liver disease by the US FDA in November, 2016. Marketing 
Applications for TAF 25 mg tablets for the treatment of CHB have been filed in a number of 
global territories.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Vemlidy®, (GS-7340, TAF, or L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-
methylethoxy] methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1) is a 
novel oral prodrug of TFV, a nucleotide analog that inhibits HIV-1 reverse transcription. 
Tenofovir is metabolized intracellularly to the active metabolite, TFV-DP, a competitive 
inhibitor of HIV-1 reverse transcriptase (RT) and HBV reverse transcriptase (HBV 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, which is being used in the Phase 3 studies 
GS-US-320-0108 and GS-US-320-0110, is considered comparable based on physical/chemical 
properties to GS-7340-02 that has been used in previous studies and a number of ongoing 
studies. GS-7340-03 was also used in the Phase 1b study GS-US-320-0101. 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 current Investigator’s Brochure 
for TAF.


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1.2.2.
Preclinical Pharmacology and Toxicology
Virology
Following its release from the prodrug TAF, TFV is metabolized intracellularly to the active 
metabolite, TFV-DP, a competitive inhibitor of HBV polymerase/reverse transcriptase (pol/RT) 
and HIV-1 RT that terminates the elongation of the viral DNA chain during the process of HBV 
and retroviral replication.
Compared to TDF, TAF is relatively stable in plasma, but rapidly converts to TFV inside cells. 
The cellular enzymes responsible for conversion of TAF to TFV are cathepsin A (CatA), which 
is broadly expressed in cells, and carboxylesterase 1 (CES1), which is highly expressed in liver. 
In HBV target cells, primary human hepatocytes, TAF is primarily hydrolyzed by CES1 with 
CatA making a minor contribution {Murakami 2015}. In HIV-1 target cells, primary human 
lymphoid cells, CatA is the major enzyme hydrolyzing TAF to TFV. In vitro studies have shown 
no significant variation for conversion to TFV and antiviral activity of TAF within PBMCs and 
macrophages from multiple donors. The covalent anti-hepatitis C virus (HCV) protease 
inhibitors (PIs) telaprevir and boceprevir were identified as the only potent inhibitors of CatA 
mediated hydrolysis of TAF in a biochemical assay (PC-120-2001).
TAF is a potent inhibitor of HBV replication, exhibiting in vitro activity comparable to that of 
TDF with an effective concentration (EC50) value of 18 nM. Additionally, TAF is similarly 
active in vitro against wild-type genotype A-H HBV clinical isolates (PC-320-2003). TAF also 
exhibits potent anti-HIV activity in lymphoid T-cells, primary human PBMCs, and macrophages 
with EC50 values ranging from 3 to 14 nM. The in vitro activity of TAF against HIV-1 is 
100- to 600-fold greater than TFV and 4- to 6-fold greater than TDF {Robbins 1998}. In MT-2 
cells, TAF shows low cytotoxicity with a selectivity index of > 10,000. Based on data generated 
with the parent nucleotide TFV, TAF is active against a wide range of HIV-1 subtypes and also 
against HIV-2. 
For further information on the virology of TAF, (GS-7340), refer to the current investigator’s 
brochure for TAF.
Safety Pharmacology
The IC20 and the IC50 for the inhibitory effect of TAF fumarate on human ether-a-go-go-related 
gene (hERG) potassium current was estimated to be greater than 30 μM (PC-120-2005). TAF in 
the monofumarate form has been evaluated to determine potential functional 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). TAF at 1000 mg/kg reduced distal transit and 
increased stomach weights starting 2 hours postdosing, with reversibility beginning by 6 hours 
after dosing. The no observed effect level (NOEL) for gastrointestinal motility was 100 mg/kg.


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Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments were performed using TAF monofumarate 
(GS-7340-02), and all study data described reflect the dosage of the monofumarate. For 
reference, 100 mg of TAF monofumarate 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 2.5 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 tenofovir in the cells of the lymphoreticular system. The
primary route of elimination of tenofovir is renal excretion of unchanged drug based on
intravenous studies of TFV. Following oral administration of GS-7340-02, approximately
15% of a radiolabeled dose is recovered in dog urine in 24 hours. Tenofovir was the major
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of
tenofovir in dogs and fecal elimination of tenofovir 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.
Nonclinical Toxicology
Because of lack of exposure to the prodrug TAF in mice and rats and achievable TFV exposures 
being less than previously tested in studies with TDF, Gilead and regulatory agencies have 
agreed that neither carcinogenicity studies nor a peri/postnatal study with TAF were warranted as 
they would not add to the overall risk evaluation or risk management of TAF.


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The oral toxicity of TAF was evaluated in mice, rats, dogs, and monkeys for treatment periods 
up to 9 months. Based on recommendations that renal karyomegaly is not a dose-limiting effect 
{Foran 1997} and observations in the rat that renal karyomegaly is not sufficient to induce renal 
toxicity or predict oncogenicity (M990205) (M990204), its toxicological significance is 
questionable and, therefore, it was not considered an adverse effect in determining the NOAEL.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day; the 9-month dog 
study defined a No observed adverse effect level (NOAEL) of 2 mg/kg/day, and the 28-day 
nonhuman primate study defined a NOAEL of ≥ 30 mg/kg/day. While no NOAEL was 
determined in the 13-week mouse study, the relevance of the nasal findings to humans is unclear.
TAF had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day. There was 
some evidence at 6 and 18/12 mg/kg/day for an effect to slightly prolong PR intervals. 
Additionally, at Week 39, TAF appeared to reversibly reduce heart rate with an associated mild 
QT prolongation. At Week 39, significant decreases in serum tri-iodothyronine (T3) were noted 
for animals receiving 18/12 mg/kg/day when compared to controls, which may have been 
associated with the slight prolongation of PR intervals. After the 3-month recovery period, serum 
T3 values returned to levels similar to the control group animals at the end of the study.
TAF was not genotoxic in either in vitro or in vivo assays. TAF fumarate had no adverse effects 
on male or female fertility parameters in rats. There was no effect on fetal viability or fetal 
development in pregnant rats administered doses of TAF monofumarate up to 200 mg/kg/day or 
in pregnant rabbits administered TAF monofumarate up to 100 mg/kg/day the highest doses 
tested. In the rat, a minor (7.7%) decrease in mean fetal body weight compared to the control 
group was observed at 200 mg/kg/day, which was a maternally toxic dose. At the NOAEL for 
embryo-fetal development of 200 mg/kg/day in rats, AUCtau values for TAF and TFV on Day 17 
were 0.65 and 35.7 μg•h/kg, respectively. At the NOEL for embryo-fetal development of 
100 mg/kg/day in rabbits, AUCtau values for TAF and TFV on Day 20 were 
10.7 and 23.5 μg•h/kg, respectively. The TFV exposures in both species were > 30-fold higher 
than the TFV AUCinf after a 25-mg dose of TAF monofumarate in humans.
For further information on TAF, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the 
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB 
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program 
for CHB includes 2 ongoing Phase 3 studies in HBeAg-negative and HBeAg-positive subjects 
with CHB, a completed Phase 1b antiviral activity and safety/tolerability study in subjects with 
CHB, as well as several completed Phase 1 safety, pharmacokinetics (PK)/pharmacodynamics 
(PD), and drug interaction studies in healthy subjects (including Chinese and Japanese subjects) 
and in subjects with impaired renal or hepatic function.
In some studies, TAF was administered as a single agent or as part of the F/TAF, 
FTC/RPV/TAF, or E/C/F/TAF FDC tablets.


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TAF clinical studies which are ongoing or planned are listed below:

GS-US-320-1092, a Phase 2/3 study to evaluate the pharmacokinetics, safety, and antiviral 
Efficacy of TAF in Adolescents with Chronic Hepatitis B Virus Infection 

GS-US-320-3912, a Phase 2 study to evaluate the efficacy and safety of TAF versus TDF 
300 in subjects with CHB and Stage 2 or greater chronic kidney disease who have received a 
liver transplant

GS-US-320-4035, A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of 
Switching to Tenofovir Alafenamide (TAF) from Tenofovir Disoproxil Fumarate (TDF) or 
Other Oral Antiviral Treatment (OAV) in Virologically Suppressed Chronic Hepatitis B 
(CHB) Subjects with Renal Impairment and/or Hepatic Impairment
Please refer to the latest version of the investigator’s brochure for further information on the 
clinical program.
An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below as follows:

GS-US-320-0108: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-negative subjects.

GS-US-320-0110: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-positive subjects.
In both of these similarly designed noninferiority studies, subjects were randomized in a 2:1 ratio 
to receive either TAF 25 mg or TDF 300 mg once daily for 96 weeks. Randomization was 
stratified by plasma HBV DNA level (< 7, ≥ 7 to < 8, and ≥ 8 log10 IU/mL for 
Study GS-US-320-0108; < 8 and ≥ 8 log10 IU/mL for Study GS-US-320-0110) and OAV 
treatment status (treatment naive vs treatment experienced) at screening. In both studies, all 
subjects completing 96 weeks of double-blind therapy are eligible to continue open-label 
treatment with TAF 25 mg for an additional 48 weeks. Both protocols were amended in 
February 2016 (Amendment 3 of GS-US-320-0108 and GS-US-320-0110) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase from Week 144 to 
Week 384 (8 year total study period).


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Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen 
(Number of Subjects)
Data Presented
GS-US-320-0108
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-negative subjects with CHB
TAF 25 mg once daily (N = 285)
TDF 300 mg once daily (N = 140)
Week 48 efficacy, 
PK, and safety
GS-US-320-0110
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-positive subjects with CHB
TAF 25 mg once daily (N = 581)
TDF 300 mg once daily (N = 292)
Week 48 efficacy, 
PK, and safety
Demographic and disease characteristics were generally similar between the TAF and TDF 
groups in both studies and are representative of patient population of HBeAg-negative subjects 
in Study GS-US-320-0108 and HBeAg-positive subjects in Study GS-US-320-0110. In both 
studies the majority of subjects were male (> 60%) and Asian (> 70%). As would be expected 
based on the 2 distinct study populations, subjects in Study GS-US-320-0108 were older 
(median age: 47 years; range: 19-80 years) than subjects in Study GS-US-320-0110 (median age: 
36 years; range: 18-69 years). Differences in baseline characteristics between the 2 studies 
included HBV DNA levels (median levels were 5.7 and 7.9 log10 IU/mL for GS-US-320-0108
and GS-US-320-0110, respectively), serum ALT levels (median values were 67 and 85 U/L for 
GS-US-320-0108 and GS-US-320-0110, respectively), and number of years positive for HBV 
(6.0 and 4.0 years [median values] for GS-US-320-0108 and GS-US-320-0110, respectively). 
The distribution of HBV genotypes was similar between treatment groups in both studies with 
the most common genotypes being C (46.1%), D (24.3%), and B (20.4%).
Efficacy of TAF in Subjects with CHB
Primary Endpoint Analysis
For both studies, the primary efficacy endpoint was the proportion of subjects with plasma
HBV DNA < 29 IU/mL at Week 48. Table 1-2 presents HBV DNA outcomes for
Studies GS-US-320-0108 {Buti 2016} and GS-US-320-0110 {Chan 2016} for subjects at 
Week 48. In both studies, similar rates of HBV DNA suppression were achieved in the 
2 treatment groups when assessed using the M = F method at Week 48 for the Full Analysis Set 
(FAS). The percentages of subjects with HBV DNA levels < 29 IU/mL at Week 48 were as 
follows:

Study GS-US-320-0108: TAF 94.0%, TDF 92.9%; difference in proportions 
(baseline stratum-adjusted): 1.8%, 95% CI: −3.6% to 7.2%

Study GS-US-320-0110: TAF 63.9%, TDF 66.8%; difference in proportions
(baseline stratum-adjusted): −3.6%, 95% CI: −9.8% to 2.6%


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In both studies, because the lower bound of the 2-sided 95% CI of the difference (TAF − TDF)
in the response rate was greater than the prespecified −10% margin, the TAF group met the
primary endpoint of noninferiority to the TDF group.
Table 1-2.
GS US 320 0108 and GS US 320 0110: HBV DNA Outcome at 
Week 48 Using HBV DNA of < 29 IU/mL, Missing = Failure 
(Full Analysis Set)
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
(N = 285)
TDF 300 mg
(N = 140)
TAF 25 mg
(N = 581)
TDF 300 mg
(N = 292)
HBV DNA < 29 IU/mL
268 (94.0%)
130 (92.9%)
371 (63.9%)
195 (66.8%)
P-valuea
0.47
0.25
Difference in Proportions (95% CI)b
1.8% (−3.6% to 7.2%)
−3.6% (−9.8% to 2.6%)
HBV DNA ≥ 29 IU/mL
7 (2.5%)
4 (2.9%)
183 (31.5%)
88 (30.1%)
No Virologic Data at Week 48
10 (3.5%)
6 (4.3%)
27 (4.6%)
9 (3.1%)
Discontinued Study Drug Due to Lack of Efficacy
0
0
1 (0.2%)
0
Discontinued Study Drug Due to AE/Death
3 (1.1%)
1 (0.7%)
6 (1.0%)
3 (1.0%)
Discontinued Study Drug Due to Other Reasonsc
6 (2.1%)
4 (2.9%)
19 (3.3%)
6 (2.1%)
Missing Data During Window but on Study Drug
1 (0.4%)
1 (0.7%)
1 (0.2%)
0
a
P-value for the superiority test comparing the percentages of HBV DNA < 29 IU/mL was from the CMH test stratified by 
baseline HBV DNA categories and oral antiviral treatment status strata.
b
Difference in the proportion between treatment groups and its 95% CI were calculated based on the MH proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
c
Discontinuation due to other reasons included subjects who prematurely discontinued study drug due to investigator's 
discretion, withdrew consent, lost to follow-up, noncompliance with study drug, protocol violation, pregnancy, and study 
termination by sponsor.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Table 12; GS-US-320-0110 Week 48 CSR, Section 15.1, Table 12. 
Biochemical Analyses
Table 1-3 presents the proportion of subjects with ALT normalization at Week 48 for both 
studies (GS-US-320-0108) and (GS-US-320-0110) when determined by central laboratory 
criteria and by AASLD criteria (upper limit of normal range: ≤ 30 U/L for males and ≤ 19 U/L 
for females {Lok 2009, Terrault 2015}), respectively.
For Study GS-US-320-0108, the percentage of subjects with normalized ALT (i.e., ALT > ULN 
at baseline but within the normal range at Week 48) using the central laboratory criteria was 
numerically higher for the TAF group compared with the TDF group for all time points from 
Weeks 4 through 48. When assessed at Week 48, rates of ALT normalization were not 
significantly different between the 2 treatment groups by the Missing = Failure (M = F) method 
for the Full Analysis Set (FAS). Using the AASLD criteria, the percentage of subjects with 
normalized ALT was significantly higher in the TAF group than in the TDF group at for all time 
points from Week 8 onward using the M = F method.


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For Study GS-US-320-0110, the percentage of subjects with normalized ALT using the central 
laboratory criteria was numerically higher for the TAF group compared with the TDF group for 
all time points from Weeks 8 through 48. When assessed at Week 48, rates of normalization 
were not significantly different between the 2 treatment groups by the M = F method for the 
FAS. Using the AASLD criteria, the percentage of subjects with normalized ALT was 
significantly higher in the TAF group than in the TDF group for all time points from 
Weeks 8 through 48 using the M = F method.
Overall, the percentage of subjects with normalized ALT at Week 48 was higher in 
Study GS-US-320-0108 compared with Study GS-US-320-0110 using the central laboratory 
criteria and similar across the 2 studies using the AASLD criteria.
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with 
ALT Normalization at Week 48, Missing = Failure (Full Analysis Set 
with Baseline ALT > ULN)
Normalized ALT
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
TDF 300 mg
TAF 25 mg
TDF 300 mg
Central Laboratorya
(N = 236)
(N = 121)
(N = 537)
(N = 268)
Week 48
196/236 (83.1%)
91/121 (75.2%)
384/537 (71.5%)
179/268 (66.8%)
Proportion Difference (95% CI)
8.0% (−1.3% to 17.2%)
4.6% (−2.3% to 11.4%)
p-value
0.076
0.18
AASLDb
(N = 276)
(N = 138)
(N = 572)
(N = 290)
Week 48
137/276 (49.6%)
44/138 (31.9%)
257/572 (44.9%)
105/290 (36.2%)
Proportion Difference (95% CI)
17.9% (8.0% to 27.7%)
8.7% (1.8% to 15.6%)
p-value
< 0.001
0.014
a
Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males
≥69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.
b
AASLD ULN for ALT criteria are as follows: ≤ 30 U/L for males and ≤ 19 U/L for females.
P-value was from the Cochran-Mantel-Haenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment 
status strata
Difference in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Tables 23.1.1 and 23.2.1; GS-US-320-0110 Week 48 CSR, Section 15.1, 
Tables 23.1.1 and 23.2.1
Serological Analyses
In Study GS-US-320-0108, no subject in either treatment group experienced HBsAg loss by
Week 48. In Study GS-US-320-0110, 4 subjects (0.7%) in the TAF group and 1 subject (0.3%)
in the TDF group experienced HBsAg loss at Week 48. Three of the 4 subjects in the TAF group
and none in the TDF group also experienced HBsAg seroconversion at Week 48.


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In Study GS-US-320-0110, the proportion of subjects with HBeAg loss or seroconversion to
anti-HBe at Week 48 was also evaluated; these data are presented on Table 1-4. A total of
78 (13.8%) and 34 (11.9%) subjects in the TAF and TDF groups, respectively, had HBeAg loss
at Week 48. A total of 58 (10.3%) and 23 (8.1%) subjects in the TAF and TDF groups,
respectively, experienced HBeAg seroconversion at Week 48.
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or 
Seroconversion at Week 48, Missing = Failure 
(Serologically Evaluable Full Analysis Set)
GS-US-320-0110
TAF 25 mg
(N = 565)
TDF 300 mg
(N = 285)
TAF 25 mg vs TDF 300 mg
p-value
Prop Diff
(95% CI)
HBeAg Loss, n (%)
78/565 (13.8%)
34/285 (11.9%)
0.47
1.8%
(−3.0% to 6.5%)
HBeAg Seroconversion, n (%)
58/565 (10.3%)
23/285 (8.1%)
0.32
2.1%
(−2.0% to 6.3%)
P-values were from the Cochran-Mantel-Haenszel test stratified by baseline HBV DNA categories and oral antiviral treatment 
status. Differences in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel 
proportions adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion included subjects who were HBeAg positive and 
HBeAb negative/missing at baseline. HBeAg loss was defined as changes from HBeAg-positive at baseline to HBeAg-negative 
at a post-baseline visit with baseline anti-HBe negative/missing. HBeAg seroconversion was defined as HBeAg loss and 
anti-HBe change from negative/missing at baseline to positive at a post-baseline visit.
Source: GS-US-320-0110 Week 48 CSR, Section 15.1, Table 19.1
Virologic Resistance Analysis
In an integrated analysis of Studies GS-US-320-0108 and GS-US-320-0110, 24 subjects (2.8%)
in the TAF group and 14 subjects (3.2%) in the TDF group qualified for population-based
sequence analysis after up to 48 weeks of treatment. Among the 24 subjects in the TAF group
who qualified for population-based sequence analysis, 15 had no changes detected in the pol/RT
sequence from baseline, 4 were unable to be sequenced, and 5 had polymorphic site
substitutions. Among the 14 subjects in the TDF treatment group who qualified for
population-based sequence analysis, 6 had no changes detected in the pol/RT sequence from
baseline, 4 were unable to be sequenced, 2 had polymorphic site substitutions, and 2 had a 
conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated with 
resistance to TFV were detected by sequencing and phenotypic analysis through 48 weeks of the 
study in either treatment group.
Safety of TAF in CHB Subjects
The principal sources of safety data for TAF are presented above in Table 1-1 and consist of 
2 Phase 3 studies in subjects with CHB, Study GS-US-320-0108 and GS-US-320-0110. Subjects
included in the Safety Analysis Set received at least 1 dose of study drug.


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Overall Extent of Exposure
Of the 2387 subjects screened in Studies GS-US-320-0108 and GS-US-320-0110 combined,
1301 were randomized (TAF 867 subjects; TDF 434 subjects), and 1298 received at least 1 dose
of study drugs (TAF 866 subjects; TDF 432 subjects); 3 subjects (TAF 1 subject; TDF 
2 subjects) did not receive study drug due to withdrawal of consent. As of the Week 48 data
cutoff date for each Phase 3 study, a total of 1208 subjects (TAF 93.1%, 806 subjects; 
TDF 93.1%, 402 subjects) were continuing double-blind study drugs, and 27 subjects
(TAF 2.1%, 18 subjects; TDF 2.1%, 9 subjects) had entered the open-label phase as of the
Week 48 data cutoff date. Of the 1298 subjects randomized and treated, 63 subjects (4.9%)
discontinued blinded study drugs (TAF 4.8%, 42 subjects; TDF 4.9%, 21 subjects), and
61 subjects (TAF 40 subjects; TDF 21 subjects) discontinued from the study prior to the
Week 48 data cutoff date. Similar rates of discontinuation and reasons for treatment
discontinuation were observed for TAF compared with TDF. The most common reasons for
premature discontinuation of blinded study treatment were withdrew consent (TAF 1.6%,
14 subjects; TDF 1.6%, 7 subjects); adverse event (AE; TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects); and lost to follow-up (TAF 0.7%, 6 subjects; TDF 0.7%, 3 subjects). The most
common reasons for discontinuation from the study were: subjects withdrew consent (TAF 2.0%,
17 subjects; TDF 2.1%, 9 subjects), lost to follow-up (TAF 0.8%, 7 subjects; TDF 0.7%, 
3 subjects), and AEs (TAF 0.3%, 3 subjects; TDF 0.9%, 4 subjects).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures were nearly identical
between the 2 treatment groups (TAF 56.1 [48.1, 64.4] weeks; TDF 56.1 [48.1, 64.7] weeks.
More than half of the subjects in each treatment group had received blinded study drug for
≥56 weeks at the time of the Week 48 data cutoff date for each Phase 3 study (TAF 60.5 %,
524 subjects; TDF 62.0 %, 268 subjects). There was no statistically significant difference
between groups in the overall Kaplan-Meier estimate of time to premature discontinuation of
blinded study drug.


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Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set)
Duration of Exposure to Study Regimen (Weeks)
GS-US-320-0108 and GS-US-320-0110
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
N
866
432
Mean (SD)
58.9 (14.71)
59.0 (15.58)
Median
56.1
56.1
Q1, Q3
48.1, 64.4
48.1, 64.7
Min, Max
0.1, 96.3
0.1, 96.3
Total Exposure to Study Drug n(%)
≥ 4 Weeks [28 days]
860 (99.3%)
426 (98.6%)
≥ 8 weeks [56 days]
858 (99.1%)
426 (98.6%)
≥ 12weeks [84 days]
854 (98.6%)
423 (97.9%)
≥ 16 Weeks [112 days]
851 (98.3%)
422 (97.7%)
≥ 20 Weeks [140 days]
851 (98.3%)
422 (97.7%)
≥ 24 Weeks [168 days]
851 (98.3%)
419 (97.0%)
≥ 28 Weeks [196 days]
849 (98.0%)
418 (96.8%)
≥ 32 Weeks [224 days]
843 (97.3%)
418 (96.8%)
≥ 36 Weeks [252 days]
838 (96.8%)
418 (96.8%)
≥ 40 Weeks [280 days]
835 (96.4%)
418 (96.8%)
≥ 44 Weeks [308 days]
832 (96.1%)
418 (96.8%)
≥ 48 Weeks [336 days]
669 (77.3%)
346 (80.1%)
≥ 56 Weeks [392 days]
524 (60.5%)
268 (62.0%)
≥ 64 Weeks [448 days]
356 (41.1%)
174 (40.3%)
≥ 72 Weeks [504 days]
190 (21.9%)
92 (21.3%)
≥ 80 Weeks [560 days]
89 (10.3%)
46 (10.6%)
≥ 88 Weeks [616 days]
36 (4.2%)
24 (5.6%)
Duration of exposure to blinded study drug was the number of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date of blinded study drug.
Source: TAF Week 48 ISS, Table 4


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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-6 presents an overall summary of AEs by treatment group for the TAF Phase 3 Safety 
Population. Similar percentages of subjects in each treatment group had experienced at least 
1 AE (TAF 70.2 %, 608 subjects; TDF 67.4%, 291 subjects) and had experienced at least
1 Grade 3 or 4 AE (TAF 4.5 %, 39 subjects; TDF 3.9 %, 17 subjects). In addition, 57 subjects
(TAF 4.2%, 36 subjects; TDF 4.9 %, 21 subjects) had at least 1 SAE, with no subjects
experiencing a treatment-related SAE. A similar percentage of subjects in each treatment group
experienced an AE leading to discontinuation of study drugs (TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects). No deaths occurred in any subject on treatment. There were 2 deaths which occurred
after treatment was discontinued and were considered non-treatment emergent (1 subject in each
treatment group).
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of 
Adverse Events in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Adverse Events
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Subjects Experiencing Any AE
608 (70.2%)
291 (67.4%)
Subjects Experiencing Any Grade 2, 3, or 4 AE
221 (25.5%)
120 (27.8%)
Subjects Experiencing Any Grade 3 or 4 AE
39 (4.5%)
17 (3.9%)
Subjects Experiencing Any Study Drug-Related AE
123 (14.2%)
68 (15.7%)
Subjects Experiencing Any Grade 2, 3, or 4 Study Drug-Related AE
33 (3.8%)
21 (4.9%)
Subjects Experiencing Any Grade 3 or 4 Study Drug-Related AE
6 (0.7%)
2 (0.5%)
Subjects Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Subjects Experiencing Any Study Drug-Related SAE
0
0
Subjects Experiencing Any AE Leading to Premature Study Drug 
Discontinuation
9 (1.0%)
5 (1.2%)
Subjects Experiencing Any AE Leading to Dose Modification or 
Study Drug Interruption
17 (2.0%)
7 (1.6%)
Deatha
0
0
a
Treatment-emergent death refers to the death occurred between the first dose date and the last dose date (inclusive). Adverse 
events were mapped according to MedDRA Version 18.
Treatment-emergent AEs was defined as follows:
1)
Any AEs with onset date of on or after the study drug start date and no later than the study drug stop date for those who 
discontinued study drug permanently, or
2)
Any AE with an onset date on or after the study drugs start date for those who had not discontinued study drug permanently, 
or
3)
Any AEs leading to study drug discontinuation
Source: TAF Week 48 ISS, Table 6


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Common Adverse Events
Table 1-7 presents AEs reported for ≥ 5% of subjects for any treatment group by system organ
class (SOC) and preferred term (PT) in the TAF Phase 3 Safety Population. The rate and types of
AEs were similar in the 2 treatment groups. Overall, the 3 most frequently reported AEs by
treatment group were as follows:

TAF group — upper respiratory tract infection (9.9%, 86 subjects), nasopharyngitis 
(9.9%, 86 subjects), and headache (9.5%, 82 subjects)

TDF group — headache (8.3%, 36 subjects), upper respiratory tract infection
(7.4%, 32 subjects), and nasopharyngitis (7.2%, 31 subjects)
Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for
≥5% of Subjects in Either Treatment Group in the TAF Phase 3 
Safety Population (Safety Analysis Set)
Adverse Events by System Organ Class and Preferred Terma,b,c
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects Experiencing Any Adverse Event
608 (70.2%)
291 (67.4%)
Gastrointestinal disorders
227 (26.2%)
108 (25.0%)
Nausea
43 (5.0%)
22 (5.1%)
General disorders and administration site conditions
125 (14.4%)
62 (14.4%)
Fatigue
49 (5.7%)
23 (5.3%)
Infections and infestations
259 (29.9%)
121 (28.0%)
Upper respiratory tract infection
86 (9.9%)
32 (7.4%)
Nasopharyngitis
86 (9.9%)
31 (7.2%)
Nervous system disorders
149 (17.2%)
60 (13.9%)
Headache
82 (9.5%)
36 (8.3%)
Respiratory, thoracic and mediastinal disorders
106 (12.2%)
44 (10.2%)
Cough
55 (6.4%)
27 (6.3%)
a
Adverse events were mapped according to MedDRA Version 18.
b
SOC were presented alphabetically, and PT was presented by decreasing order of the total frequencies.
c
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 7
Adverse Events by Severity
The majority of AEs reported in the TAF Phase 3 Safety Population were Grade 1 or 2. A similar
percentage of subjects in each treatment group experienced at least 1 Grade 3 AE (TAF 4.5%,
39 subjects; TDF 3.9%, 17 subjects). No subjects in either group had a Grade 4 AE. The only
Grade 3 AE that occurred in more than 2 subjects in either treatment group were increased ALT
(TAF 0.6%, 5 subjects; TDF 0.7%, 3 subjects) and hepatocellular carcinoma (HCC)
(TAF 0 subjects; TDF 0.7%, 3 subjects). Four Grade 3 ALT increases (TAF 3 subjects;
TDF 1 subject) were assessed as related to study drug.


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Serious Adverse Events
Table 1-8 presents SAEs reported for > 1 subjects for any treatment group in the TAF Phase 3
Safety Population. A similar percentage of subjects experienced SAEs in each treatment group
(TAF 4.2%, 36 subjects; TDF 4.9%, 21 subjects). None of the SAEs were considered related to
study drugs by the investigators. Hepatocellular carcinoma was reported for 6 subjects
(TAF 0.1%, 1 of 866 subjects; TDF 1.2%, 5 of 432 subjects). Other SAEs reported in > 1 subject
in either treatment group were cellulitis, hand fracture, dizziness, and calculus ureteric.
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by 
Treatment Regimen in > 1 Subject in the TAF Phase 3 Safety 
Population (Safety Analysis Set)
Preferred Terma,b
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects (%) Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Hepatocellular carcinoma
1 (0.1%)
5 (1.2%)
Cellulitis
0
3 (0.7%)
Hand fracture
2 (0.2%)
0
Dizziness
2 (0.2%)
0
Calculus ureteric
2 (0.2%)
0
a
Adverse events were mapped according to MedDRA Version 18.
b
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 14
Summary of Bone Safety
Bone safety was assessed in the TAF Phase 3 Safety Population due to decreases in bone mineral 
density (BMD) and mineralization defects that have been seen in subjects treated with TDF.
Summary of Fractures
In the TAF Phase 3 Safety Population, the incidence of fracture events was uncommon 
(TAF 0.7%, 6 of 866 subjects; TDF 0.2%, 1 of 432 subjects; p = 0.44). Six of the 7 reported 
fractures were associated with trauma and 1 subject, in the TAF group, had a spinal compression 
fracture identified incidentally on a computed tomography (CT) scan. In the TAF group, 
4 fractures were reported as SAEs (hand fracture [3 subjects] and 1 spinal compression fracture). 
In the TDF group, 1 fracture (lower limb fracture) was reported as an SAE. Of the 7 subjects 
who had fractures, 4 subjects in the TAF group (tibia fracture, spinal compression identified
incidentally, hand fracture [2 subjects]) had normal hip and spine BMD T-scores at all 
timepoints, 2 subjects in the TAF group (hand fracture and traumatic spinal compression 
fracture) had hip and/or spine baseline BMD T-scores consistent with osteoporosis at baseline, 
1 subject in the TDF group (lower limb fracture) had normal hip and spine BMD at baseline 
which worsened while on treatment. All fractures were considered unrelated to the study drugs 
by the investigators and, none resulted in discontinuation of study drugs.


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Summary of Bone Mineral Density
Percentage change from baseline in hip BMD and spine BMD were the first and second key 
alpha-controlled safety endpoints, respectively, for both studies. Subjects receiving TAF 
experienced significantly less BMD reduction than those receiving TDF. At Week 48, the mean 
(SD) percentage decreases from baseline were as follows:

Hip: TAF −0.163% (2.2437 %); TDF −1.860 % (2.4525 %)

Spine: TAF −0.570 % (2.9147 %); TDF −2.366 % (3.2051 %)
Table 1-9 presents measure of BMD at Week 48. Percentage changes from baseline in hip and 
spine BMD were the first and second key alpha-controlled safety endpoints in 
Studies GS-US-320-0108 and GS-US-320-0110. Mean percentage decreases from baseline in 
BMD at the hip or spine were smaller in the TAF group compared with the TDF group 
(p < 0.001). A lower percentage of subjects in the TAF group had a > 3% decrease in hip BMD 
compared with subjects in the TDF group (8.4% TAF; 26.7% TDF). Similarly, a lower 
percentage of subjects in the TAF group had a > 3% decrease in spine BMD compared with 
subjects in the TDF group (TAF 19.5%; TDF 38.1%). At Week 48, fewer subjects had 
≥7% decrease in hip BMD (TAF 0.4%; TDF 2.0%) and ≥ 5% decrease in spine BMD 
(TAF 6.3%; TDF 20.4%) in the TAF group compared with the TDF group.


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Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral 
Density at Week 48 (Hip DXA Analysis Set and 
Spine DXA Analysis Set)
N
TAF 25 mg
N
TDF 300 mg
Hip DXA Analysis Set
Mean (SD) Percent Change in Hip BMD
807
−0.163 (2.2437)
404
−1.860 (2.4525)
P-Valuea
< 0.001
Difference in LSM
1.697 (1.420, 1.974)
Subjects with > 3% Decrease in Hip BMD, n (%)
807
68 (8.4%)
404
108 (26.7%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Hip BMD, n (%)
807
55 (6.8%)
404
8 (2.0%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Hip BMD, n (%)
807
383 (47.5%)
404
83 (20.5%)
Spine DXA Analysis Set
Mean (SD) Percent Change in Spine BMD
814
−0.570 (2.9147)
407
−2.366 (3.2051)
P-Valuea
< 0.001
Difference in LSM
1.796 (1.437, 2.155)
Subjects with > 3% Decrease in Spine BMD, n (%)
814
159 (19.5%)
407
155 (38.1%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Spine BMD, n (%)
814
89 (10.9%)
407
11 (2.7%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Spine BMD, n (%)
814
331 (40.7%)
407
89 (21.9%)
DXA = dual-energy x-ray absorptiometry; LSM = least-squares mean
a
P-values, difference in least squares means, and its 95% CI were from the ANOVA model including treatment as a 
fixed effect.
b
P-values were calculated from the Cochran-Mantel-Haenszel test for ordinal data (row mean scores differ statistic was used).
Source: TAF Week 48 ISS, Tables 23.1.2, 23.2.2, 25.1, and 25.2 and Request 7633 Tables 2.1 and 2.2
Renal Safety
In the TAF Phase 3 Safety Population in Studies GS-US-320-0108 and GS-US-320-0110
(TAF 25 mg N = 866, TDF 300 mg N = 432; Total N = 1301), no cases of proximal renal
tubulopathy (including Fanconi syndrome) or renal failure were reported in either treatment
group. No subject in the TAF Phase 3 Safety population experienced a renal SAE or AE
resulting in discontinuation of study drugs while on study.
Summary of Renal Laboratory Parameters
Change from baseline in serum creatinine was the third key alpha-controlled safety endpoint.
Overall, increases from baseline in mean values for serum creatinine were smaller in the TAF
group compared with the TDF group. Mean (SD) changes from baseline at Week 48 were
0.010 (0.1140) mg/dL for the TAF group and 0.024 (0.0974) mg/dL for the TDF group
(p = 0.012). Graded serum creatinine abnormalities were reported for 6 subjects (0.7%) in the
TAF group; all of which were Grade 1 or 2. Of the 6 subjects, 5 subjects had isolated serum


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relevant medical history of hypertension and diabetes, had multiple instances of graded
creatinine elevations and eGFR ≤ 50 mL/min. No subjects in the TDF group had graded serum
creatinine elevations.
In the TAF group, decreases from baseline in median eGFRCG values were significantly smaller
compared with the TDF group. Median (Q1, Q3) changes from baseline at Week 48 were
−1.2 (−8.4, 7.5) mL/min in the TAF group and −5.4 (−12.0, 3.0) mL/min in the TDF group
(p < 0.001). The overall number of subjects who had any confirmed renal laboratory abnormality
(ie, confirmed increases from baseline in creatinine of at least 0.5 mg/dL, or eGFRCG below
50 mL/min, or confirmed phosphorus < 2 mg/dL, was small (TAF 0.6%, 5 subjects; TDF 1.6%,
7 subjects). Most instances were isolated, transient, and resolved without treatment.
Summary of Proteinuria by Urinalysis (Dipstick) and by Quantitative Assessment
A similar percentage of subjects in each treatment group had at least 1 recorded, graded
proteinuria by dipstick while on study; most of which were Grade 1. Table 1-10 presents a
summary of the quantitative markers of proteinuria, urine protein to creatinine ratio (UPCR) and
urine albumin to creatinine ratio (UACR). There was a significant difference between the
2 treatment groups in median percentage changes from baseline in 1 of the quantitative markers
of proteinuria UPCR at Week 48. The median (Q1, Q3) percentage change in UPCR was
6.0 (−31.0, 57.6) mg/g in the TAF group and 16.5 (−21.6, 72.4) mg/g in the TDF group
(p = 0.010). Although not statistically significant, the median percentage change from baseline in
UACR was lower in the TAF group compared with the TDF group. Median percentage changes
from baseline in the markers of proximal tubular dysfunction, urine retinol binding protein
(RBP) to creatinine ratio and urine beta-2-microglobulin to creatinine ratio were smaller in the
TAF group compared with the TDF group (p < 0.001 for the differences between the 2 groups at
Weeks 24 and 48).
Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine 
Creatinine Ratios at Week 48 in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Parameter
Median Percentage Change (%) (Q1, Q3)
P-Valuea
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
UPCR (mg/g)
6.0 (−31.0, 57.6)
16.5 (−21.6, 72.4)
0.010
UACR (mg/g)
6.9 (−25.8, 46.7)
12.2 (−21.0, 63.5)
0.073
Urine RBP to Urine Creatinine Ratio (μg/g)
−0.3 (−23.2, 33.3)
25.1 (−7.9, 73.2)
< 0.001
Urine Beta-2-Microglobulin to Creatinine Ratio (μg/g)
−3.5 (−34.3, 32.0)
37.9 (−4.6, 152.4)
< 0.001
UACR = urine albumin to creatinine ratio; UPCR = urine protein to creatinine ratio
% Change = Change from baseline at a postbaseline visit/baseline × 100%.
a
P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.
Source: TAF Week 48 ISS, Tables 34.1, 34.2, 34.3, and 34.4


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Graded Laboratory Abnormalities
Most subjects participating in Studies GS-US-320-0108 and GS-US-320-0110 experienced at
least 1 laboratory abnormality of Grade 1 or higher (TAF 94.8%, 814 of 859 subjects; TDF
91.1%, 390 of 428 subjects). The majority of subjects had abnormalities that were Grade 1 or 2
at worst severity (TAF 63.4%, 545 subjects; TDF 61.7%, 264 subjects). Grade 3 laboratory
abnormalities occurred in 26.2% (225 subjects) in the TAF group and 22.4% (96 subjects) in the
TDF group; Grade 4 laboratory abnormalities were less common, occurring in 5.1% 
(44 subjects) in the TAF group and 7.0% (30 subjects) in the TDF group. In total, a similar 
percentage of subjects in each group had at least 1 Grade 3 or 4 laboratory abnormality 
(TAF 31.3%, 269 subjects; TDF 29.4%, 126 subjects).
Table 1-11 presents a summary of the subject incidence of Grade 3 or 4 serum chemistry or
urinalysis abnormalities reported for ≥ 1% in either treatment group for the overall TAF Phase 3
Safety Population. The only Grade 3 or 4 serum chemistry laboratory abnormality that occurred
in > 5% of subjects overall in each of the treatment groups individually was ALT elevation
(TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects). In the TDF group, Grade 3 or 4 elevations of
AST also occurred in > 5% of subjects overall (TAF 3.3%, 28 subjects; TDF 5.4%, 23 subjects).
Grade 3 urinalysis abnormalities included occult blood (TAF 7.7%, 66 subjects; TDF 7.0%,
30 subjects), urine erythrocytes (TAF 7.7%, 59 subjects; TDF 9.1%, 35 subjects), and urine
glucose (TAF 4.8%, 41 subjects; TDF 1.2%, 5 subjects). The majority of subjects (88.6%;
124 of 140 subjects) who had Grade 3 urine occult blood or urine erythrocytes were women of
child bearing potential (defined as age ≤ 54 years). The abnormalities were generally
asymptomatic and not associated with AEs; none of the events were considered related to study
drugs. Among the 41 subjects in the TAF group with Grade 3 urine glucose on treatment,
18 subjects (43.9%) had Grade 3 urine glucose at either screening or baseline, while the majority
of the remaining 23 subjects had a medical history relevant for diabetes mellitus and/or had a 
graded elevation in blood glucose, or experienced an isolated and transient occurrence of 
Grade 3 urine glucose.


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Table 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent 
Grade 3 or 4 Laboratory Abnormalities Reported for at Least 
1% of Subjects in Either Treatment Group in the Overall TAF 
Phase 3 Safety Population (Safety Analysis Set)
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Maximum Postbaseline Toxicity Grade (N)
859
428
Grade 3
225 (26.2%)
96 (22.4%)
Grade 4
44 (5.1%)
30 (7.0%)
Chemistry
Alanine Aminotransferase (N)
859
428
Grade 3
52 (6.1%)
27 (6.3%)
Grade 4
18 (2.1%)
13 (3.0%)
Amylase (N)
859
427
Grade 3
22 (2.6%)
9 (2.1%)
Aspartate Aminotransferase (N)
859
428
Grade 3
25 (2.9%)
18 (4.2%)
Grade 4
3 (0.3%)
5 (1.2%)
Creatine Kinase (N)
859
428
Grade 3
16 (1.9%)
7 (1.6%)
Grade 4
9 (1.0%)
6 (1.4%)
Fasting Glucose (Hyperglycemia) (N)
857
425
Grade 3
9 (1.1%)
0
Fasting LDL Cholesterol (N)
837
417
Grade 3
37 (4.4%)
1 (0.2%)
Nonfasting Glucose (Hyperglycemia) (N)
856
426
Grade 3
25 (2.9%)
7 (1.6%)
Urinalysis
Occult Blood (N)
859
426
Grade 3
66 (7.7%)
30 (7.0%)
Urine Erythrocytes (N)
768
386
Grade 3
59 (7.7%)
35 (9.1%)
Urine Glucose (N)
859
426
Grade 3
41 (4.8%)
5 (1.2%)
Denominator for percentage (N) is the number of subjects in the safety analysis set with at least 1 postbaseline laboratory value 
for the test.
Subjects were counted once for the maximum postbaseline severity for each laboratory test. For urinalysis (ie, urine glucose, 
urine protein, and urine RBC), the highest grade is Grade 3.
For nonfasting glucose, the maximum postbaseline toxicity grades, instead of treatment-emergent abnormalities, were 
summarized, because nonfasting glucose test was not done at baseline.
‘Hyper’ means high and ‘Hypo’ means low.
Source: TAF Week 48 ISS, Table 20
Hepatic Laboratory Abnormalities
In Studies GS-US-320-0108 and GS-US-320-0110 the incidence of graded hepatic laboratory
abnormalities through the Week 48 data cutoff date was generally lower for subjects in the TAF
group compared with subjects in the TDF group, and included ALT increased 


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(TAF 22.8%,196 subjects; TDF 30.4%, 130 subjects), AST increased (TAF 22.2%, 191 subjects; 
TDF 25.2%, 108 subjects), total bilirubin increased (TAF 12.7%, 109 subjects; TDF 10.0%, 
43 subjects), gamma-glutamyltransferase (GGT) increased (TAF 7.5%, 64 subjects; TDF 10.0%, 
43 subjects), alkaline phosphatase increased (TAF 2.2%, 19 subjects; TDF 5.4%, 23 subjects), 
and albumin decreased (TAF 0.9%, 8 subjects; TDF 1.9%, 8 subjects).
Hepatic laboratory abnormalities in both treatment groups were generally Grade 1 or 2 at
maximum severity; Grade 3 or 4 ALT abnormalities and Grade 3 or 4 AST abnormalities were
observed in lower percentages of subjects in the TAF group compared with the TDF group
(ALT: TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects; AST: TAF 3.3%, 28 subjects; TDF 5.4%,
23 subjects), while Grade 3 or 4 bilirubin elevations were observed in comparable percentages of
subjects in the TAF group (0.3%, 3 subjects) compared with the TDF group (0.2%, 1 subject).
Hepatic laboratory abnormalities were generally not associated with hepatic AEs.
Hepatic Flares
An ALT elevation was defined as treatment-emergent serum ALT > 2 × baseline value and
> 10 × ULN, with or without associated symptoms. Through Week 48, ALT elevations were
observed for 16 subjects (1.8%) in the TAF group and 9 subjects (2.1%) of subjects in the TDF
group. Most of the events were at isolated time points within the first 8 weeks of dosing and
resolved without recurrence while the subject remained on study drug. An ALT elevation that
was confirmed at 2 consecutive postbaseline visits was considered an ALT flare. The incidence
of these events was balanced between the treatment groups. Five subjects (0.6%) in the TAF
group and 4 subjects (0.9%) in the TDF group had a treatment-emergent ALT flare. With the
exception of 2 events, ALT flares occurred early in the dosing period; for 7 of the 9 subjects, the
ALT flares resolved without recurrence while the subject remained on study drug.
Metabolic Laboratory Parameters
Administration of TDF has been associated with lower fasting low-density lipoprotein (LDL) 
and high-density lipoprotein (HDL) as compared with other antiviral agents. As plasma TFV
exposures are approximately 90% lower with TAF administration than with TDF, fasting lipid
concentrations remained relatively stable through Week 48 in the TAF treatment group, while
TDF administration resulted in the expected lipid-lowering TFV effect, with decreases from
baseline in fasting lipid parameters observed in the TDF group. Median decreases from baseline
in total cholesterol, LDL, HDL, and triglycerides were greater in the TDF group than the TAF
group, with TDF subjects demonstrating reductions in all parameters at Week 48. The difference
between groups in median change from baseline was statistically significant a Week 48 for total
cholesterol, direct LDL, HDL, and triglycerides (p < 0.001). Median (Q1, Q3) changes from
baseline at Week 48 for fasting lipid parameters were as follows:

Total cholesterol: TAF −2 (−17, 17) mg/dL; TDF −24 (−42, −6) mg/dL

LDL: TAF 4 (−9, 20) mg/dL; TDF −9 (−25, 5) mg/dL

HDL: TAF −3 (−10, 2) mg/dL; TDF −9 (−17, −3) mg/dL

Triglycerides: TAF 6 (−13, 26) mg/dL; TDF −7 (−27, 10) mg/dL


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The median (Q1, Q3) change from baseline at Week 48 in total cholesterol to HDL ratio was
0.2 (−0.1, 0.5) in the TAF group and 0.2 (−0.2, 0.5) in the TDF group (p = 0.16 for the difference 
between treatment groups).
Eight subjects (0.9%) in the TAF group had Grade 3 elevated fasting cholesterol; 
7 of the 8 subjects had a history of hyperlipidemia and/or elevated fasting cholesterol at baseline.
There were no subjects with Grade 4 elevated fasting cholesterol in the TAF group, and none
with Grade 3 or 4 elevated fasting cholesterol in the TDF group. Thirty-seven subjects (4.4%) in
the TAF group and 1 subject (0.2%) in the TDF group had Grade 3 elevated fasting LDL.
Overall, changes in median values of total cholesterol, LDL, HDL, and triglycerides in the TAF
group were not clinically relevant, and none of the subjects with Grade 3 elevations in fasting
lipids had clinical AEs associated with lipid abnormalities.
1.3.
Information about Tenofovir Disoproxil Fumarate (TDF)
For further information on TDF (Viread®), refer to the current investigator’s brochure for TDF.
1.4.
Rationale for This Study
Given improved treatment options for CHB, more patients are living longer lives while on 
prolonged treatment. However, as these patients age, comorbidities increase and they are at 
greater risk for bone and renal disease. Because TAF is more stable in plasma than TDF, and
also provides higher intracellular levels of the active phosphorylated metabolite TFV-DP to 
target cells (eg, HBV-infected hepatocytes) with approximately 90% lower circulating levels of 
TFV relative to TDF at therapeutically active doses {Agarwal 2015, Babusis 2013, 
Murakami 2015}, an improved safety profile has been demonstrated with TAF when compared 
with TDF through 48 Weeks {Buti 2016, Chan 2016}. In HIV infection, switching virologically 
suppressed (HIV RNA < 50 copies/mL) patients from TDF-based antiretroviral regimens to a 
once-a-day, single tablet TAF-based regimen Descovy® (E/C/F/TAF) resulted in noninferior 
efficacy (i.e. maintenance of viral suppression) and improved bone mineral density and renal 
function at Week 48 compared with those who continued taking their TDF-based regimen 
{Mills 2016}.
Thus, patients with CHB, particularly those with advanced age, who are currently virally 
suppressed on TDF, may benefit from switching therapy to TAF by maintaining viral 
suppression while resulting in improved safety of bone and renal parameters compared to TDF
treatment.
1.5.
Risk/Benefit Assessment for the Study
This concept is supported by recent results of a large dataset of 1733 HIV-infected, treatment 
naive subjects randomized to receive treatment with the FDC of E/C/F/TAF or E/C/F/TDF [STB; 
Stribild®]). Renal and bone parameters were significantly less affected in subjects who received 
E/C/F/TAF compared with E/C/F/TDF {Sax 2015}. Moreover, in a large, prospective, 
randomized (2:1) open-label switch study in 1443 virally suppressed, HIV-infected subjects 
(959 subjects randomized to E/C/F/TAF and 477 to continue TDF-based antiretroviral regimens), 


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results at Week 48 showed that viral suppression was maintained while bone and renal 
parameters were significantly improved in the E/C/F/TAF group {Mills 2016}. In adult subjects 
with CHB, a global Phase 3 program for TAF consisting of 2 prospective, randomized, 
active-controlled studies with 1 each in HBeAg-negative (Study GS-US-320-0108) and 
HBeAg-positive (Study GS-US-320-0110) subjects is currently ongoing. Primary endpoint data 
shows that TAF is as effective as TDF for viral suppression at Week 48. In addition, renal and 
bone safety parameters were improved with TAF treatment relative to TDF. In a pooled analysis 
of both studies, patients receiving TAF experienced significantly smaller mean percentage 
decreases from baseline in hip and spine bone mineral density at week 48 (p < 0.001), and the 
median change in estimated glomerular filtration rate (eGFRCG) from baseline to week 48 was 
less with TAF compared with TDF (-1.2 mL/min vs. −5.4 mL/min; p < 0.001). In addition, 
significantly smaller changes in biomarkers of bone turnover (bone formation markers: 
osteocalcin, bone-specific alkaline phosphatase, and procollagen type 1 N-terminal propeptide, 
and the bone resorption marker, C-type collagen sequence) and quantitative markers of proximal 
tubular function (beta-2 microglobulin to creatinine and retinol binding protein to creatinine 
ratios) were seen in TAF subjects compared with TDF subjects at Week 48.
TDF has been used in clinical practice for the treatment of CHB for many years and its use and 
safety profile is very well understood by clinicians. Moreover, in ongoing HBV studies 
GS-US-320-0108 and GS-US-320-0110, subjects on TAF have similar rates of HBV DNA 
suppression as the TDF group, with TAF meeting the primary endpoint of noninferiority to the 
TDF group at Week 48. Thus, patients with CHB who are currently virally suppressed on TDF, 
should experience no greater risk as pertains to viral suppression by switching therapy to TAF
from TDF. Moreover, throughout the study, subjects will be closely monitored at intervals that 
are above those recommended by treatment guidelines for the use of TDF, therefore subjects 
who remain on TDF therapy will benefit from additional monitoring. 
For subjects receiving TAF, adult data from the Phase 3 studies indicates that TAF is safe and 
effective. 
The benefit/risk for this study is therefore considered positive.
1.6.
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 as follows:

To evaluate the efficacy of switching to TAF 25 mg QD versus continued TDF 300 mg QD
in virologically suppressed subjects with chronic HBV as determined by the proportion of 
subjects with HBV DNA ≥20 IU/mL (as defined by the modified US FDA-defined snapshot
algorithm) at Week 48

To compare the safety and tolerability of switching to TAF 25 mg QD versus continuing 
TDF 300 mg QD in virologically suppressed subjects with chronic HBV at Week 48
The key secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued 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 switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 48
Other secondary objectives of this study are as follows: 

To evaluate the proportion of subjects with HBV DNA < 20 IU/mL and target detected/not
detected (i.e. < LLOD) at Week 48 in subjects switched to TAF 25 mg QD versus continued 
TDF 300 mg QD

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD for 
48 weeks followed by open-label TAF for 48 weeks as determined by the percent change 
from baseline in hip and spine bone mineral density (BMD) at Week 96

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 96

To compare the serological response (loss of HBsAg and seroconversion to anti-HBs, and 
loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Week 48

To compare biochemical response (normal ALT and normalized ALT) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Week 48


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
To compare the change in fibrosis as assessed by FibroTest® after switching to TAF 25 mg 
QD versus continued TDF 300 mg QD at Weeks 48 

To evaluate the comparative open-label efficacy and safety of switching to TAF 25 mg QD 
from Week 48 through Week 96 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with continued TDF 300 mg QD for 48 weeks and then switched 
to open-label TAF 25 mg QD
The exploratory objectives of this study are as follows:
 
 
 
 
 
 
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3.
STUDY DESIGN
3.1.
Study Treatment Plan and Regimen
This is a randomized, double-blind, multicenter, active-controlled study to evaluate the safety 
and efficacy of TAF 25 mg QD in virologically suppressed subjects who switch from TDF to 
TAF compared to continued TDF treatment.
Approximately 460 subjects (with approximately 50% of subjects being ≥50 years old) will be 
randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD and matched placebo of TDF 
300 mg QD or Gilead-provided TDF 300 mg QD and matched placebo of TAF 25 mg QD.
At randomization, subjects will be stratified by screening HBeAg status (HBeAg-negative vs. 
HBeAg-positive) and age (≥ 50 or < 50 years).

Treatment Arm A: approximately 230 subjects administered TAF 25 mg QD and matched 
placebo of Tenofovir DF (TDF) 300 mg QD

Treatment Arm B: approximately 230 subjects administered Gilead-provided TDF 300 mg 
QD and matched placebo of TAF 25 mg QD
The duration of double blind treatment is 48 weeks. All subjects who complete 48 weeks of 
treatment are eligible for participation in the open label TAF 25 mg extension period for an 
additional 48 weeks (through Week 96). During the double-blind period, subjects with a 
confirmed creatinine clearance by Cockcroft Gault Method (eGFRCG) < 50 ml/min, and > 20% 
decline in eGFR by CKD-EPI (cystatin C) compared to baseline 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 during the double blind phase of the study will have 
the study drug permanently discontinued. Subjects with confirmed eGFRCG < 50 mL/min will 
not undergo dose modification to every other day during the open-label TAF 25 mg extension 
period, nor will treatment be permanently discontinued for confirmed eGFRCG < 30 mL/min 
during the open-label extension period.
Subjects who permanently discontinue study drug (either prematurely or at the end of study 
[Week 96]) 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 appropriate 
alternative, HBV therapy, whichever occurs first. Use of appropriate, alternative HBV therapy is 
strongly encouraged.
Subjects with HBsAg loss, and 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 prior to Week 48 are not permitted to discontinue
study drug prior to the Week 48 visit. Subjects with HBsAg loss with confirmed seroconversion
will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule 
(Appendix 2) through Week 96/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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The primary analysis will occur at Week 48 with the primary efficacy endpoint being the 
proportion of subjects with HBV DNA ≥20 IU/mL, as determined by the modified US 
FDA-defined snapshot algorithm.
An external, independent, multidisciplinary DMC will review the progress and safety of this 
study. The committee will convene after the last subject enrolled completes Week 24 of the 
study. However, Gilead will defer to the DMC for any decision to convene earlier or more 
frequently. At each meeting, the DMC will review routine safety and DXA data and will make 
recommendations regarding modification of the study treatment.
Subjects with a history of or current diagnosis of compensated cirrhosis (i.e. those with cirrhosis 
without laboratory or clinical evidence of decompensated liver disease) 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, a Fibrotest score ≥0.75, 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. Available information regarding hepatic status will be assessed by Child-Pugh 
score and will be captured in the electronic case report forms at Baseline, Weeks 48 and 96. The 
change in fibrosis as assessed by Fibrotest® will be performed in all subjects participating in the 
trial at Baseline, and Weeks 48, and 96/ED.
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 biomarkers with study drug response, including efficacy and/or 
adverse events and to increase knowledge and understanding of the biology of chronic hepatitis 
B and related diseases. The specific analyses will include, but will not be limited to, the 
biomarkers 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.

Fasting Urine Biomarkers including, but not limited to, retinol binding protein (RBP) and
beta-2 microglobulin 

Fasting Serum Bone Biomarkers including, but not limited to, C-type collagen sequence 
(CTX) and procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected from all subjects in a fasted state at Baseline and 
Weeks 4, 12, 24, 48, 72, and 96/ED. 
 
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3.2.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.
End of Study
End of Study is defined as when the last subject has completed 96 weeks of treatment, or when
the last subject has completed 96 weeks of treatment and up to 24 weeks of treatment free 
follow-up if appropriate, alternative anti-HBV treatment is not initiated after completing 
96 weeks of study treatment.
3.4.
Post Study Care
Once a subject has completed their study participation, the long-term care of the participant will 
return to the responsibility of their primary treating physicians.
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 460 subjects (with approximately 50% of subjects being ≥50 years old) will be 
randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD and matched placebo of TDF 
300 mg QD or Gilead-provided TDF 300 mg QD and matched placebo of TAF 25 mg QD. 
4.2.
Inclusion 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; consent must 
be obtained prior to initiation of study procedures
2) Adult male and non-pregnant, non-lactating female subjects, ≥18 years of age 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 5).
3) Documented evidence of chronic HBV infection previously (e.g., documented HBsAg 
positive for more than 6 months)
4) Maintained on TDF 300 mg QD for at least 48 weeks, and as monotherapy for CHB for at 
least 24 weeks prior to screening and with viral suppression (HBV DNA < LLOQ by local 
laboratory assessment) for a minimum of 12 weeks prior to Screening, and including a 
Screening HBV DNA value of < 20 IU/mL (by central laboratory)
5) Estimated creatinine clearance ≥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)
6) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
7) 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 5.


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3) Co-infection with HCV, HIV, or HDV

Subjects who are HCV positive, but have a documented negative HCV RNA, are eligible
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5) Current evidence of, or recent (≤5 years) history 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 > 5 × ULN
e) Albumin < 3.0 mg/dL
f)
INR > 1.5 × ULN (unless stable on anticoagulant regimen)
g) Total bilirubin > 2.5 × ULN
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator
9) Malignancy within 5 years prior to Screening, with the exception of specific cancers that are 
cured by surgical resection (e.g. basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible.
10) Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic 
agents, or agents capable of modifying renal excretion
11) Known hypersensitivity to study drugs, metabolites, or formulation excipients
12) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
13) 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.
14) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
15) Use of any prohibited medications as described in Section 5.4. Subjects on prohibited 
medications who are otherwise eligible will need a wash out period of at least 30 days prior 
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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
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. Eligible subjects (n = 300) will be randomized 1:1 to receive either blinded TAF 
25 mg and TDF matched placebo (n = 150) or TDF 300 mg and TAF matched placebo (n = 150) 
for 48 weeks. Subjects will be stratified by HBeAg status (HBeAg-negative [and anti-HBe 
positive] vs. HBeAg-positive) and age (> 50 years vs. < 50 years). At Week 48, all subjects will 
be switched to open-label TAF 25 mg QD for an additional 48 weeks (through Week 96/ED). 
For the entire duration of the study, subjects and investigators 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 IXRS system 
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).
5.2.
Description and Handling of Tenofovir Alafenamide (TAF) and TDF
5.2.1.
Formulation
5.2.1.1.
Vemlidy® (Tenofovir Alafenamide [TAF] Tablets)
Vemlidy® (TAF) 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is 
equivalent to 25 mg of Vemlidy® (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 


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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.
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.
5.2.2.
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 packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the FDA, EU Guideline to Good Manufacturing 
Practice −Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.3.
Storage and Handling
TAF, TDF, and their matched placebo tablets should be stored at controlled room temperature of 
25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage 
conditions are specified on the label. Until dispensed to the subjects, all bottles of study drugs 
should be stored in a securely locked area, accessible only to authorized site personnel. 


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To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of Tenofovir Alafenamide (TAF) and TDF
Subjects will be randomly assigned (1:1) to receive one of the following treatments in a blinded 
fashion:

Treatment Arm A: approximately 230 subjects administered TAF 25 mg QD and matched 
placebo of Tenofovir DF (TDF) 300 mg QD

Treatment Arm B: approximately 230 subjects administered Gilead-provided TDF 300 mg 
QD and matched placebo of TAF 25 mg QD
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 or without food. 
Subjects taking TDF 300 mg QD with food prior to randomization should continue to take study 
drug with food; subjects taking TDF 300 mg QD without food prior to randomization should 
continue to take study drug without food during the study period.
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 last study visit, need to be recorded in the source documents and eCRFs.
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:

Investigational agents or devices for any indication

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid


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
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
Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e., P-gp) with study drug(s) may result in PK interactions.
Examples of representative medications which are prohibited from 21 days prior to Day 1 
through the end of treatment are listed below:
Table 5-1.
Disallowed Concomitant Medications
Medication Class
Prohibited Medications
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin: 
may lower concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
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.
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) bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP 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 bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP 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 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. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
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 3.1.
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 randomization to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment 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 with 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 hip and spine. The Baseline DXA scan can be performed at any time during the
Screening period to ensure the results are received prior to the first dose of the study drug 
and therefore should be completed at least 14 days prior to the Baseline visit

Blood sample for:
plasma HBV DNA (must be < 20 IU/mL at time of Screening to be eligible).
Serum chemistry and liver function tests, hematology, serum HBsAg (quantitative), 
HBV serology (qualitative HBsAg and HBeAg), ruling out 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 and drug screen
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
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 (including HBV disease 
and treatment history)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 


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
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, PT/INR, plasma 
HBV DNA, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
virology (resistance surveillance), 
 and vitamin D assessment

Serum 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®

Child-Pugh Score (Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment). 

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), 
 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI)

Complete the “Fracture Risk Assessment” (FRAX®) eCRF
6.3.
Treatment Assessments
6.3.1.
Double Blind Visits (Visit Window ± 3 days)
6.3.1.1.
Week 4

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature
PPD
PPD
PPD


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
Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

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), 
 

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), 
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

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
virology (resistance surveillance), 

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), 
PPD
PPD
PPD
PPD


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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 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 (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 
6.3.1.4.
Week 24

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

DXA scan of hip and spine (within ±14 days of the expected visit date)

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
PPD
PPD


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
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 (qualitative HBsAg and HBeAg), 
 

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), 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI)
6.3.1.5.
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

Fasting blood sample for 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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 
PPD
PPD
PPD
PPD


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6.3.1.6.
Week 48 (visit window is −14 days)

Complete physical examination with 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 hip and spine (within −14 days of the expected visit date)

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

Blood sample for serum chemistry and liver function tests, hematology, PT/INR, plasma 
HBV DNA, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
virology (resistance surveillance), 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Child-Pugh Score (Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment)

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), 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI)

Retrieve blinded study drug and dispense open label study drug
PPD
PPD
PPD


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6.3.2.
Open Label Visits (Visit Window ± 7 days)
6.3.2.1.
Week 60

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 open label study drugs

Fasting blood sample for 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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg) virology 
(resistance surveillance), 

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), 
6.3.2.2.
Week 72

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

DXA scan of hip and spine (within ± 14 days of the expected visit date)

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense open label study drugs
PPD
PPD


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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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
serum HBsAg (quantitative), HBV serology (qualitative HBeAg and HBsAg), virology 
(resistance surveillance),

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), 
6.3.2.3.
Week 96

Complete physical examination with 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 hip and spine (within ± 14 days of the expected visit date)

Review concomitant medications

Review adverse events 

Perform study drug accountability (no study drug will be dispensed at Week 96 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, PT/INR, plasma 
HBV DNA, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
virology (resistance surveillance), 

 

Estimated creatinine clearance (using the Cockcroft-Gault method)
PPD
PPD
PPD
PPD


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
Blood sample for Fibrotest®

Child-Pugh Score (Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment)

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), 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36 and WPAI)
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 original study visit schedule through Week 96/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 appropriate, alternative 
HBV therapy, whichever occurs first.
6.4.3.
Treatment-Free 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 (qualitative HBeAg, and HBsAg ), quantitative serum HBsAg, 
 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine for urinalysis
PPD
PPD


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6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (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 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
The ED Visit should be performed within 72 hours (i.e., visit window is ± 3 days) of the last 
study drug dose.

Complete physical exam with 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 visit date and is
done only if not done within the past 12 weeks of the ED visit

Review concomitant medications

Review adverse events 

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 (only collected if not done in the last 12 weeks)

Fasting urine sample for renal biomarkers (only collected if not done in the last 12 weeks)

Blood sample for serum chemistry and liver function tests, hematology, PT/INR, plasma 
HBV DNA, serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), 
virology (resistance surveillance), 
 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Child-Pugh Score (Assessment requires: total bilirubin, albumin, PT/INR, Ascites 
assessment, and Hepatic encephalopathy assessment)

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), 

Health Related Quality of Life (HRQoL) Surveys (SF-36, WPAI and CLDQ) are done only if 
not done within the past 24 weeks of the ED visit
PPD
PPD


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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. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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 during the double blind phase 
of the study will have their study drug permanently discontinued

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 
considered on a case by case basis

Therapeutic failure 

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.7.
Other Evaluations
6.7.1.
Bone and Renal Markers
The following biological specimens will be collected in this study and will be used to evaluate 
the association of exploratory biomarkers with study drug response, including efficacy and/or 
adverse events and to increase knowledge and understanding of the biology of chronic 
hepatitis B and related diseases. The specific analyses will include, but will not be limited to, the 
biomarkers listed below. 


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
Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) urine 
Biomarkers including, but not limited to, retinol binding protein (RBP) and
beta-2 microglobulin 

Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) serum 
Bone Biomarkers including, but not limited to, C-type collagen sequence (CTX) and 
procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected from all subjects at Baseline and Weeks 4, 12, 24, 48, 72, and 
96 or ED. 
 
 
6.8.
Resistance Surveillance and Virologic Rebound Management
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for potential resistance 
mutations may be attempted for any subject with HBV DNA > 69 IU/mL at Baseline and for 
subjects who experience viremia (HBV DNA ≥69 IU/mL) at Weeks 48 and 96/ED. Phenotypic 
analysis will be performed for subjects that are subjected to sequence analysis.
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 serum sample for potential resistance surveillance will be collected at 
each study visit. 
In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be asked 
to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound 
occurring within the first 12 weeks of the study, the next scheduled visit will used for follow up. 
For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 
within 2-3 weeks after the date of the original test that resulted with HBV DNA virologic 
rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for 
resistance testing will be obtained. For unscheduled visits, the subject will be required to bring 
their supply of study drug with them and be assessed for adherence by pill count, and if 
necessary, the subject will be re-counseled on adherence to study medication.
PPD


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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

Persistent or significant disability/incapacity


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
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 without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, 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 (eg, 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 (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5. 
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 (eg, 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 (eg, 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, (eg., 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 4). 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 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
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 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 30-days after last administration of study IMP must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event 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 occurs 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 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after 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.
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 to:
Gilead DSPH:
Fax: 
Email: 
Medical Monitor:
Phone:
Fax:
Email:

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.

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.
PPD
PPD
PPD
PPD
PPD
PPD


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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 associated 
with any study IMP. 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 3.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

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.


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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.
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.


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7.5.5.
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
7.5.5.1.
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.
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). 


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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.
7.5.5.2.
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:

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. 
7.5.6.
Management of Ocular Safety
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. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.


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Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
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).
7.5.7.
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, serum 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.
During the double-blind period, 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.
During the open-label TAF 25 mg extension period, subjects who meet the above eGFR criteria 
(i.e. confirmed CLCr ≥ 30 mL/min to < 50 mL/min and > 20% reduction from baseline in eGFR 
by CKD-EPI equation) are not required to undergo dose modification to every other day dosing 
of study drug, and subjects with confirmed CLCr < 30 mL/min are not required to permanently 
discontinue study drug.


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All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis are recommended to 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.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports of 
adverse events associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE and AE in an infant following exposure from breastfeeding.
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 and 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).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.
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.


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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 (eg, 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 Gilead DSPH 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:
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
 or email 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
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 Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead 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 as follows:

To evaluate the efficacy of switching to TAF 25 mg QD versus continued TDF 300 mg QD
in virologically suppressed subjects with chronic HBV as determined by the proportion of 
subjects with HBV DNA ≥20 IU/mL (as defined by the modified US FDA-defined snapshot
algorithm) at Week 48

To compare the safety and tolerability of switching to TAF 25 mg QD versus continuing 
TDF 300 mg QD in virologically suppressed subjects with chronic HBV at Week 48
The key secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued 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 switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 48
Other secondary objectives of this study are as follows: 

To evaluate the proportion of subjects with HBV DNA < 20 IU/mL and target detected/not 
detected (i.e. < LLOD) at Week 48 in subjects switched to TAF 25 mg QD versus continued 
TDF 300 mg QD

To compare the safety of switching to TAF 25 mg QD for 96 weeks versus continued TDF
300 mg QD for 48 weeks followed by open-label TAF for 48 weeks as determined by the 
percent change from baseline in hip and spine bone mineral density (BMD) at Week 96

To compare the safety of switching to TAF 25 mg QD for 96 weeks versus continued TDF 
300 mg QD for 48 weeks followed by open-label TAF for 48 weeks as determined by the 
change from baseline in estimated creatinine clearance by Cockcroft-Gault method (eGFRCG) 
at Week 96

To compare the serological response (loss of HBsAg and seroconversion to anti-HBs, and 
loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Week 48


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
To compare biochemical response (normal ALT and normalized ALT) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Week 48

To compare the change in fibrosis as assessed by FibroTest® for switching to TAF 25 mg QD
versus continued TDF 300 mg QD at Week 48

To evaluate the comparative open-label efficacy and safety of switching to TAF 25 mg QD 
from Week 48 through Week 96 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with continued TDF 300 mg QD for 48 weeks and then switched 
to open-label TAF 25 mg QD at Week 96
The exploratory objectives of this study are as follows:
 
 
 
 
 
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot algorithm) at Week 48.
8.1.3.
Secondary Endpoint
The secondary efficacy endpoints are:

The proportion of subjects with HBV DNA ≥20 IU/mL (as determined by the modified 
US FDA-defined snapshot algorithm) at Week 96

The proportion of subjects with HBV DNA < 20 IU/mL and target detected/not detected
(i.e. < LLOD) at Weeks 48 and 96, as determined by the modified US FDA-defined snapshot
algorithm

The proportion of subjects with HBeAg loss and proportion with seroconversion to anti-HBe 
at Weeks 48 and 96
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
The proportion of subjects with HBsAg loss and proportion with seroconversion to anti-HBs 
at Weeks 48 and 96

The proportion of subjects with normal ALT and proportion with normalized ALT 
(by central laboratory and AASLD criteria) at Weeks 48 and 96

The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48 and 96
The key secondary safety endpoints are:

The percent change from baseline in hip bone mineral density (BMD) at Week 48

The percent change from baseline in spine bone mineral density (BMD) at Week 48

The change from baseline in eGFRCG (measured by Cockcroft-Gault method) at Week 48
The secondary safety endpoints are:

The percent change from baseline in hip bone mineral density (BMD) at Week 96

The percent change from baseline in spine bone mineral density (BMD) at Week 96

The change from baseline in eGFRCG (measured by Cockcroft-Gault method) at Week 96
8.1.4.
Other Endpoints of Interest

The change from baseline in serum markers of bone turnover at Weeks 48, and 96

The change from baseline in urine markers of renal tubular dysfunction at Weeks 48 and 96

The effect of treatment on health related to quality of life (via SF-36, CLDQ and WPAI 
questionnaires) at Weeks 48 and 96
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
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.
8.2.1.2.
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
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8.2.1.3.
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.
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.
8.2.1.5.
DXA
8.2.1.5.1.
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.
8.2.1.5.2.
Spine DXA Analysis Set
The Spine DXA Analysis Set includes 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.
8.3.
Data Handling Conventions
For key secondary safety endpoints, an analysis will be performed using the last observation 
carried forward (LOCF) method to impute missing data.
For other categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach except for the endpoints of HBV DNA ≥ 20 IU/mL and HBV DNA 
< 20 IU/mL.
For the remaining endpoints, values for missing data will not be imputed, unless specified 
otherwise.
8.4.
Multiplicity Adjustments
To control type I error for the assessment of the primary efficacy endpoint and key secondary 
safety endpoints, the hypothesis testing will be performed in a sequential order. The primary 
hypothesis of non-inferiority of TAF 25 mg QD vs. TDF 300 mg QD with respect to the 
proportion of subjects with HBV DNA ≥ 20 IU/mL (as defined by the modified US FDA-defined 
snapshot algorithm) at Week 48 will be tested first. The non-inferiority test will be performed 
using a two-sided, 0.05 alpha level. If non-inferiority is established, then multiplicity adjustments 
will be performed for the following endpoints using a fallback procedure {Wiens 2005} in the 
sequential order given below with a pre-specified two-sided alpha level:


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a) Percentage change from baseline in Hip BMD at Week 48 (alpha = 0.02)
b) Percentage change from baseline in Spine BMD at Week 48 (alpha = 0.01)
c) Change from baseline in Creatinine clearance (eGFRCG) at Week 48 (alpha = 0.02)
d) Superiority test for proportion of subjects with HBV DNA ≥ 20 IU/mL at Week 48
(alpha = 0.00)
8.5.
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 
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Baseline data will include a summary of body weight, height, body mass index, HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous TDF use and other oral 
nucleoside/nucleotide treatment experience, previous interferon experience, and HBV genotype 
by history.
8.6.
Efficacy Analysis
8.6.1.
Primary Analysis
The primary analysis will be performed when the last subject has completed Week 48
assessments or discontinued prematurely. The primary analysis will consist of a non-inferiority 
evaluation of efficacy of TAF versus TDF, with respect to the proportion of subjects with HBV
DNA ≥20 IU/mL at Week 48 (as defined by the modified FDA snapshot Algorithm). It will be 
concluded that TAF is not inferior to the TDF if the upper bound of the two-sided 
95% confidence interval of the difference between treatment arms (TAF arm – TDF arm) in the 
response rate is less than 4% (i.e., a margin of 4% is applied to non-inferiority assessment). The 
95% confidence interval will be constructed using the normal approximation method based on 
stratified Mantel-Haenszel proportions, where stratification factors are HBeAg status 
(HBeAg positive or negative) and age (≥50 or < 50 years).
8.6.1.1.
Modified US FDA-Defined Snapshot Alogrithm
The US FDA-defined snapshot algorithm, developed for HIV-1 clinical trials, has been modified 
for use in HBV {U. S. Department of Health and Human Services 2015} using on-treatment 
HBV DNA values of < 20 IU/mL and ≥20 IU/mL.
The analysis window at Week 48 is defined as from Study Day 294 to Study Day 377, inclusive.
All HBV DNA data collected on-treatment will be used in the snapshot algorithm. Virologic 
outcome will be defined as the following categories: 

HBV DNA < 20 IU/mL: this includes subjects who have the last available on-treatment 
HBV DNA < 20 IU/mL in the Week 48 analysis window

HBV DNA ≥20 IU/mL: this includes subjects who
1) Have the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 48 analysis 
window, or
2) Do not have on-treatment HBV DNA data available in the Week 48 analysis window and
a) Discontinue study drug prior to or in the Week 48 analysis window due to lack of 
efficacy, or
b) Discontinue study drug prior to or in the Week 48 analysis window due to reason
other than lack of efficacy and have the last available on-treatment HBV DNA 
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
No Virologic Data in the Week 48 Analysis Window: this includes subjects who do not
have on-treatment HBV DNA data available in the Week 48 analysis window for any of the 
following reasons:
1) Discontinuation of study drug prior to or within the Week 48 analysis window due to 
reasons other than lack of efficacy and the last available on-treatment HBV DNA value is 
< 20 copies/mL, or
2) Missing data within the window but who are on study drug treatment
8.6.2.
Analyses of Secondary Endpoints
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 may 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, 
may be used to compare the treatment groups, in an exploratory manner. Missing data will be 
handled by the missing = failure approach except for the endpoints of HBV DNA ≥20 IU/mL
and HBV DNA < 20 IU/mL.
8.7.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last 
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment and treatment-free follow-up periods will be included in data listings.
8.7.1.
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 detailswill be
provided in the Statistical Analysis Plan (SAP).
The change from baseline in in eGFRCG at Week 48 will be analyzed using a 2-sided Wilcoxon 
rank sum test to compare the 2 treatment groups. The details will be provided in the SAP.
8.7.2.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP administration data. 
Exposure data will be summarized by treatment group.
8.7.3.
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.


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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 
IMP up to the date of last dose of IMP. 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
8.7.4.
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 4.
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 IMP or after the subject has been 
discontinued from treatment will be included in a data listing.
8.8.
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.


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8.9.
Sample Size
With respect to the primary efficacy endpoint of proportion of suppressed subjects with 
HBV DNA ≥20 IU/mL (current assay LLOQ), as determined by the modified US FDA-defined 
snapshot algorithm, at Week 48, when the sample sizes are 230 (TAF 25 mg arm) and 230
(TDF 300 mg arm), a two-group, large-sample normal approximation test of proportions with a 
one-sided 0.025 significance level will have 80% power to establish non-inferiority of TAF to 
TDF. It is assumed that both treatment arms will have subjects who have HBV DNA ≥ 20 IU/mL 
(as defined by the modified US FDA-defined snapshot algorithm) at a rate of 2.4% at Week 48
(based on the rates of suppressed subjects having HBV DNA ≥ 29 IU/mL [the LLOQ of assay 
during those studies] after 48 weeks of treatment from the combined data of studies 
GS-US-174-0102 and GS-US-174-0103 with the ratio of HBeAg- to HBeAg+ subjects assumed 
to be 2:1), with a non-inferiority margin of 4%.
The proposed sample size (n = 230 for the TAF 25 mg arm, n = 230 for the TDF 300 mg arm) 
also provides > 99% power to detect a 1.81% difference in the percentage change from baseline 
in hip BMD at Week 48 (assuming a 1.47% [SD 2.71%] change from baseline in TAF 25 mg 
arm and −0.34% [SD 2.83%] change from baseline in the TDF 300 mg arm, with a two-sided 
α = 0.05); a > 99% power to detect a 2.00% difference in the percentage change from baseline in 
spine BMD at Week 48 (assuming a 1.56% [SD 3.84%] change from baseline in the TAF 25 mg 
arm and −0.44% [SD 4.14%] change in the TDF 300 mg arm, with a two-sided α = 0.05); 
a 97% power to detect a 4.9 mL/min difference in the change from baseline in eGFRCG at 
Week 48 (assuming a 1.3 mL/min [SD 13.2] change from baseline in the TAF 25 mg arm and 
−3.6 mL/min [SD 13.0] change from baseline in the TDF 300 mg arm, with a two-sided 
α = 0.05). These assumptions were derived from an HIV switch study (GS-US-292-0109) due to 
the unavailability of switch data from TAF HBV studies.
8.10.
Data Monitoring Committee
An external, independent, multidisciplinary DMC will convene and review the progress and 
safety of this study after the last subject enrolled completes 24 weeks of the study. However, 
Gilead will defer to the DMC for any decision to convene earlier or more frequently. At each
meeting, the DMC will review routine safety and DXA data and will make recommendations 
regarding modification of the study treatment.
The DMC’s specific activities will be defined by a mutually agreed 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 treatment.


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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, 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 subinvestigators 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 subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) 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/EC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC 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/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial 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 
investigator must use the most current IRB/IEC/EC approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 


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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/IEC/EC. 
 
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/IEC/EC, 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 for further details. 
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, 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);

Documentation of the reason(s) a consented subject is not enrolled
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
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. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. 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 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 


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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
At the start of the study, the study monitor will evaluate the 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. 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 IRB/IEC/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented approval from all necessary 
bodies before modifications can be implemented.


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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.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with 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.


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Amendment 1
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9.3.3.
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.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Gilead Sciences, Inc.
Amendment 1
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21 December 2016
10.
REFERENCES
Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et al. Twenty-eight day safety, 
antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of 
chronic hepatitis B infection. J Hepatol 2015;62 (3):533-40.
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.
Berger A, Gohl P, Sturmer M, Rabenau HF, Nauck M, Doerr HW. Detection and quantitation of 
HBV DNA in miniaturized samples: multi centre study to evaluate the 
performance of the COBAS (R) AmpliPrep/COBAS (R) TaqMan (R) hepatitis B 
virus (HBV) test v2.0 by the use of plasma or serum specimens. J Virol Methods 
2010;169 (2):404-8.
Buti M, Gane E, Seto WK, Chan HLY, Chuang WL, Stepanova T, et al. Tenofovir alafenamide 
versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-
negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, 
non-inferiority trial. Lancet Gastroenterol Hepatol 2016;1:196-206.
Centers for Disease Control (CDC), Division of Viral Hepatitis. Viral Hepatitis Surveillance 
United States, 2013.  2013.
Chan HLY, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide 
versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic 
hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority 
trial. Lancet 2016.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection [published version]. J 
Hepatology 2012;57:167-85.
Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on
disease progression and prognostic factors. J Hepatol 2008;48 (2):335-52.
Foran JA. Principles for the Selection of Doses in Chronic Rodent Bioassays. Environ Health 
Perspect 1997;105 (1):18-20.
G. B. D. Mortality Causes of Death Collaborators. Global, regional, and national age-sex specific 
all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a 
systematic analysis for the Global Burden of Disease Study 2013. Lancet 
2015;385 (9963):117-71.


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
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Page 98
21 December 2016
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
2015;1 (4):505-27.
Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. 
Hepatol International 2012;6:531-61.
Liu Y, Corsa AC, Buti M, Cathcart AL, Flaherty JF, Miller MD, et al. No detectable resistance to 
tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic
hepatitis B after 8 years of treatment. J Viral Hepat 2016.
Lok AS, McMahon BJ. AASLD Practice Guideline Update: Chronic hepatitis B: update 2009. 
Hepatology 2009;50 (3):661-2.
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.
Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet 
Infect Dis 2016;16 (1):43-52.
Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of Efficient 
Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus 
Therapy [Accepted Manuscript]. Antimicrob Agents Chemother 2015;59 
(6):3563-9.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: 
new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 
2012;30 (12):2212-9.
Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency 
virus activity and cellular metabolism of a potential prodrug of the acyclic 
nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), 
Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother 1998;42 
(3):612-7.
Ruane PJ, Dejesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral 
Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir 
Alafenamide as 10-Day Monotherapy in HIV-1-Positive Adults. J Acquir Immune 
Defic Syndr 2013;63 (4):449-55.


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 December 2016
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-
blind, phase 3, non-inferiority trials. Lancet 2015;385:2606-15.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic 
hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an 
expert panel on behalf of the European Society of Pediatric Gastroenterology, 
Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
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.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2015.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Revision 1. November 2015.
Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 2005;15 (6):929-42.
World Health Organization (WHO). Guidelines for the Prevention, Care and Treatment of 
Persons with Chronic Hepatitis B Infection. 2015a.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015b.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Vemlidy®, Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


PPD
PPD
Vemlidy®. Tenofovir Alafenamide (TAF) 
Protocol GS-US-320-40 18 
Gilead Sciences, Inc. 
Final 
Amendment I 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRrVE 
FOSTER CITY, CA 94404 
STUDYACKNOWLEDGEMffiNT 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Switching 
from Tenofovir Disoproxil Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 
25mg QD in Subjects with Chronic Hepatitis B who are Virologically Suppressed 
GS-US-320-4018, Amendment 1, 21 December 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
~~~
ro~v~a~
l.~------------~ 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
l 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 effo11 to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copic.:s 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 101 
21 December2016 


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Appendix 2.
Study Procedures Table
Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
Informed Consent
x
Inclusion/Exclusion Criteria
x
x
Medical History (including HBV disease and treatment history)
x
x
Concomitant Medications
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
Complete Physical Examination with weight and vital signs
x
x
x
x
x
x
x
Height 
x
Body Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom driven Physical Examination
x
x
x
x
x
x
x
Health Related Quality of Life (CLDQ, SF-36, WPAI)m
x
x
x
x
x
Serum Chemistry and Liver Testsb
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
Fasting metabolic panelc
x
x
x
x
x
x
x
x
x
Pregnancy testing (women of child-bearing potential only)
serum
urine (+ve test to be confirmed with serum)
x
x
x
x
x
x
x
x
x
x
x
x
Estimated Creatinine Clearance by Cockcroft-Gault method
(eGFRCG)
x
x
x
x
x
x
x
x
x
x
x
x
x
HBV serology (qualitative HBsAg and HBeAg) and
quantitative HBsAgi
x
x
x
x
x
x
x
x
x
x
x


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Amendment 1
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Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
HCV, HDV, HIV Testing
x
α-fetoprotein (AFP)
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine drug screen
x
DXA scans (Hip & Spine)d
x
x
x
x
x
x
ECGe
x
x
x
x
Plasma HBV DNA levels
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomization
x
Study Drug Accountability
x
x
x
x
x
x
x
x
x
Study Drug Dispensation
x
x
x
x
x
x
x
x
x
FibroTest®
x
x
x
x
Child Pugh Scoren
x
x
x
x
Serum Cystatin Cl
x
Fasting Blood for Bone Biomarkerf
x
x
x
x
x
x
x
x
Fasting Urine for Renal Biomarkerf
x
x
x
x
x
x
x
x
Fracture Risk Assessment (FRAX)
x
Virology (Sequence analysis of HBV pol/RT for 
resistance surveillance)j
x
x
x
x
x
x
x
x
x
x
x
Vitamin D
x


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
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Amendment 1
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21 December 2016
Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24
36
48k
60
72
96
EDg
a
Vital signs include blood pressure, pulse, respiration rate and temperature
b
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. At Baseline, Weeks 24, 48, 72, 96, and 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: PT/INR will be done at Screening, Week 48, 96 and ED and then as a reflex only test for ALT flares.
c
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). At Baseline, Weeks 12, 24, 36, 48, 60, 72, and 96/ED analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry panel.
d
The Baseline DXA can be performed at any time during the Screening period, but should be completed at least 14 days prior to the Baseline visit to ensure results are received prior to 
the first dose of study drug. The Week 24 DXA window is ± 14 days. The Week48 DXA window is −14 days only. DXA required for Early Discontinuation (ED) visit if not done 
within the last 12 weeks and should be done within ±14 days of the expected ED visit date
e
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
f
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
g
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
h
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-HBs on or after the Week 24 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the original study visit schedule through Week 96/ED. 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 appropriate, alternative HBV
therapy, whichever occurs first. Initiation of appropriate, alternative HBV therapy is highly encouraged.
i
HBeAb and HBsAb reflex testing will be performed as needed.
j
Resistance sequence analysis may be performed at BL for subjects with HBV DNA ≥69 IU/mL and may be attempted for viremic subjects (HBV DNA ≥ 69 IU/mL) at 
Wks 48 and 96/ED. Phenotypic analysis will be performed for subjects that are subjected to sequence analysis. As it may not be known at the time of the visit whether a subject is 
viremic or if it will be their last study visit, a virology sample will be collected as each visit. In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be 
asked to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound occurring within the first 12 weeks of the study, the next scheduled visit will used for 
follow up. For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 2-3 weeks after the date of the original test that resulted with HBV DNA 
virologic rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for resistance testing will be obtained. For unscheduled visits, the subject will be 
required to bring their supply of study drug with them and be assessed for adherence by pill count, and if necessary, the subject will be re-counseled on adherence to study medication.
k
The visit window for Week 48 visit is −14 days only.
l
Serum Cystatin C will be done when eGFRCG falls < 50 ml/min during blinded period of study.
m
Health Related Quality of Life surveys required for Early Discontinuation (ED) visit if not done within the last 24 weeks of the expected ED visit date
n
Child Pugh Score will be assessed at Baseline (Day 1), Weeks 48 and 96. Assessment requires: total bilirubin, albumin, PT/INR, Ascites assessment, and Hepatic encephalopathy 
assessment
PPD


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Final
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Amendment 1
CONFIDENTIAL
Page 105
21 December 2016
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
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
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
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
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


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
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Amendment 1
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21 December 2016
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 
≥ 7 Months#
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
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


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Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
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
—
—
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%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
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Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 December 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
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


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 December 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                        
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                     
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
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


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 110
21 December 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(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               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 111
21 December 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
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
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
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
LDL (Fasting)
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
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


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Protocol GS-US-320-4018
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Gilead Sciences, Inc.
Amendment 1
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21 December 2016
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
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 113
21 December 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
Page 114
21 December 2016
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 (eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years 
(with repeat testing at same 
visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences (eg, malignant 
hypertension) OR
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences 
(eg, tamponade) OR Urgent 
intervention indicated


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
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21 December 2016
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, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Embolic event 
(eg, pulmonary embolism, 
life-threatening thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


Vemlidy®, Tenofovir Alafenamide (TAF)
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Amendment 1
CONFIDENTIAL
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21 December 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced 
to 70% to 80%
FEV1 or peak flow 50% to 
69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak 
flow 25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social 
& functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse 
oximetry 90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in 
affected eye(s) 
Visual Changes 
(from baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing 
greater than minimal 
interference with usual social 
& functional activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in 
affected eye(s)


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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 
[eg, tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(eg, diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
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 (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 
48 hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis 
(functional- symptomatic)
Also see Mucositis/Stomatitis 
for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability 
to perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences (eg, 
hypotensive shock)


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


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


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


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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia
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 [eg, tube feeding or 
total parenteral nutrition]


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


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


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(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 
(eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other than 
HIV infection)
Localized, no systemic 
antiμbial treatment indicated 
AND Symptoms causing no 
or minimal interference with 
usual social & functional 
activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than 
simple incision and drainage) 
indicated
Life-threatening 
consequences 
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of TAF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies in 
animals (rats and rabbits) of TAF have demonstrated no adverse effect on fertility orembryo-fetal 
development. However, there are no clinical studies of TAF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable
effective contraceptive measure. They must have a negative serum pregnancy test at Screening
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. At minimum, a
pregnancy test will be performed at the end of relevant systemic exposure. In the event of a
delayed menstrual period (over one month between menstruations), a pregnancy test must be
performed to rule out pregnancy. This is even true for women of childbearing potential with
infrequent or irregular periods. They must also agree to one of the following from Screening
until the end of relevant systemic exposure.


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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of < 1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use
condoms when engaging in intercourse of reproductive potential.


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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.6.2.1.

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Switching from Tenofovir Disoproxil 
Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 
25mg QD in Subjects with Chronic Hepatitis B who are 
Virologically Suppressed
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
115561
2016-003632-20
Indication:
Chronic Hepatitis B
Protocol ID:
GS-US-320-4018
Gilead Sciences 
Study Director:
Name:
Telephone:
Fax:
Mobile:
Email:
Gilead Sciences 
Medical Monitor:
Name:
Telephone:
Fax:
Mobile:
Email: 
Protocol Version/Date:
Original:
30 September 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................18
1.
INTRODUCTION ..............................................................................................................................................22
1.1.
Background ............................................................................................................................................22
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................24
1.2.1.
General Information .............................................................................................................24
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................25
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................27
1.3.
Information about Tenofovir Disoproxil Fumarate (TDF).....................................................................45
1.4.
Rationale for This Study ........................................................................................................................45
1.5.
Risk/Benefit Assessment for the Study..................................................................................................45
1.6.
Compliance ............................................................................................................................................46
2.
OBJECTIVES.....................................................................................................................................................47
3.
STUDY DESIGN................................................................................................................................................49
3.1.
Study Treatment Plan and Regimen.......................................................................................................49
3.2.
Biomarker Testing..................................................................................................................................50
3.2.1.
Biomarker Samples to Address the Study Objectives ..........................................................50
3.2.2.
Biomarker Samples for Optional Future Research...............................................................51
3.2.3.
............................................51
3.3.
End of Study...........................................................................................................................................51
3.4.
Post Study Care......................................................................................................................................51
4.
SUBJECT POPULATION..................................................................................................................................52
4.1.
Number of Subjects and Subject Selection ............................................................................................52
4.2.
Inclusion Criteria....................................................................................................................................52
4.3.
Exclusion Criteria...................................................................................................................................53
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................55
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................55
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................55
5.2.
Description and Handling of Tenofovir Alafenamide (TAF) and TDF..................................................56
5.2.1.
Formulation..........................................................................................................................56
5.2.2.
Packaging and Labeling .......................................................................................................56
5.2.3.
Storage and Handling...........................................................................................................57
5.3.
Dosage and Administration of Tenofovir Alafenamide (TAF) and TDF...............................................57
5.4.
Prior and Concomitant Medications.......................................................................................................58
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos...................................................................................................................................59
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................59
6.
STUDY PROCEDURES ....................................................................................................................................60
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................60
6.2.
Pretreatment Assessments......................................................................................................................60
6.2.1.
Screening Visit .....................................................................................................................60
6.2.2.
Baseline Assessments...........................................................................................................61
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6.3.
Treatment Assessments..........................................................................................................................62
6.3.1.
Double Blind Visits (Visit Window ± 3 days) .....................................................................62
6.3.2.
Open Label Visits (Visit Window ± 7 days) ........................................................................67
6.4.
Post-Treatment Assessments..................................................................................................................69
6.4.1.
HBsAg Loss and Seroconversion Subjects ..........................................................................69
6.4.2.
All Other Subjects Who Discontinue Study Drug................................................................69
6.4.3.
Treatment-Free Follow Up Visit Assessments (All Subjects)..............................................69
6.5.
Assessments for Premature Discontinuation from Study.......................................................................69
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................70
6.7.
Other Evaluations...................................................................................................................................71
6.7.1.
Bone and Renal Markers ......................................................................................................71
6.8.
Resistance Surveillance and Virologic Rebound Management..............................................................72
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................73
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................73
7.1.1.
Adverse Events.....................................................................................................................73
7.1.2.
Serious Adverse Events........................................................................................................73
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................74
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................74
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................74
7.2.2.
Assessment of Severity ........................................................................................................75
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................75
7.4.
Gilead Reporting Requirements.............................................................................................................77
7.5.
Toxicity Management ............................................................................................................................77
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................78
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................78
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................78
7.5.4.
Management of Bone Evaluation.........................................................................................78
7.5.5.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................79
7.5.6.
Management of Ocular Safety..............................................................................................80
7.5.7.
Management of Potential Nephrotoxicity.............................................................................81
7.6.
Special Situations Reports......................................................................................................................82
7.6.1.
Definitions of Special Situations..........................................................................................82
7.6.2.
Instructions for Reporting Special Situations.......................................................................82
8.
STATISTICAL CONSIDERATIONS................................................................................................................84
8.1.
Analysis Objectives and Endpoints........................................................................................................84
8.1.1.
Analysis Objectives..............................................................................................................84
8.1.2.
Primary Endpoint .................................................................................................................85
8.1.3.
Secondary Endpoint .............................................................................................................85
8.1.4.
Other Endpoints of Interest ..................................................................................................86
8.2.
Analysis Conventions.............................................................................................................................86
8.2.1.
Analysis Sets ........................................................................................................................86
8.3.
Data Handling Conventions ...................................................................................................................87
8.4.
Multiplicity Adjustments........................................................................................................................87
8.5.
Demographic Data and Baseline Characteristics ...................................................................................89
8.6.
Efficacy Analysis ...................................................................................................................................89
8.6.1.
Primary Analysis..................................................................................................................89
8.6.2.
Analyses of Secondary Endpoints........................................................................................90
8.7.
Safety Analysis.......................................................................................................................................90
8.7.1.
Key Secondary Safety Analyses...........................................................................................90


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8.7.2.
Extent of Exposure...............................................................................................................91
8.7.3.
Adverse Events.....................................................................................................................91
8.7.4.
Laboratory Evaluations ........................................................................................................91
8.8.
Biomarker Analysis................................................................................................................................92
8.9.
Sample Size............................................................................................................................................92
8.10.
Data Monitoring Committee ..................................................................................................................93
9.
RESPONSIBILITIES..........................................................................................................................................94
9.1.
Investigator Responsibilities ..................................................................................................................94
9.1.1.
Good Clinical Practice..........................................................................................................94
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) Review and Approval ..........................................................94
9.1.3.
Informed Consent.................................................................................................................94
9.1.4.
Confidentiality......................................................................................................................95
9.1.5.
Study Files and Retention of Records ..................................................................................95
9.1.6.
Case Report Forms...............................................................................................................96
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................97
9.1.8.
Inspections............................................................................................................................97
9.1.9.
Protocol Compliance............................................................................................................97
9.2.
Sponsor Responsibilities ........................................................................................................................97
9.2.1.
Protocol Modifications.........................................................................................................97
9.2.2.
Study Report and Publications .............................................................................................98
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................98
9.3.1.
Payment Reporting...............................................................................................................98
9.3.2.
Access to Information for Monitoring..................................................................................98
9.3.3.
Access to Information for Auditing or Inspections ..............................................................99
9.3.4.
Study Discontinuation..........................................................................................................99
10.
REFERENCES .................................................................................................................................................100
11.
APPENDICES ..................................................................................................................................................103
Appendix 1.
Investigator Signature Page..................................................................................................104
Appendix 2.
Study Procedures Table........................................................................................................105
Appendix 3.
Management of Clinical and Laboratory Adverse Events....................................................107
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............108
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................130


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LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................30
Table 1-2.
GS US 320 0108 and GS US 320 0110: HBV DNA Outcome at Week 48 Using 
HBV DNA of < 29 IU/mL, Missing = Failure (Full Analysis Set) ........................................31
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with ALT 
Normalization at Week 48, Missing = Failure (Full Analysis Set with Baseline ALT 
> ULN) ...................................................................................................................................32
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or Seroconversion at 
Week 48, Missing = Failure (Serologically Evaluable Full Analysis Set) .............................33
Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study Drug for the 
TAF Phase 3 Safety Population (Safety Analysis Set) ...........................................................35
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................36
Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for ≥5% of 
Subjects in Either Treatment Group in the TAF Phase 3 Safety Population (Safety 
Analysis Set)...........................................................................................................................37
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by Treatment 
Regimen in > 1 Subject in the TAF Phase 3 Safety Population (Safety Analysis Set)...........38
Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral Density at 
Week 48 (Hip DXA Analysis Set and Spine DXA Analysis Set) ..........................................40
Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine Creatinine 
Ratios at Week 48 in the TAF Phase 3 Safety Population (Safety Analysis Set)...................41
Table 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent Grade 3 or 4 
Laboratory Abnormalities Reported for at Least 1% of Subjects in Either Treatment 
Group in the Overall TAF Phase 3 Safety Population (Safety Analysis Set) .........................43
Table 5-1.
Disallowed Concomitant Medications....................................................................................58


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Efficacy and Safety of Switching from Tenofovir Disoproxil 
Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 
25mg QD in Subjects with Chronic Hepatitis B who are 
Virologically Suppressed
IND Number:
EudraCT Number:
115561
2016-003632-20
Study Centers Planned:
Approximately 50 centers in North America, Europe, and 
Asia Pacific regions
Objectives:
The primary objectives of this study are as follows:

To evaluate the efficacy of switching to tenofovir alafenamide
(TAF) 25 mg QD versus continued tenofovir disoproxil 
fumarate (TDF) 300 mg QD in virologically suppressed 
subjects with chronic HBV as determined by the proportion of 
subjects with HBV DNA ≥20 IU/mL (as defined by the 
modified US FDA-defined snapshot algorithm) at Week 24

To compare the safety and tolerability of switching to TAF
25 mg QD versus continuing TDF 300 mg QD in virologically 
suppressed subjects with chronic HBV at Week 24
The key secondary objectives of this study are as follows: 

To compare the safety of switching TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the percent 
change from baseline in hip and spine bone mineral density 
(BMD) at Week 24

To compare the safety of switching to TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the change from 
baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 24


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Other secondary objectives of this study are as follows: 

To compare the safety of switching TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the percent 
change from baseline in hip and spine bone mineral density 
(BMD) at Weeks 48 and 96

To compare the safety of switching to TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the change from 
baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Weeks 48 and 96

To compare the safety and tolerability of switching to TAF 
25 mg QD versus continued TDF 300 mg QD in virologically 
suppressed subjects with chronic hepatitis B at Week 48

To evaluate the efficacy of switching to TAF 25 mg QD versus 
continued TDF 300 mg QD as determined by the proportion of 
subjects with HBV DNA ≥20 IU/mL (as defined by the 
modified US FDA-defined snapshot algorithm) at 
Weeks 48 and 96

To compare the serological response (loss of HBsAg and 
seroconversion to anti-HBs, and loss of HBeAg and 
seroconversion to anti-HBe in HBeAg-positive subjects) of 
switching to TAF 25 mg QD versus continued TDF 300 mg QD 
at Weeks 24, 48, and 96

To compare biochemical response (normal ALT and normalized 
ALT) of switching to TAF 25 mg QD versus continued TDF 
300 mg QD at Weeks 24, 48, and 96

To compare the change in fibrosis as assessed by FibroTest®
after switching to TAF 25 mg QD versus continued TDF 
300 mg QD at Weeks 48 and 96

To evaluate the comparative open-label efficacy and safety of 
switching to TAF 25 mg QD from Week 48 through Week 96 in 
subjects initially randomized to TAF 25 mg QD and in subjects
sequentially treated with continued TDF 300 mg QD for 
48 weeks and then switched to open-label TAF 25 mg QD

To evaluate the proportion of subjects with HBV DNA 
< 20 IU/mL and target detected/not detected (i.e. < LLOD) at 
Weeks 24, 48 and 96


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The exploratory objectives of this study are as follows:
 
 
 
 
 
 
Study Design:
This is a randomized, double-blind, multicenter, active-controlled 
study to evaluate the safety and efficacy of TAF 25 mg QD in 
virologically suppressed subjects who switch from TDF to TAF
compared to continued TDF treatment.
Approximately 300 subjects (with approximately 50% of subjects 
being ≥50 years old) who are virologically suppressed and actively 
taking TDF 300 mg QD, will be randomized in a 1:1 ratio (A:B) to 
receive either TAF 25 mg QD and matched placebo of TDF 300 mg 
QD, or Gilead-provided TDF 300 mg QD and matched placebo of
TAF 25 mg QD. At randomization, subjects will be stratified by 
screening HBeAg status (HBeAg-negative vs. HBeAg-positive) and 
age (≥50 or < 50 years).

Treatment Arm A: approximately 150 subjects administered 
TAF 25 mg QD and matched placebo of TDF 300 mg QD

Treatment Arm B: approximately 150 subjects administered 
Gilead-provided TDF 300 mg QD and matched placebo of TAF 
25 mg QD
The duration of double blind treatment is 48 weeks. All subjects 
who complete 48 weeks of treatment are eligible for participation in 
the open label TAF 25 mg extension period for an additional 
48 weeks (through Week 96). During the double-blind period only, 
subjects with a confirmed creatinine clearance by Cockcroft Gault 
Method (eGFRCG) < 50 ml/min, and > 20% decline in estimated 
glomerular filtration rate (eGFRCysC) by CKD-EPI (cystatin C) 
compared to baseline 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 during the 
double-blind period of the study will have the study drug 
discontinued.
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Subjects who permanently discontinue study drug (either 
prematurely or at the end of study [Week 96]) 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 appropriate alternative, HBV therapy, whichever occurs first. Use 
of appropriate, alternative HBV therapy is strongly encouraged.
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 prior to Week 24 
are not permitted to discontinue study drug prior to the Week 24 
visit. Subjects with HBsAg loss with confirmed seroconversion will 
be followed off treatment every 4 weeks for 12 weeks and then per 
the study visit schedule (Appendix 2) through Week 96/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.
The primary analysis will occur at Week 24 with the primary 
efficacy endpoint being the proportion of subjects with HBV DNA
≥20 IU/mL, as determined by the modified US FDA-defined 
snapshot algorithm.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will convene and review the progress and safety 
of this study after the last subject enrolled completes 24 weeks of 
the study. However, Gilead will defer to the DMC for any decision 
to convene earlier or more frequently. 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:
Approximately 300 subjects (approximately 150 subjects will 
receive TAF 25 mg QD and matched placebo of TDF 300 mg QD, 
and 150 subjects will receive Gilead-provided TDF 300 mg QD and 
matched placebo of TAF 25 mg QD)
Target Population:
Adult subjects with CHB who are currently (≥12 weeks) 
virologically suppressed (HBV DNA < LLOQ) while receiving 
therapy with TDF 300 mg QD for ≥48 weeks, and as monotherapy 
for > 24 weeks prior to Screening.
Duration of Treatment:
The duration of the double-blind treatment is 48 weeks. After 
completing the double-blind period, all subjects will be eligible to 
receive open label TAF 25 mg QD for an additional 48 weeks until 
Week 96. 


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Diagnosis and Main 
Eligibility Criteria:
Inclusion 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; consent must be obtained prior to initiation of 
study procedures
2) Adult male and non-pregnant, non-lactating female subjects, 
≥18 years of age 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 5).
3) Documented evidence of chronic HBV infection previously 
(e.g., documented HBsAg positive for more than 6 months)
4) Maintained on TDF 300 mg QD for at least 48 weeks, and as 
monotherapy for CHB for at least 24 weeks prior to screening
and with viral suppression (HBV DNA < LLOQ) for a 
minimum of 12 weeks prior to Screening, and including a 
Screening HBV DNA value of < 20 IU/mL (by central 
laboratory)
5) Estimated creatinine clearance ≥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)
6) Normal ECG (or if abnormal, determined by the Investigator
not to be clinically significant)
7) 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 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 5.


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3) Co-infection with HCV, HDV, HIV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by 
recent imaging)
5) Current evidence of, or recent (≤5 year) history 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 > 5 × ULN
e) Albumin < 3.0 mg/ dL
f)
INR > 1.5 × ULN (unless stable on anticoagulant regimen)
g) Total bilirubin > 2.5 × ULN
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator
9) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(e.g. basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible.
10) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), nephrotoxic agents, or agents capable of 
modifying renal excretion
11) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
12) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
13) 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.
14) Use of investigational agents within 3 months of Screening, 
unless allowed by the Sponsor
15) Use of any prohibited medications as described in Section 5.4. 
Subjects on prohibited medications, who are otherwise eligible, 
will need a wash out period of at least 30 days prior to the 
Baseline visit.


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Study Procedures/
Frequency:

Screening Visit

Treatment Period Visits: Baseline/Day 1, Weeks 4, 8, 12, 24, 36 
and 48, and open label Weeks 60, 72, and 96/Early 
Discontinuation (ED)

Subjects who permanently discontinue study drug (either 
prematurely or at the end of study [Week 96]) 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 appropriate, alternative, HBV therapy, 
whichever occurs first. Use of appropriate, alternative HBV 
therapy is strongly encouraged.

Review of concomitant medications and assessment for adverse 
events and vital signs, and weight measurement will be 
conducted at all study visits. 

Laboratory analyses (serum chemistry, hematology, eGFRCG, 
urinalysis, plasma HBV DNA levels, pregnancy testing 
[for females of childbearing potential]) will be conducted at all 
study visits. 
Screening Visit assessments include:

Complete physical examination with height, body weight, and 
vital signs and medical history (including HBV disease and 
treatment history)

INR and Alpha-fetoprotein (AFP); an AFP > 50 ng/mL at 
Screening must have an appropriate evaluation (i.e., CT scan) in 
order to rule out HCC prior to being permitted to enter the 
study.

Plasma HBV DNA levels (must be < 20 IU/mL at time of 
Screening to be eligible)

HBV serology (qualitative HBsAg, and qualitative HBeAg; 
HBeAb and HBsAb reflex testing will be performed as needed)
and quantitative HBsAg

HCV, HDV and HIV testing

Urinalysis and urine drug screen

Baseline DXA scans of the hip and spine can be conducted 
anytime during the Screening period, but should be conducted 
at least 14 days prior to the Baseline visit to ensure results are 
received prior to the first dose of study drug

ECG


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Baseline and On-treatment assessments include:

Complete physical examinations with body weight and vital 
signs will be performed at Baseline, Weeks 24, 48, 72, and 
96/ED. A symptom driven physical exam will be performed at 
all other visits.

HBV serology (qualitative HBsAg and HBeAg) and 
quantitative HBsAg will be performed at Baseline and 
Weeks 12, 24, 36, 48, 60, 72, and 96/ED. HBeAb and HBsAb 
reflex testing will be performed as needed.

Fasting blood sample for metabolic assessment (glucose and 
lipid panel [total cholesterol, HDL, direct LDL, and 
triglycerides] at Baseline and Weeks 12, 24, 36, 48, 60, 72, and 
96/ED.

FibroTest® at Baseline and at Weeks 24, 48, and 96/ED.

Serum Cystatin C (CysC) will be assessed at baseline and 
repeated if eGFRCG is confirmed to be < 50 ml/min during the 
double blind period of the study (to estimate eGFR by 
CKD-EPICysC)

Fasting blood and urine for bone and renal biomarker testing 
will be collected at Baseline and Weeks 4, 12, 24, 48, 72, and 
96/ED

Vitamin D assessment 

Fracture Risk Assessment will be evaluated at Baseline

DXA scans of the hip and spine will be conducted at 
Weeks 24, 48, 72, and 96/ED visit. The ED visit DXA should 
be done if not done within the last 12 weeks of this visit.

ECG will be performed at Weeks 48 and 96/ED.
 
 
 
 
 
 
 
 
PPD


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
Sequence analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance may be performed at
Baseline for subjects with HBV DNA ≥69 IU/mL and may be 
attempted for viremic subjects (HBV DNA ≥69 IU/mL) at 
Weeks 24, 48, and 96/ED. As it may not be known at the time 
of the visit whether a subject 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. In the event of 
unconfirmed virologic rebound (HBV DNA ≥20 IU/mL), 
subjects will be asked to return to the clinic for a scheduled or 
unscheduled blood draw. For virologic rebound occurring 
within the first 12 weeks of the study, the next scheduled visit 
will used for follow up. For virologic rebound occurring after 
Week 12, the subject will return for an unscheduled visit 2-3 
weeks after the date of the original test that resulted with 
HBV DNA virologic rebound for confirmation of virologic 
rebound. At this follow up visit, a serum blood sample for 
resistance testing will be obtained. For unscheduled visits, the 
subject will be required to bring their supply of study drug with 
them and be assessed for adherence by pill count, and if 
necessary, the subject will be re-counseled on adherence to 
study medication.
 

Health Related Quality of Life (HRQoL) Surveys (SF-36, 
WPAI and CLDQ) at Baseline, Weeks 24, 48, and 96/ED. The 
ED visit HRQoLs should be done if not done within the last 
24 weeks of this visit.
See Section 6 (Study Procedures) for further information.
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 (TDF) 300 mg QD, oral administration and 
matched placebo of Tenofovir alafenamide (TAF) 25 mg QD, 
oral administration
Open-label Treatment: NA
PPD


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Criteria for Evaluation:
Safety:
Key secondary safety endpoints include the percent change from 
baseline at Week 24 in hip and spine BMD, and the change from 
baseline at Week 24 in eGFRCG. During the double-blind period of 
the study if a subject has a confirmed creatinine clearance 
(eGFRCG) < 50 ml/min with a > 20% decline from baseline in 
eGFR by CKD-EPICysC, the subject will be required to undergo 
dose modification to every other day dosing of study drug. During 
the double-blind period, subjects with confirmed eGFRCG
< 30 mL/min will have the study drug 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 24 and 48 will be 
summarized. Percent change from baseline in BMD by DXA of the 
hip and spine hip will be assessed at Weeks 24 and 48. Change 
from eGFRCG will be assessed at every visit and summarized 
through Week 48. Adverse events and clinical laboratory tests will 
be collected at every visit and summarized through Week 48. 
Additionally, summaries of AEs, discontinuations due to AEs, and 
laboratory data including BMD measurements (via DXA scans and 
eGFRCG) by original treatment arms (TAF versus TDF) will 
continue on an annual basis through Week 96.
Efficacy:
The primary efficacy endpoint is:

Proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot
algorithm) at Week 24
The secondary efficacy endpoints are:

Proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot
algorithm) at Weeks 48 and 96

Proportion of subjects with serological response (loss of HBsAg 
and seroconversion to anti-HBs, and loss of HBeAg and 
seroconversion to anti-HBe in HBeAg-positive subjects) at 
Weeks 24, 48, and 96

Proportion of subjects with biochemical response (normal ALT 
and normalized ALT) at Weeks 24, 48, and 96

Change from baseline in fibrosis as assessed by FibroTest® at 
Weeks 48 and 96

Proportion of subjects with HBV DNA < 20 IU/mL and target 
detected/not detected (i.e. < LLOD) at Weeks 24, 48 and 96


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Statistical Methods:
The primary analysis will be performed when the last subject has 
completed Week 24 assessments or discontinued prematurely. The 
analysis will compare the TAF arm to the TDF arm.
Analysis Methods:
The primary analysis will consist of a non-inferiority evaluation of 
efficacy of TAF versus TDF, with respect to the proportion of 
subjects with HBV DNA ≥20 IU/mL (as determined by the 
modified US FDA-defined snapshot algorithm) at Week 24. It will 
be concluded that TAF is not inferior to the TDF if the upper bound 
of the two-sided 95% confidence interval of the difference between 
treatment arms (TAF arm – TDF arm) in the response rate is less 
than 6% (ie, a margin of 6% is applied to non-inferiority 
assessment). The 95% confidence interval will be constructed using 
the normal approximation method based on stratified 
Mantel-Haenszel proportions, where stratification factors are 
screening HBeAg status and age (≥ 50 or < 50 years).
The percent change from baseline in hip and spine BMD at 
Weeks 24 and 48 will be summarized and compared between the 
two treatment groups using an ANOVA model with treatment as a 
fixed effect.
The change from baseline in eGFRCG at Weeks 24 and 48 will be 
summarized and compared between the two treatment groups using 
the Wilcoxon Rank-Sum test.
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 HBV DNA ≥20 IU/mL (as determined by the 
modified US FDA-defined snapshot algorithm) at Week 24, when 
the sample sizes are 150 (TAF 25 mg arm) and 150 (TDF 300 mg 
arm), a two-group, large-sample normal approximation test of 
proportions with a one-sided 0.025 significance level will have 
97% power to establish non-inferiority. It is assumed that both 
treatment arms will have subjects who have HBV DNA ≥20 IU/mL 
(as determined by the modified US FDA-defined snapshot
algorithm) at a rate of 1.8% at Week 24 based on combined data of
suppressed subjects from studies GS-US-174-0102 and 
GS-US-174-0103 with HBeAg-negative:HBeAg-positive = 2:1), 
with a non-inferiority margin of 6%.


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This sample size also provides > 99% power to detect a 1.21% 
difference in the percentage change from baseline in hip BMD at 
Week 24 (assuming a 0.99% [SD 2.09%] change from baseline in 
TAF 25 mg arm and −0.22% [SD 1.89%] change from baseline in 
the TDF 300 mg arm, with a two-sided α = 0.05); and > 99% power 
to detect a 1.69% difference in the percentage change from baseline 
in spine BMD at Week 24 (assuming a 1.50% [SD 2.80%] change 
from baseline in the TAF 25 mg arm and −0.19% [SD 3.00%] 
change in the TDF 300 mg arm, with a two-sided α = 0.05); and 
68% power to detect a 3.6 mL/min difference in the change from 
baseline in eGFRCG at Week 24 (assuming a 1.6 mL/min [SD 13.0] 
change from baseline in the TAF 25 mg arm and −2.0 mL/min 
[SD 12.4] change from baseline in the TDF 300 mg arm, with a 
two-sided α = 0.05). These assumptions were derived from an HIV 
switch study, GS-US-292-0109, due to the unavailability of switch 
data from TAF HBV studies.
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
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil counts
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
Anti-HBe
Anti-Hepatitis B e-antigen
AR
Adverse reaction
ARV
Antiretroviral
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)
BMD
Bone mineral density
CatA
Cathepsin A
Ces1
Caboxylesterase-1
CHB
Chronic hepatitis B
CI
confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CLCr
Creatinine clearance
CLDQ
Chronic Liver Disease Questionarie
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
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
EC
Ethics committee
EC50
50% Effective Concentration
EudraCT
European clinical trials database


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E/C/F
Elvitegravir/cobicistat/emtricitabine
eGFR
Estimated glomerular filtration rate
eGFRCG
Estimated glomerular filtration rate by the Cockcroft-Gault formula
EKG / ECG
Electrocardiogram
ETV
Entecavir
EU
European Union
EVG
Elvitegravir
FAS
Full analysis set
FDA
(United States) Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice (Guidelines)
GFR
Glomerular filtration rate
GSI
Gilead Sciences, Inc.
GGT
Gamma glutamyl transferase
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B s antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HDV
Hepatitis D virus
HDPE
High-density polyethylene
hERG
Human ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
IC20
20% inhibitory concentration
IC50
50% inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent ethics committee
IMP
Investigational Medicinal Product
IRB
Institutional review board
IVRS
Interactive voice response system
IWRS
Interactive web response system
IUD
Intrauterine device
LDL
Low-density lipoprotein
LdT
Telbivudine
LAM
Lamivudine


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LLOD
Lower Limit of Detection
LLOQ
Lower Limit of Quantitation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MT-2
Human T-lymphotrophic virus-1 transformed cells
M = F
Missing = Failure
NDA
New Drug Application
NOAEL
No observed adverse effect level
NRTI
Nucleoside reverse transcriptase inhibitor
OAV
Oral antivirals
OL
Open-label
PD
Pharmacodynamic
P1NP
Procollagen type 1 amino-terminal propeptide
RBP
Retinol binding protein
pol
Polymerase
PK
Pharmacokinetic
PXR
Pregnane X receptor
PT/INR
Prothrombin time/International normalized ratio
QD
Once daily (use only in tables)
RPV
Rilpivirine
RT
Reverse transcriptase
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Set
sCr
Serum creatinine
SD
Standard deviation
SF-36
Short Form (36)
SOP
Standard Operating Procedure
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
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
UACR
Urine albumin-to-creatinine ratio


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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
WPAI
Work Productivity and Activity Impairment


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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a major public health care issue worldwide and one of the principal 
causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The hepatitis B 
virus (HBV) is easily transmissible through perinatal, percutaneous, and sexual exposure 
{Lok et al 2009}. Following acute HBV infection, 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}. Individuals who develop CHB are at substantial 
risk of cirrhosis, hepatic decompensation, and HCC, which will afflict 15% to 40% of subjects 
with CHB in the absence of effective treatment {World Health Organization (WHO) 2015a, 
Wright 2006}. Liver cancer is the third leading cause of cancer deaths globally, with the highest 
burden of disease found in regions where HBV is endemic {Global Burden of Disease Cancer 
Collaboration et al 2015}. Recent reports estimated that 250 to 350 million individuals were 
living with HBV (i.e., are hepatitis B surface antigen [HBsAg] positive) in 2010, representing a 
worldwide prevalence of 3.6%, with considerable geographic variability {Schweitzer et al 2015, 
World Health Organization (WHO) 2015b}. For example, HBV prevalence rates of 0.01%, 
0.76%, 4.0%, 5.5%, and 22.4% have been reported for the United Kingdom, Canada, Turkey, 
China, and South Sudan, respectively. In 2013, an estimated 686,000 deaths were due to HBV 
infection, placing it among the top 20 causes of mortality worldwide {G. B. D. Mortality Causes 
of Death Collaborators 2015, Ott et al 2012}.
Worldwide universal vaccination remains the goal for eliminating HBV infection and its 
complications, yet despite the availability of HBV vaccine programs in many countries, new 
HBV infections are still common even in areas of low prevalence. The World Health 
Organization estimates that each year there are over 4 million acute clinical cases of HBV 
infection globally {World Health Organization (WHO) 2015b}. In the United States (US), 
approximately 20,000 people become acutely infected each year according to an estimate from 
the Centers for Disease Control and Prevention {Centers for Disease Control (CDC) et al 2013}.
The natural history of chronic hepatitis B virus infection and disease is complex and highly 
variable. Following acute hepatitis B infection, up to 90% of newborns who are vertically 
infected, and 25-50% of children who acquire HBV within the first 6 years of life, will become 
chronic carriers of the virus when the immune system is thought to be immature, compared to 
immunocompetent individuals who become infected during adulthood (< 1%) 
{Fattovich et al 2008, Sarin et al 2015}. CHB has traditionally been characterized by 
four distinct phases of variable duration that reflect the dynamics of viral replication and the 
evolving host immune response {Fattovich et al 2008, Sokal et al 2013}. In the first, or the 
immune tolerant phase, individuals have high plasma levels of HBV DNA, detectable hepatitis B 
surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), with normal or slightly elevated 
serum alanine transaminase (ALT) levels reflective of minimal inflammation and fibrosis. This 
phase typically extends into late childhood or adolescence, and is followed by an 
HBeAg-positive, immune-active phase wherein ALT levels are persistently elevated along with 


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fluctuating levels of HBV DNA, reflective of moderate to severe inflammation or fibrosis. This 
phase may be followed by loss of HBeAg with seroconversion to anti-HBe. In the inactive CHB 
phase, subjects have undetectable or low levels of HBV DNA (< 2000 IU/mL), the presence of 
anti-HBe antibody, and normal or minimal elevation in serum ALT, which reflects minimal 
inflammation but with variable fibrosis. This third phase can evolve in a subgroup of individuals 
to an HBeAg-negative, immune reactivation phase, in which ALT levels and HBV DNA levels 
are increased. Subjects develop HBeAg-negative CHB as a result of variants that arise in the 
precore or core promoter region of the virus {Sarin et al 2015}. The goal of anti-HBV therapy is 
to improve long-term survival and quality of life by reducing disease progression to cirrhosis, 
decompensated liver disease, and HCC {Sarin et al 2015, Terrault et al 2015}. As seroclearance 
of HBsAg is a rare spontaneous occurrence in patients with CHB, durable anti-HBe 
seroconversion in HBeAg-positive subjects is sometimes considered a reasonable endpoint, 
associated with improved prognosis, including a reduced risk of HCC. However, in many 
subjects who discontinue treatment following anti-HBe seroconversion, disease relapse with 
increased levels of viremia can occur {Sarin et al 2015}. Successful reduction of viremia to 
levels below assay detection leads to reduced inflammation and slowing or reversal of fibrosis 
{Marcellin et al 2013}.
Currently, there are 2 approved options for treatment of CHB: injectable interferons and oral 
antiviral (OAV) agents. Of these, treatment with OAV agents has been more successful in 
achieving and maintaining a high degree of viral suppression in subjects with CHB. The 
development of nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) was a major 
breakthrough for the treatment of CHB, providing effective suppression of viral replication and 
reducing the risk of long-term complications {Marcellin et al 2013, World Health Organization 
(WHO) 2015a}. However, several N[t]RTIs possess a low barrier for viral resistance 
development, including lamivudine (LAM), telbivudine, (TBV) and adefovir dipivoxil (ADV) 
{European Association for the Study of the Liver (EASL) 2012, Liaw et al 2012}. Additionally, 
while development of resistance to entecavir (ETV) is low in treatment-naïve subjects, the 
cumulative probability of ETV resistance increases substantially with long-term use in subjects, 
particularly in subjects who are refractory to lamivudine, and those with lamivudine resistance 
(up to 57% through 6 years of treatment) {Tenney et al 2009}. In contrast, resistance to tenofovir 
disoproxil fumarate (TDF; Viread®) has not been documented through 6 years of use 
{Kitrinos et al 2014}.
Tenofovir (TFV) is a nucleotide analog with limited oral bioavailability that inhibits reverse 
transcription in HIV-1 and HBV. TDF, an oral prodrug of TFV, was first approved for the 
treatment of HIV infection in 2001 to be given in combination with other antiretroviral (ARV) 
agents and was approved for treatment of CHB as monotherapy in 2008. TDF is currently 
approved in over 165 countries, including the US, Canada, Europe, Japan, Taiwan, South Korea, 
and China, with more than 3,393,649 patient-years of use worldwide for both HIV and HBV 
infections since first marketing approval. TDF is a first-line treatment for CHB in all major 
treatment guidelines {European Association for the Study of the Liver (EASL) 2012, 
Sarin et al 2015, Terrault et al 2015}. Although highly effective, use of TDF is associated with 
nephrotoxicity and bone-related toxicity in some subjects. 


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Tenofovir alafenamide (TAF) is a phosphonamide prodrug of TFV that is more stable in plasma 
than TDF, and provides higher intracellular levels of the active phosphorylated metabolite 
TFV-DP to target cells (eg, HBV-infected hepatocytes and HIV-infected lymphoid cells) with 
approximately 90% lower circulating levels of TFV relative to TDF at therapeutically active 
doses {Agarwal et al 2015, Babusis et al 2013, Murakami et al 2015, Ruane et al 2013}. The 
distinct metabolism of TAF offers the potential for an improved safety profile when compared 
with TDF. In support of this concept are recent results from a large dataset of 1733 HIV-infected, 
treatment naive subjects randomized to receive treatment with the fixed-dose combination [FDC] 
of elvitegravir (E), cobicistat (C), emtricitabine (F), TAF [E/C/F/TAF; Genvoya®] or E/C/F/TDF 
[STB; Stribild®]). Renal and bone parameters were significantly less affected in subjects who 
received E/C/F/TAF compared with E/C/F/TDF {Sax et al 2015}. In a recent open-label Phase 3 
study, HIV-1-infected patients were switched from a TDF-based regimen to a TAF-based 
regimen with data supporting the efficacy and safety of switching regimens. In adult subjects 
with CHB, a global Phase 3 program for TAF consisting of 2 prospective, randomized, 
active-controlled studies with 1 each in HBeAg-negative (Study GS-US-320-0108) and 
HBeAg-positive (Study GS-US-320-0110) subjects is currently ongoing as described below.
Efficacy and safety results at Week 48 from Studies GS-US-320-0108 and GS-US-320-0110 are 
summarized below in Section 1.2.3. Marketing Applications for TAF 25 mg tablets for the 
treatment of CHB in adults have been filed in the US, EU, Japan, Taiwan and other territories 
worldwide.
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, (2E)-2-butenedioate (2:1) is 
a next generation oral prodrug of TFV, a nucleotide analog that inhibits HIV-1 reverse 
transcription. Tenofovir is metabolized intracellularly to the active metabolite, TFV-DP, a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) and HBV reverse transcriptase (HBV 
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, which is being used in the 
Phase 3 studies GS-US-320-0108 and GS-US-320-0110, is considered comparable based on 
physical/chemical properties to GS-7340-02 that has been used in previous studies and a number 
of ongoing studies. GS-7340-03 was also used in the Phase 1b study GS-US-320-0101. 
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 current Investigator’s Brochure 
for TAF.


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1.2.2.
Preclinical Pharmacology and Toxicology
Virology
Following its release from the prodrug TAF, TFV is metabolized intracellularly to the active 
metabolite, TFV-DP, a competitive inhibitor of HBV polymerase/reverse transcriptase (pol/RT) 
and HIV-1 RT that terminates the elongation of the viral DNA chain during the process of HBV 
and retroviral replication.
Compared to TDF, TAF is relatively stable in plasma, but rapidly converts to TFV inside cells. 
The cellular enzymes responsible for conversion of TAF to TFV are cathepsin A (CatA), which 
is broadly expressed in cells, and carboxylesterase 1 (CES1), which is highly expressed in liver. 
In HBV target cells, primary human hepatocytes, TAF is primarily hydrolyzed by CES1 with 
CatA making a minor contribution {Murakami et al 2015}. In HIV-1 target cells, primary human 
lymphoid cells, CatA is the major enzyme hydrolyzing TAF to TFV. In vitro studies have shown 
no significant variation for conversion to TFV and antiviral activity of TAF within PBMCs and 
macrophages from multiple donors. The covalent anti-hepatitis C virus (HCV) protease 
inhibitors (PIs) telaprevir and boceprevir were identified as the only potent inhibitors of CatA 
mediated hydrolysis of TAF in a biochemical assay (PC-120-2001).
TAF is a potent inhibitor of HBV replication, exhibiting in vitro activity comparable to that of 
TDF with an effective concentration (EC50) value of 18 nM. Additionally, TAF is similarly 
active in vitro against wild-type genotype A-H HBV clinical isolates (PC-320-2003). TAF also 
exhibits potent anti-HIV activity in lymphoid T-cells, primary human PBMCs, and macrophages 
with EC50 values ranging from 3 to 14 nM. The in vitro activity of TAF against HIV-1 is 
100- to 600-fold greater than TFV and 4- to 6-fold greater than TDF {Robbins et al 1998}. In 
MT-2 cells, TAF shows low cytotoxicity with a selectivity index of > 10,000. Based on data 
generated with the parent nucleotide TFV, TAF is active against a wide range of HIV-1 subtypes 
and also against HIV-2. 
For further information on the virology of TAF, (GS-7340), refer to the current investigator’s 
brochure for TAF.
Safety Pharmacology
The IC20 and the IC50 for the inhibitory effect of TAF fumarate on human ether-a-go-go-related 
gene (hERG) potassium current was estimated to be greater than 30 μM (PC-120-2005). TAF in 
the monofumarate form has been evaluated to determine potential functional 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). TAF at 1000 mg/kg reduced distal transit and 
increased stomach weights starting 2 hours postdosing, with reversibility beginning by 6 hours 
after dosing. The no observed effect level (NOEL) for gastrointestinal motility was 100 mg/kg.


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Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments were performed using TAF monofumarate 
(GS-7340-02), and all study data described reflect the dosage of the monofumarate. For 
reference, 100 mg of TAF monofumarate 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 2.5 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 tenofovir in the cells of the lymphoreticular system. The
primary route of elimination of tenofovir is renal excretion of unchanged drug based on
intravenous studies of TFV. Following oral administration of GS-7340-02, approximately
15% of a radiolabeled dose is recovered in dog urine in 24 hours. Tenofovir was the major
species present in the urine (90%), with about 3.4% of TAF also present. Biliary excretion of
tenofovir in dogs and fecal elimination of tenofovir 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.
Nonclinical Toxicology
Because of lack of exposure to the prodrug TAF in mice and rats and achievable TFV exposures 
being less than previously tested in studies with TDF, Gilead and regulatory agencies have 
agreed that neither carcinogenicity studies nor a peri/postnatal study with TAF were warranted as 
they would not add to the overall risk evaluation or risk management of TAF.


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The oral toxicity of TAF was evaluated in mice, rats, dogs, and monkeys for treatment periods 
up to 9 months. Based on recommendations that renal karyomegaly is not a dose-limiting effect 
{Foran 1997} and observations in the rat that renal karyomegaly is not sufficient to induce renal 
toxicity or predict oncogenicity (M990205) (M990204), its toxicological significance is 
questionable and, therefore, it was not considered an adverse effect in determining the NOAEL.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day; the 9-month dog 
study defined a No observed adverse effect level (NOAEL) of 2 mg/kg/day, and the 28-day 
nonhuman primate study defined a NOAEL of ≥ 30 mg/kg/day. While no NOAEL was 
determined in the 13-week mouse study, the relevance of the nasal findings to humans is unclear.
TAF had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day. There was 
some evidence at 6 and 18/12 mg/kg/day for an effect to slightly prolong PR intervals. 
Additionally, at Week 39, TAF appeared to reversibly reduce heart rate with an associated mild 
QT prolongation. At Week 39, significant decreases in serum tri-iodothyronine (T3) were noted 
for animals receiving 18/12 mg/kg/day when compared to controls, which may have been 
associated with the slight prolongation of PR intervals. After the 3-month recovery period, serum 
T3 values returned to levels similar to the control group animals at the end of the study.
TAF was not genotoxic in either in vitro or in vivo assays. TAF fumarate had no adverse effects 
on male or female fertility parameters in rats. There was no effect on fetal viability or fetal 
development in pregnant rats administered doses of TAF monofumarate up to 200 mg/kg/day or 
in pregnant rabbits administered TAF monofumarate up to 100 mg/kg/day the highest doses 
tested. In the rat, a minor (7.7%) decrease in mean fetal body weight compared to the control 
group was observed at 200 mg/kg/day, which was a maternally toxic dose. At the NOAEL for 
embryo-fetal development of 200 mg/kg/day in rats, AUCtau values for TAF and TFV on Day 17 
were 0.65 and 35.7 μg•h/kg, respectively. At the NOEL for embryo-fetal development of 
100 mg/kg/day in rabbits, AUCtau values for TAF and TFV on Day 20 were 
10.7 and 23.5 μg•h/kg, respectively. The TFV exposures in both species were > 30-fold higher 
than the TFV AUCinf after a 25-mg dose of TAF monofumarate in humans.
For further information on TAF, (GS-7340), refer to the current investigator’s brochure for TAF.
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
As of December 2015, a total of 1286 subjects have received at least 1 dose of TAF 25 mg in the 
TAF clinical program, including 866 subjects in the TAF Phase 3 studies in subjects with CHB 
and 420 subjects in TAF single-agent Phase 1 studies. The TAF clinical development program 
for CHB includes 2 ongoing Phase 3 studies in HBeAg-negative and HBeAg-positive subjects 
with CHB, a completed Phase 1b antiviral activity and safety/tolerability study in subjects with 
CHB, as well as several completed Phase 1 safety, pharmacokinetics (PK)/pharmacodynamics 
(PD), and drug interaction studies in healthy subjects (including Chinese and Japanese subjects) 
and in subjects with impaired renal or hepatic function.
In some studies, TAF was administered as a single agent or as part of the F/TAF, 
FTC/RPV/TAF, or E/C/F/TAF FDC tablets.


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TAF clinical studies are listed below:

GS-US-320-0101, a Phase 1b study to evaluate the pharmacokinetics, safety, viral kinetics, 
and anti-HBV activity of TAF in treatment-naive adults with CHB (completed) 
{Agarwal et al 2015} (completed)

GS-US-320-1228, a Phase 1 study to evaluate the pharmacokinetics, safety, and tolerability 
of TAF in healthy Japanese and non-Japanese subjects (completed)

GS-US-320-1229, a Phase 1 study to evaluate the pharmacokinetics of a single dose and 
repeat doses of TAF 25 mg in healthy Chinese subjects (completed; data analysis is ongoing)

GS-US-320-1382, a Phase 1 study to evaluate the effect of food on a single dose of TAF 
25 mg in healthy subjects (completed)

GS-US-320-1615, a Phase 1 study to evaluate the pharmacokinetics of a single dose of TAF 
25 mg in subjects with severe hepatic impairment and subjects with normal liver function 
(completed)

GS-US-320-0108, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg once 
daily versus TDF 300 mg once daily for the treatment of HBeAg-negative subjects with CHB 
(ongoing)

GS-US-320-0110, a Phase 3 study to evaluate the safety and efficacy of TAF 25 mg once 
daily versus TDF 300 mg once daily for the treatment of HBeAg-positive subjects with CHB 
(ongoing)

GS-US-320-1092, a Phase 2/3 study to evaluate the pharmacokinetics, safety, and antiviral 
Efficacy of TAF in Adolescents with Chronic Hepatitis B Virus Infection (ongoing)

GS-US-320-3912, a Phase 2 study to evaluate the efficacy and safety of TAF versus TDF 
300 in subjects with CHB and Stage 2 or greater chronic kidney disease who have received a 
liver transplant

GS-US-120-0107, a Phase 1, Partially-Blinded, Randomized, Placebo- and 
Positive-Controlled Study to Evaluate the Effect of GS-7340 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 TAF in subjects with severe renal impairment (completed)

GS-US-120-0109, a Phase 1 mass balance study to evaluate the pharmacokinetics, 
metabolism and excretion of TAF in healthy subjects (completed)

GS-US-120-0114, a Phase 1 study to evaluate the pharmacokinetics of TAF in subjects with 
normal, mild, and moderately impaired hepatic function (completed)


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
GS-US-120-1538, a Phase 1 pharmacokinetic study that evaluated the drug interaction 
potential between TAF and MDZ (oral and intravenous) in healthy subjects (completed)

GS-US-120-1554, a Phase 1 pharmacokinetic study that evaluated the drug interaction 
potential between TAF and RPV in healthy subjects (completed)

GS-US-311-1386, a Phase 1 study that evaluated the effect of food on the PK of TAF and 
FTC when administered as an F/TAF fixed-dose combination tablet in healthy subjects 
(completed)

GS-US-311-1387, a Phase 1 study that evaluated the drug-drug interaction (DDI) potential 
between CBZ and TAF administered as F/TAF in healthy subjects (completed)

GS-US-311-1790, a Phase 1 study that evaluated the DDI potential between F/TAF or 
GS-9883 and norgestimate/ethinyl estradiol in healthy female subjects (completed)
Please refer to the latest version of the investigator’s brochure for information on the clinical 
program.
An overview of the 2 Phase 3 studies evaluating the efficacy and safety of TAF in Marketing 
Applications is provided in Table 1-1. The Phase 3 studies are described below as follows:

GS-US-320-0108: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-negative subjects.

GS-US-320-0110: This ongoing Phase 3, randomized, double-blind, noninferiority, 
international, multicenter study is comparing the efficacy, safety, and tolerability of TAF 
25 mg once daily versus TDF 300 mg once daily for 48 weeks for the treatment of CHB 
infection in treatment-naive and treatment-experienced HBeAg-positive subjects.
In both of these similarly designed noninferiority studies, subjects were randomized in a 2:1 ratio 
to receive either TAF 25 mg or TDF 300 mg once daily for 96 weeks. Randomization was 
stratified by plasma HBV DNA level (< 7, ≥ 7 to < 8, and ≥ 8 log10 IU/mL for 
Study GS-US-320-0108; < 8 and ≥ 8 log10 IU/mL for Study GS-US-320-0110) and OAV 
treatment status (treatment naive vs treatment experienced) at screening. In both studies, all 
subjects completing 96 weeks of double-blind therapy are eligible to continue open-label 
treatment with TAF 25 mg for an additional 48 weeks. Both protocols were amended in 
February 2016 (Amendment 3 of GS-US-320-0108 and GS-US-320-0110) to extend the 
double-blind period to 144 weeks (3 years) and the open-label phase from Week 144 to 
Week 384 (8 year total study period).


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Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen 
(Number of Subjects)
Data Presented
GS-US-320-0108
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-negative subjects with CHB
TAF 25 mg once daily (N = 285)
TDF 300 mg once daily (N = 140)
Week 48 efficacy, 
PK, and safety
GS-US-320-0110
Phase 3, randomized, double-blind 
study to evaluate the safety and 
efficacy of TAF vs TDF in 
HBeAg-positive subjects with CHB
TAF 25 mg once daily (N = 581)
TDF 300 mg once daily (N = 292)
Week 48 efficacy, 
PK, and safety
Demographic and disease characteristics were generally similar between the TAF and TDF 
groups in both studies and are representative of patient population of HBeAg-negative subjects 
in Study GS-US-320-0108 and HBeAg-positive subjects in Study GS-US-320-0110. In both 
studies the majority of subjects were male (> 60%) and Asian (> 70%). As would be expected 
based on the 2 distinct study populations, subjects in Study GS-US-320-0108 were older 
(median age: 47 years; range: 19-80 years) than subjects in Study GS-US-320-0110 (median age: 
36 years; range: 18-69 years). Differences in baseline characteristics between the 2 studies 
included HBV DNA levels (median levels were 5.7 and 7.9 log10 IU/mL for GS-US-320-0108
and GS-US-320-0110, respectively), serum ALT levels (median values were 67 and 85 U/L for 
GS-US-320-0108 and GS-US-320-0110, respectively), and number of years positive for HBV 
(6.0 and 4.0 years [median values] for GS-US-320-0108 and GS-US-320-0110, respectively). 
The distribution of HBV genotypes was similar between treatment groups in both studies with 
the most common genotypes being C (46.1%), D (24.3%), and B (20.4%).
Efficacy of TAF in Subjects with CHB
Primary Endpoint Analysis
For both studies, the primary efficacy endpoint was the proportion of subjects with plasma
HBV DNA < 29 IU/mL at Week 48. Table 1-2 presents HBV DNA outcomes for
Studies GS-US-320-0108 {Buti et al 2016} and GS-US-320-0110 {Chan et al 2016} for subjects 
at Week 48. In both studies, similar rates of HBV DNA suppression were achieved in the 
2 treatment groups when assessed using the M = F method at Week 48 for the Full Analysis Set
(FAS). The percentages of subjects with HBV DNA levels < 29 IU/mL at Week 48 were as 
follows:

Study GS-US-320-0108: TAF 94.0%, TDF 92.9%; difference in proportions 
(baseline stratum-adjusted): 1.8%, 95% CI: −3.6% to 7.2%

Study GS-US-320-0110: TAF 63.9%, TDF 66.8%; difference in proportions
(baseline stratum-adjusted): −3.6%, 95% CI: −9.8% to 2.6%


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In both studies, because the lower bound of the 2-sided 95% CI of the difference (TAF − TDF)
in the response rate was greater than the prespecified −10% margin, the TAF group met the
primary endpoint of noninferiority to the TDF group.
Table 1-2.
GS US 320 0108 and GS US 320 0110: HBV DNA Outcome at 
Week 48 Using HBV DNA of < 29 IU/mL, Missing = Failure 
(Full Analysis Set)
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
(N = 285)
TDF 300 mg
(N = 140)
TAF 25 mg
(N = 581)
TDF 300 mg
(N = 292)
HBV DNA < 29 IU/mL
268 (94.0%)
130 (92.9%)
371 (63.9%)
195 (66.8%)
P-valuea
0.47
0.25
Difference in Proportions (95% CI)b
1.8% (−3.6% to 7.2%)
−3.6% (−9.8% to 2.6%)
HBV DNA ≥ 29 IU/mL
7 (2.5%)
4 (2.9%)
183 (31.5%)
88 (30.1%)
No Virologic Data at Week 48
10 (3.5%)
6 (4.3%)
27 (4.6%)
9 (3.1%)
Discontinued Study Drug Due to Lack of Efficacy
0
0
1 (0.2%)
0
Discontinued Study Drug Due to AE/Death
3 (1.1%)
1 (0.7%)
6 (1.0%)
3 (1.0%)
Discontinued Study Drug Due to Other Reasonsc
6 (2.1%)
4 (2.9%)
19 (3.3%)
6 (2.1%)
Missing Data During Window but on Study Drug
1 (0.4%)
1 (0.7%)
1 (0.2%)
0
a
P-value for the superiority test comparing the percentages of HBV DNA < 29 IU/mL was from the CMH test stratified by 
baseline HBV DNA categories and oral antiviral treatment status strata.
b
Difference in the proportion between treatment groups and its 95% CI were calculated based on the MH proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
c
Discontinuation due to other reasons included subjects who prematurely discontinued study drug due to investigator's 
discretion, withdrew consent, lost to follow-up, noncompliance with study drug, protocol violation, pregnancy, and study 
termination by sponsor.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Table 12; GS-US-320-0110 Week 48 CSR, Section 15.1, Table 12. 
Biochemical Analyses
Table 1-3 presents the proportion of subjects with ALT normalization at Week 48 for both 
studies (GS-US-320-0108) and (GS-US-320-0110) when determined by central laboratory 
criteria and by AASLD criteria (upper limit of normal range: ≤ 30 U/L for males and ≤ 19 U/L 
for females {Lok et al 2009, Terrault et al 2015}), respectively.
For Study GS-US-320-0108, the percentage of subjects with normalized ALT (i.e., ALT > ULN 
at baseline but within the normal range at Week 48) using the central laboratory criteria was 
numerically higher for the TAF group compared with the TDF group for all time points from 
Weeks 4 through 48. When assessed at Week 48, rates of ALT normalization were not 
significantly different between the 2 treatment groups by the Missing = Failure (M = F) method 
for the Full Analysis Set (FAS). Using the AASLD criteria, the percentage of subjects with 
normalized ALT was significantly higher in the TAF group than in the TDF group at for all time 
points from Week 8 onward using the M = F method.


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For Study GS-US-320-0110, the percentage of subjects with normalized ALT using the central 
laboratory criteria was numerically higher for the TAF group compared with the TDF group for 
all time points from Weeks 8 through 48. When assessed at Week 48, rates of normalization 
were not significantly different between the 2 treatment groups by the M = F method for the 
FAS. Using the AASLD criteria, the percentage of subjects with normalized ALT was 
significantly higher in the TAF group than in the TDF group for all time points from 
Weeks 8 through 48 using the M = F method.
Overall, the percentage of subjects with normalized ALT at Week 48 was higher in 
Study GS-US-320-0108 compared with Study GS-US-320-0110 using the central laboratory 
criteria and similar across the 2 studies using the AASLD criteria.
Table 1-3.
GS-US-320-0108 and GS-US-320-0110: Proportion of Subjects with 
ALT Normalization at Week 48, Missing = Failure (Full Analysis Set 
with Baseline ALT > ULN)
Normalized ALT
GS-US-320-0108
GS-US-320-0110
TAF 25 mg
TDF 300 mg
TAF 25 mg
TDF 300 mg
Central Laboratorya
(N = 236)
(N = 121)
(N = 537)
(N = 268)
Week 48
196/236 (83.1%)
91/121 (75.2%)
384/537 (71.5%)
179/268 (66.8%)
Proportion Difference (95% CI)
8.0% (−1.3% to 17.2%)
4.6% (−2.3% to 11.4%)
p-value
0.076
0.18
AASLDb
(N = 276)
(N = 138)
(N = 572)
(N = 290)
Week 48
137/276 (49.6%)
44/138 (31.9%)
257/572 (44.9%)
105/290 (36.2%)
Proportion Difference (95% CI)
17.9% (8.0% to 27.7%)
8.7% (1.8% to 15.6%)
p-value
< 0.001
0.014
a
Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males
≥69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.
b
AASLD ULN for ALT criteria are as follows: ≤ 30 U/L for males and ≤ 19 U/L for females.
P-value was from the Cochran-Mantel-Haenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment 
status strata
Difference in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel proportions 
adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Source: GS-US-320-0108 Week 48 CSR, Section 15.1, Tables 23.1.1 and 23.2.1; GS-US-320-0110 Week 48 CSR, Section 15.1, 
Tables 23.1.1 and 23.2.1
Serological Analyses
In Study GS-US-320-0108, no subject in either treatment group experienced HBsAg loss by
Week 48. In Study GS-US-320-0110, 4 subjects (0.7%) in the TAF group and 1 subject (0.3%)
in the TDF group experienced HBsAg loss at Week 48. Three of the 4 subjects in the TAF group
and none in the TDF group also experienced HBsAg seroconversion at Week 48.


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In Study GS-US-320-0110, the proportion of subjects with HBeAg loss or seroconversion to
anti-HBe at Week 48 was also evaluated; these data are presented on Table 1-4. A total of
78 (13.8%) and 34 (11.9%) subjects in the TAF and TDF groups, respectively, had HBeAg loss
at Week 48. A total of 58 (10.3%) and 23 (8.1%) subjects in the TAF and TDF groups,
respectively, experienced HBeAg seroconversion at Week 48.
Table 1-4.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or 
Seroconversion at Week 48, Missing = Failure 
(Serologically Evaluable Full Analysis Set)
GS-US-320-0110
TAF 25 mg
(N = 565)
TDF 300 mg
(N = 285)
TAF 25 mg vs TDF 300 mg
p-value
Prop Diff
(95% CI)
HBeAg Loss, n (%)
78/565 (13.8%)
34/285 (11.9%)
0.47
1.8%
(−3.0% to 6.5%)
HBeAg Seroconversion, n (%)
58/565 (10.3%)
23/285 (8.1%)
0.32
2.1%
(−2.0% to 6.3%)
P-values were from the Cochran-Mantel-Haenszel test stratified by baseline HBV DNA categories and oral antiviral treatment 
status. Differences in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel 
proportions adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion included subjects who were HBeAg positive and 
HBeAb negative/missing at baseline. HBeAg loss was defined as changes from HBeAg-positive at baseline to HBeAg-negative 
at a post-baseline visit with baseline anti-HBe negative/missing. HBeAg seroconversion was defined as HBeAg loss and 
anti-HBe change from negative/missing at baseline to positive at a post-baseline visit.
Source: GS-US-320-0110 Week 48 CSR, Section 15.1, Table 19.1
Virologic Resistance Analysis
In an integrated analysis of Studies GS-US-320-0108 and GS-US-320-0110, 24 subjects (2.8%)
in the TAF group and 14 subjects (3.2%) in the TDF group qualified for population-based
sequence analysis after up to 48 weeks of treatment. Among the 24 subjects in the TAF group
who qualified for population-based sequence analysis, 15 had no changes detected in the pol/RT
sequence from baseline, 4 were unable to be sequenced, and 5 had polymorphic site
substitutions. Among the 14 subjects in the TDF treatment group who qualified for
population-based sequence analysis, 6 had no changes detected in the pol/RT sequence from
baseline, 4 were unable to be sequenced, 2 had polymorphic site substitutions, and 2 had a 
conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated with 
resistance to TFV were detected by sequencing and phenotypic analysis through 48 weeks of the 
study in either treatment group.
Safety of TAF in CHB Subjects
The principal sources of safety data for TAF are presented above in Table 1-1 and consist of 
2 Phase 3 studies in subjects with CHB, Study GS-US-320-0108 and GS-US-320-0110. Subjects
included in the Safety Analysis Set received at least 1 dose of study drug.


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Overall Extent of Exposure
Of the 2387 subjects screened in Studies GS-US-320-0108 and GS-US-320-0110 combined,
1301 were randomized (TAF 867 subjects; TDF 434 subjects), and 1298 received at least 1 dose
of study drugs (TAF 866 subjects; TDF 432 subjects); 3 subjects (TAF 1 subject; TDF 
2 subjects) did not receive study drug due to withdrawal of consent. As of the Week 48 data
cutoff date for each Phase 3 study, a total of 1208 subjects (TAF 93.1%, 806 subjects; 
TDF 93.1%, 402 subjects) were continuing double-blind study drugs, and 27 subjects
(TAF 2.1%, 18 subjects; TDF 2.1%, 9 subjects) had entered the open-label phase as of the
Week 48 data cutoff date. Of the 1298 subjects randomized and treated, 63 subjects (4.9%)
discontinued blinded study drugs (TAF 4.8%, 42 subjects; TDF 4.9%, 21 subjects), and
61 subjects (TAF 40 subjects; TDF 21 subjects) discontinued from the study prior to the
Week 48 data cutoff date. Similar rates of discontinuation and reasons for treatment
discontinuation were observed for TAF compared with TDF. The most common reasons for
premature discontinuation of blinded study treatment were withdrew consent (TAF 1.6%,
14 subjects; TDF 1.6%, 7 subjects); adverse event (AE; TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects); and lost to follow-up (TAF 0.7%, 6 subjects; TDF 0.7%, 3 subjects). The most
common reasons for discontinuation from the study were: subjects withdrew consent (TAF 2.0%,
17 subjects; TDF 2.1%, 9 subjects), lost to follow-up (TAF 0.8%, 7 subjects; TDF 0.7%, 
3 subjects), and AEs (TAF 0.3%, 3 subjects; TDF 0.9%, 4 subjects).
Table 1-5 summarizes the duration of exposure to blinded study drug in the TAF Phase 3 Safety
Population. Median (first quartile [Q1], third quartile [Q3]) exposures were nearly identical
between the 2 treatment groups (TAF 56.1 [48.1, 64.4] weeks; TDF 56.1 [48.1, 64.7] weeks.
More than half of the subjects in each treatment group had received blinded study drug for
≥56 weeks at the time of the Week 48 data cutoff date for each Phase 3 study (TAF 60.5 %,
524 subjects; TDF 62.0 %, 268 subjects). There was no statistically significant difference
between groups in the overall Kaplan-Meier estimate of time to premature discontinuation of
blinded study drug.


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Table 1-5.
GS-US-320-0108 and GS-US-320-0110: Subjects Exposed to Study 
Drug for the TAF Phase 3 Safety Population (Safety Analysis Set)
Duration of Exposure to Study Regimen (Weeks)
GS-US-320-0108 and GS-US-320-0110
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
N
866
432
Mean (SD)
58.9 (14.71)
59.0 (15.58)
Median
56.1
56.1
Q1, Q3
48.1, 64.4
48.1, 64.7
Min, Max
0.1, 96.3
0.1, 96.3
Total Exposure to Study Drug n(%)
≥ 4 Weeks [28 days]
860 (99.3%)
426 (98.6%)
≥ 8 weeks [56 days]
858 (99.1%)
426 (98.6%)
≥ 12weeks [84 days]
854 (98.6%)
423 (97.9%)
≥ 16 Weeks [112 days]
851 (98.3%)
422 (97.7%)
≥ 20 Weeks [140 days]
851 (98.3%)
422 (97.7%)
≥ 24 Weeks [168 days]
851 (98.3%)
419 (97.0%)
≥ 28 Weeks [196 days]
849 (98.0%)
418 (96.8%)
≥ 32 Weeks [224 days]
843 (97.3%)
418 (96.8%)
≥ 36 Weeks [252 days]
838 (96.8%)
418 (96.8%)
≥ 40 Weeks [280 days]
835 (96.4%)
418 (96.8%)
≥ 44 Weeks [308 days]
832 (96.1%)
418 (96.8%)
≥ 48 Weeks [336 days]
669 (77.3%)
346 (80.1%)
≥ 56 Weeks [392 days]
524 (60.5%)
268 (62.0%)
≥ 64 Weeks [448 days]
356 (41.1%)
174 (40.3%)
≥ 72 Weeks [504 days]
190 (21.9%)
92 (21.3%)
≥ 80 Weeks [560 days]
89 (10.3%)
46 (10.6%)
≥ 88 Weeks [616 days]
36 (4.2%)
24 (5.6%)
Duration of exposure to blinded study drug was the number of weeks between the first dose and the last dose of blinded study 
drug. If the last dose date of blinded study drug is missing for subjects prematurely discontinued blinded study drug, or for 
subjects still on blinded study drug, the latest of nonmissing blinded study drug start and end dates or clinic and laboratory visit 
dates (excluding open-label and treatment-free follow-up visits) was used to impute the last dose date of blinded study drug.
Source: TAF Week 48 ISS, Table 4


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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-6 presents an overall summary of AEs by treatment group for the TAF Phase 3 Safety 
Population. Similar percentages of subjects in each treatment group had experienced at least 
1 AE (TAF 70.2 %, 608 subjects; TDF 67.4%, 291 subjects) and had experienced at least
1 Grade 3 or 4 AE (TAF 4.5 %, 39 subjects; TDF 3.9 %, 17 subjects). In addition, 57 subjects
(TAF 4.2%, 36 subjects; TDF 4.9 %, 21 subjects) had at least 1 SAE, with no subjects
experiencing a treatment-related SAE. A similar percentage of subjects in each treatment group
experienced an AE leading to discontinuation of study drugs (TAF 1.0%, 9 subjects; TDF 1.2%,
5 subjects). No deaths occurred in any subject on treatment. There were 2 deaths which occurred
after treatment was discontinued and were considered non-treatment emergent (1 subject in each
treatment group).
Table 1-6.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of 
Adverse Events in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Adverse Events
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Subjects Experiencing Any AE
608 (70.2%)
291 (67.4%)
Subjects Experiencing Any Grade 2, 3, or 4 AE
221 (25.5%)
120 (27.8%)
Subjects Experiencing Any Grade 3 or 4 AE
39 (4.5%)
17 (3.9%)
Subjects Experiencing Any Study Drug-Related AE
123 (14.2%)
68 (15.7%)
Subjects Experiencing Any Grade 2, 3, or 4 Study Drug-Related AE
33 (3.8%)
21 (4.9%)
Subjects Experiencing Any Grade 3 or 4 Study Drug-Related AE
6 (0.7%)
2 (0.5%)
Subjects Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Subjects Experiencing Any Study Drug-Related SAE
0
0
Subjects Experiencing Any AE Leading to Premature Study Drug 
Discontinuation
9 (1.0%)
5 (1.2%)
Subjects Experiencing Any AE Leading to Dose Modification or 
Study Drug Interruption
17 (2.0%)
7 (1.6%)
Deatha
0
0
a
Treatment-emergent death refers to the death occurred between the first dose date and the last dose date (inclusive). Adverse 
events were mapped according to MedDRA Version 18.
Treatment-emergent AEs was defined as follows:
1)
Any AEs with onset date of on or after the study drug start date and no later than the study drug stop date for those who 
discontinued study drug permanently, or
2)
Any AE with an onset date on or after the study drugs start date for those who had not discontinued study drug permanently, 
or
3)
Any AEs leading to study drug discontinuation
Source: TAF Week 48 ISS, Table 6


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Common Adverse Events
Table 1-7 presents AEs reported for ≥ 5% of subjects for any treatment group by system organ
class (SOC) and preferred term (PT) in the TAF Phase 3 Safety Population. The rate and types of
AEs were similar in the 2 treatment groups. Overall, the 3 most frequently reported AEs by
treatment group were as follows:

TAF group — upper respiratory tract infection (9.9%, 86 subjects), nasopharyngitis 
(9.9%, 86 subjects), and headache (9.5%, 82 subjects)

TDF group — headache (8.3%, 36 subjects), upper respiratory tract infection
(7.4%, 32 subjects), and nasopharyngitis (7.2%, 31 subjects)
Table 1-7.
GS-US-320-0108 and GS-US-320-0110: Adverse Events Reported for
≥5% of Subjects in Either Treatment Group in the TAF Phase 3 
Safety Population (Safety Analysis Set)
Adverse Events by System Organ Class and Preferred Terma,b,c
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects Experiencing Any Adverse Event
608 (70.2%)
291 (67.4%)
Gastrointestinal disorders
227 (26.2%)
108 (25.0%)
Nausea
43 (5.0%)
22 (5.1%)
General disorders and administration site conditions
125 (14.4%)
62 (14.4%)
Fatigue
49 (5.7%)
23 (5.3%)
Infections and infestations
259 (29.9%)
121 (28.0%)
Upper respiratory tract infection
86 (9.9%)
32 (7.4%)
Nasopharyngitis
86 (9.9%)
31 (7.2%)
Nervous system disorders
149 (17.2%)
60 (13.9%)
Headache
82 (9.5%)
36 (8.3%)
Respiratory, thoracic and mediastinal disorders
106 (12.2%)
44 (10.2%)
Cough
55 (6.4%)
27 (6.3%)
a
Adverse events were mapped according to MedDRA Version 18.
b
SOC were presented alphabetically, and PT was presented by decreasing order of the total frequencies.
c
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 7
Adverse Events by Severity
The majority of AEs reported in the TAF Phase 3 Safety Population were Grade 1 or 2. A similar
percentage of subjects in each treatment group experienced at least 1 Grade 3 AE (TAF 4.5%,
39 subjects; TDF 3.9%, 17 subjects). No subjects in either group had a Grade 4 AE. The only
Grade 3 AE that occurred in more than 2 subjects in either treatment group were increased ALT
(TAF 0.6%, 5 subjects; TDF 0.7%, 3 subjects) and hepatocellular carcinoma (HCC)
(TAF 0 subjects; TDF 0.7%, 3 subjects). Four Grade 3 ALT increases (TAF 3 subjects;
TDF 1 subject) were assessed as related to study drug.


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Serious Adverse Events
Table 1-8 presents SAEs reported for > 1 subjects for any treatment group in the TAF Phase 3
Safety Population. A similar percentage of subjects experienced SAEs in each treatment group
(TAF 4.2%, 36 subjects; TDF 4.9%, 21 subjects). None of the SAEs were considered related to
study drugs by the investigators. Hepatocellular carcinoma was reported for 6 subjects
(TAF 0.1%, 1 of 866 subjects; TDF 1.2%, 5 of 432 subjects). Other SAEs reported in > 1 subject
in either treatment group were cellulitis, hand fracture, dizziness, and calculus ureteric.
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Serious Adverse Events by 
Treatment Regimen in > 1 Subject in the TAF Phase 3 Safety 
Population (Safety Analysis Set)
Preferred Terma,b
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Number of Subjects (%) Experiencing Any SAE
36 (4.2%)
21 (4.9%)
Hepatocellular carcinoma
1 (0.1%)
5 (1.2%)
Cellulitis
0
3 (0.7%)
Hand fracture
2 (0.2%)
0
Dizziness
2 (0.2%)
0
Calculus ureteric
2 (0.2%)
0
a
Adverse events were mapped according to MedDRA Version 18.
b
Multiple AEs were counted only once per subject for each SOC and PT, respectively.
Source: TAF Week 48 ISS, Table 14
Summary of Bone Safety
Bone safety was assessed in the TAF Phase 3 Safety Population due to decreases in bone mineral 
density (BMD) and mineralization defects that have been seen in subjects treated with TDF.
Summary of Fractures
In the TAF Phase 3 Safety Population, the incidence of fracture events was uncommon 
(TAF 0.7%, 6 of 866 subjects; TDF 0.2%, 1 of 432 subjects; p = 0.44). Six of the 7 reported 
fractures were associated with trauma and 1 subject, in the TAF group, had a spinal compression 
fracture identified incidentally on a computed tomography (CT) scan. In the TAF group, 
4 fractures were reported as SAEs (hand fracture [3 subjects] and 1 spinal compression fracture). 
In the TDF group, 1 fracture (lower limb fracture) was reported as an SAE. Of the 7 subjects 
who had fractures, 4 subjects in the TAF group (tibia fracture, spinal compression identified
incidentally, hand fracture [2 subjects]) had normal hip and spine BMD T-scores at all 
timepoints, 2 subjects in the TAF group (hand fracture and traumatic spinal compression 
fracture) had hip and/or spine baseline BMD T-scores consistent with osteoporosis at baseline, 
1 subject in the TDF group (lower limb fracture) had normal hip and spine BMD at baseline 
which worsened while on treatment. All fractures were considered unrelated to the study drugs 
by the investigators and, none resulted in discontinuation of study drugs.


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Summary of Bone Mineral Density
Percentage change from baseline in hip BMD and spine BMD were the first and second key 
alpha-controlled safety endpoints, respectively, for both studies. Subjects receiving TAF 
experienced significantly less BMD reduction than those receiving TDF. At Week 48, the mean 
(SD) percentage decreases from baseline were as follows:

Hip: TAF −0.163% (2.2437 %); TDF −1.860 % (2.4525 %)

Spine: TAF −0.570 % (2.9147 %); TDF −2.366 % (3.2051 %)
Table 1-9 presents measure of BMD at Week 48. Percentage changes from baseline in hip and 
spine BMD were the first and second key alpha-controlled safety endpoints in 
Studies GS-US-320-0108 and GS-US-320-0110. Mean percentage decreases from baseline in 
BMD at the hip or spine were smaller in the TAF group compared with the TDF group 
(p < 0.001). A lower percentage of subjects in the TAF group had a > 3% decrease in hip BMD 
compared with subjects in the TDF group (8.4% TAF; 26.7% TDF). Similarly, a lower 
percentage of subjects in the TAF group had a > 3% decrease in spine BMD compared with 
subjects in the TDF group (TAF 19.5%; TDF 38.1%). At Week 48, fewer subjects had 
≥7% decrease in hip BMD (TAF 0.4%; TDF 2.0%) and ≥ 5% decrease in spine BMD 
(TAF 6.3%; TDF 20.4%) in the TAF group compared with the TDF group.


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Table 1-9.
GS-US-320-0108 and GS-US-320-0110: Measures of Bone Mineral 
Density at Week 48 (Hip DXA Analysis Set and 
Spine DXA Analysis Set)
N
TAF 25 mg
N
TDF 300 mg
Hip DXA Analysis Set
Mean (SD) Percent Change in Hip BMD
807
−0.163 (2.2437)
404
−1.860 (2.4525)
P-Valuea
< 0.001
Difference in LSM
1.697 (1.420, 1.974)
Subjects with > 3% Decrease in Hip BMD, n (%)
807
68 (8.4%)
404
108 (26.7%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Hip BMD, n (%)
807
55 (6.8%)
404
8 (2.0%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Hip BMD, n (%)
807
383 (47.5%)
404
83 (20.5%)
Spine DXA Analysis Set
Mean (SD) Percent Change in Spine BMD
814
−0.570 (2.9147)
407
−2.366 (3.2051)
P-Valuea
< 0.001
Difference in LSM
1.796 (1.437, 2.155)
Subjects with > 3% Decrease in Spine BMD, n (%)
814
159 (19.5%)
407
155 (38.1%)
P-Valueb
< 0.001
Subjects with > 3% Increase in Spine BMD, n (%)
814
89 (10.9%)
407
11 (2.7%)
P-Valueb
< 0.001
Subjects with no Decrease (≥ Zero %Change) in Spine BMD, n (%)
814
331 (40.7%)
407
89 (21.9%)
DXA = dual-energy x-ray absorptiometry; LSM = least-squares mean
a
P-values, difference in least squares means, and its 95% CI were from the ANOVA model including treatment as a 
fixed effect.
b
P-values were calculated from the Cochran-Mantel-Haenszel test for ordinal data (row mean scores differ statistic was used).
Source: TAF Week 48 ISS, Tables 23.1.2, 23.2.2, 25.1, and 25.2 and Request 7633 Tables 2.1 and 2.2
Renal Safety
In the TAF Phase 3 Safety Population in Studies GS-US-320-0108 and GS-US-320-0110
(TAF 25 mg N = 866, TDF 300 mg N = 432; Total N = 1301), no cases of proximal renal
tubulopathy (including Fanconi syndrome) or renal failure were reported in either treatment
group. No subject in the TAF Phase 3 Safety population experienced a renal SAE or AE
resulting in discontinuation of study drugs while on study.
Summary of Renal Laboratory Parameters
Change from baseline in serum creatinine was the third key alpha-controlled safety endpoint.
Overall, increases from baseline in mean values for serum creatinine were smaller in the TAF
group compared with the TDF group. Mean (SD) changes from baseline at Week 48 were
0.010 (0.1140) mg/dL for the TAF group and 0.024 (0.0974) mg/dL for the TDF group
(p = 0.012). Graded serum creatinine abnormalities were reported for 6 subjects (0.7%) in the
TAF group; all of which were Grade 1 or 2. Of the 6 subjects, 5 subjects had isolated serum


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relevant medical history of hypertension and diabetes, had multiple instances of graded
creatinine elevations and eGFR ≤ 50 mL/min. No subjects in the TDF group had graded serum
creatinine elevations.
In the TAF group, decreases from baseline in median eGFRCG values were significantly smaller
compared with the TDF group. Median (Q1, Q3) changes from baseline at Week 48 were
−1.2 (−8.4, 7.5) mL/min in the TAF group and −5.4 (−12.0, 3.0) mL/min in the TDF group
(p < 0.001). The overall number of subjects who had any confirmed renal laboratory abnormality
(ie, confirmed increases from baseline in creatinine of at least 0.5 mg/dL, or eGFRCG below
50 mL/min, or confirmed phosphorus < 2 mg/dL, was small (TAF 0.6%, 5 subjects; TDF 1.6%,
7 subjects). Most instances were isolated, transient, and resolved without treatment.
Summary of Proteinuria by Urinalysis (Dipstick) and by Quantitative Assessment
A similar percentage of subjects in each treatment group had at least 1 recorded, graded
proteinuria by dipstick while on study; most of which were Grade 1. Table 1-10 presents a
summary of the quantitative markers of proteinuria, urine protein to creatinine ratio (UPCR) and
urine albumin to creatinine ratio (UACR). There was a significant difference between the
2 treatment groups in median percentage changes from baseline in 1 of the quantitative markers
of proteinuria UPCR at Week 48. The median (Q1, Q3) percentage change in UPCR was
6.0 (−31.0, 57.6) mg/g in the TAF group and 16.5 (−21.6, 72.4) mg/g in the TDF group
(p = 0.010). Although not statistically significant, the median percentage change from baseline in
UACR was lower in the TAF group compared with the TDF group. Median percentage changes
from baseline in the markers of proximal tubular dysfunction, urine retinol binding protein
(RBP) to creatinine ratio and urine beta-2-microglobulin to creatinine ratio were smaller in the
TAF group compared with the TDF group (p < 0.001 for the differences between the 2 groups at
Weeks 24 and 48).
Table 1-10.
GS-US-320-0108 and GS-US-320-0110: Renal Biomarkers to Urine 
Creatinine Ratios at Week 48 in the TAF Phase 3 Safety Population 
(Safety Analysis Set)
Parameter
Median Percentage Change (%) (Q1, Q3)
P-Valuea
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
UPCR (mg/g)
6.0 (−31.0, 57.6)
16.5 (−21.6, 72.4)
0.010
UACR (mg/g)
6.9 (−25.8, 46.7)
12.2 (−21.0, 63.5)
0.073
Urine RBP to Urine Creatinine Ratio (μg/g)
−0.3 (−23.2, 33.3)
25.1 (−7.9, 73.2)
< 0.001
Urine Beta-2-Microglobulin to Creatinine Ratio (μg/g)
−3.5 (−34.3, 32.0)
37.9 (−4.6, 152.4)
< 0.001
UACR = urine albumin to creatinine ratio; UPCR = urine protein to creatinine ratio
% Change = Change from baseline at a postbaseline visit/baseline × 100%.
a
P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.
Source: TAF Week 48 ISS, Tables 34.1, 34.2, 34.3, and 34.4


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Graded Laboratory Abnormalities
Most subjects participating in Studies GS-US-320-0108 and GS-US-320-0110 experienced at
least 1 laboratory abnormality of Grade 1 or higher (TAF 94.8%, 814 of 859 subjects; TDF
91.1%, 390 of 428 subjects). The majority of subjects had abnormalities that were Grade 1 or 2
at worst severity (TAF 63.4%, 545 subjects; TDF 61.7%, 264 subjects). Grade 3 laboratory
abnormalities occurred in 26.2% (225 subjects) in the TAF group and 22.4% (96 subjects) in the
TDF group; Grade 4 laboratory abnormalities were less common, occurring in 5.1% 
(44 subjects) in the TAF group and 7.0% (30 subjects) in the TDF group. In total, a similar 
percentage of subjects in each group had at least 1 Grade 3 or 4 laboratory abnormality 
(TAF 31.3%, 269 subjects; TDF 29.4%, 126 subjects).
Table 1-11 presents a summary of the subject incidence of Grade 3 or 4 serum chemistry or
urinalysis abnormalities reported for ≥ 1% in either treatment group for the overall TAF Phase 3
Safety Population. The only Grade 3 or 4 serum chemistry laboratory abnormality that occurred
in > 5% of subjects overall in each of the treatment groups individually was ALT elevation
(TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects). In the TDF group, Grade 3 or 4 elevations of
AST also occurred in > 5% of subjects overall (TAF 3.3%, 28 subjects; TDF 5.4%, 23 subjects).
Grade 3 urinalysis abnormalities included occult blood (TAF 7.7%, 66 subjects; TDF 7.0%,
30 subjects), urine erythrocytes (TAF 7.7%, 59 subjects; TDF 9.1%, 35 subjects), and urine
glucose (TAF 4.8%, 41 subjects; TDF 1.2%, 5 subjects). The majority of subjects (88.6%;
124 of 140 subjects) who had Grade 3 urine occult blood or urine erythrocytes were women of
child bearing potential (defined as age ≤ 54 years). The abnormalities were generally
asymptomatic and not associated with AEs; none of the events were considered related to study
drugs. Among the 41 subjects in the TAF group with Grade 3 urine glucose on treatment,
18 subjects (43.9%) had Grade 3 urine glucose at either screening or baseline, while the majority
of the remaining 23 subjects had a medical history relevant for diabetes mellitus and/or had a 
graded elevation in blood glucose, or experienced an isolated and transient occurrence of 
Grade 3 urine glucose.


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Table 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent 
Grade 3 or 4 Laboratory Abnormalities Reported for at Least 
1% of Subjects in Either Treatment Group in the Overall TAF 
Phase 3 Safety Population (Safety Analysis Set)
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Maximum Postbaseline Toxicity Grade (N)
859
428
Grade 3
225 (26.2%)
96 (22.4%)
Grade 4
44 (5.1%)
30 (7.0%)
Chemistry
Alanine Aminotransferase (N)
859
428
Grade 3
52 (6.1%)
27 (6.3%)
Grade 4
18 (2.1%)
13 (3.0%)
Amylase (N)
859
427
Grade 3
22 (2.6%)
9 (2.1%)
Aspartate Aminotransferase (N)
859
428
Grade 3
25 (2.9%)
18 (4.2%)
Grade 4
3 (0.3%)
5 (1.2%)
Creatine Kinase (N)
859
428
Grade 3
16 (1.9%)
7 (1.6%)
Grade 4
9 (1.0%)
6 (1.4%)
Fasting Glucose (Hyperglycemia) (N)
857
425
Grade 3
9 (1.1%)
0
Fasting LDL Cholesterol (N)
837
417
Grade 3
37 (4.4%)
1 (0.2%)
Nonfasting Glucose (Hyperglycemia) (N)
856
426
Grade 3
25 (2.9%)
7 (1.6%)
Urinalysis
Occult Blood (N)
859
426
Grade 3
66 (7.7%)
30 (7.0%)
Urine Erythrocytes (N)
768
386
Grade 3
59 (7.7%)
35 (9.1%)
Urine Glucose (N)
859
426
Grade 3
41 (4.8%)
5 (1.2%)
Denominator for percentage (N) is the number of subjects in the safety analysis set with at least 1 postbaseline laboratory value 
for the test.
Subjects were counted once for the maximum postbaseline severity for each laboratory test. For urinalysis (ie, urine glucose, 
urine protein, and urine RBC), the highest grade is Grade 3.
For nonfasting glucose, the maximum postbaseline toxicity grades, instead of treatment-emergent abnormalities, were 
summarized, because nonfasting glucose test was not done at baseline.
‘Hyper’ means high and ‘Hypo’ means low.
Source: TAF Week 48 ISS, Table 20
Hepatic Laboratory Abnormalities
In Studies GS-US-320-0108 and GS-US-320-0110 the incidence of graded hepatic laboratory
abnormalities through the Week 48 data cutoff date was generally lower for subjects in the TAF
group compared with subjects in the TDF group, and included ALT increased 


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(TAF 22.8%,196 subjects; TDF 30.4%, 130 subjects), AST increased (TAF 22.2%, 191 subjects; 
TDF 25.2%, 108 subjects), total bilirubin increased (TAF 12.7%, 109 subjects; TDF 10.0%, 
43 subjects), gamma-glutamyltransferase (GGT) increased (TAF 7.5%, 64 subjects; TDF 10.0%, 
43 subjects), alkaline phosphatase increased (TAF 2.2%, 19 subjects; TDF 5.4%, 23 subjects), 
and albumin decreased (TAF 0.9%, 8 subjects; TDF 1.9%, 8 subjects).
Hepatic laboratory abnormalities in both treatment groups were generally Grade 1 or 2 at
maximum severity; Grade 3 or 4 ALT abnormalities and Grade 3 or 4 AST abnormalities were
observed in lower percentages of subjects in the TAF group compared with the TDF group
(ALT: TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects; AST: TAF 3.3%, 28 subjects; TDF 5.4%,
23 subjects), while Grade 3 or 4 bilirubin elevations were observed in comparable percentages of
subjects in the TAF group (0.3%, 3 subjects) compared with the TDF group (0.2%, 1 subject).
Hepatic laboratory abnormalities were generally not associated with hepatic AEs.
Hepatic Flares
An ALT elevation was defined as treatment-emergent serum ALT > 2 × baseline value and
> 10 × ULN, with or without associated symptoms. Through Week 48, ALT elevations were
observed for 16 subjects (1.8%) in the TAF group and 9 subjects (2.1%) of subjects in the TDF
group. Most of the events were at isolated time points within the first 8 weeks of dosing and
resolved without recurrence while the subject remained on study drug. An ALT elevation that
was confirmed at 2 consecutive postbaseline visits was considered an ALT flare. The incidence
of these events was balanced between the treatment groups. Five subjects (0.6%) in the TAF
group and 4 subjects (0.9%) in the TDF group had a treatment-emergent ALT flare. With the
exception of 2 events, ALT flares occurred early in the dosing period; for 7 of the 9 subjects, the
ALT flares resolved without recurrence while the subject remained on study drug.
Metabolic Laboratory Parameters
Administration of TDF has been associated with lower fasting low-density lipoprotein (LDL) 
and high-density lipoprotein (HDL) as compared with other antiviral agents. As plasma TFV
exposures are approximately 90% lower with TAF administration than with TDF, fasting lipid
concentrations remained relatively stable through Week 48 in the TAF treatment group, while
TDF administration resulted in the expected lipid-lowering TFV effect, with decreases from
baseline in fasting lipid parameters observed in the TDF group. Median decreases from baseline
in total cholesterol, LDL, HDL, and triglycerides were greater in the TDF group than the TAF
group, with TDF subjects demonstrating reductions in all parameters at Week 48. The difference
between groups in median change from baseline was statistically significant a Week 48 for total
cholesterol, direct LDL, HDL, and triglycerides (p < 0.001). Median (Q1, Q3) changes from
baseline at Week 48 for fasting lipid parameters were as follows:

Total cholesterol: TAF −2 (−17, 17) mg/dL; TDF −24 (−42, −6) mg/dL

LDL: TAF 4 (−9, 20) mg/dL; TDF −9 (−25, 5) mg/dL

HDL: TAF −3 (−10, 2) mg/dL; TDF −9 (−17, −3) mg/dL

Triglycerides: TAF 6 (−13, 26) mg/dL; TDF −7 (−27, 10) mg/dL


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The median (Q1, Q3) change from baseline at Week 48 in total cholesterol to HDL ratio was
0.2 (−0.1, 0.5) in the TAF group and 0.2 (−0.2, 0.5) in the TDF group (p = 0.16 for the difference 
between treatment groups).
Eight subjects (0.9%) in the TAF group had Grade 3 elevated fasting cholesterol; 
7 of the 8 subjects had a history of hyperlipidemia and/or elevated fasting cholesterol at baseline.
There were no subjects with Grade 4 elevated fasting cholesterol in the TAF group, and none
with Grade 3 or 4 elevated fasting cholesterol in the TDF group. Thirty-seven subjects (4.4%) in
the TAF group and 1 subject (0.2%) in the TDF group had Grade 3 elevated fasting LDL.
Overall, changes in median values of total cholesterol, LDL, HDL, and triglycerides in the TAF
group were not clinically relevant, and none of the subjects with Grade 3 elevations in fasting
lipids had clinical AEs associated with lipid abnormalities.
1.3.
Information about Tenofovir Disoproxil Fumarate (TDF)
For further information on TDF (Viread®), refer to the current investigator’s brochure for TDF 
(Viread®).
1.4.
Rationale for This Study
Given improved treatment options for CHB, more patients are living longer lives while on 
prolonged treatment. However, as these patients age, comorbidities increase and they are at 
greater risk for bone and renal disease. Because TAF is more stable in plasma than TDF, and
also provides higher intracellular levels of the active phosphorylated metabolite TFV-DP to 
target cells (eg, HBV-infected hepatocytes) with approximately 90% lower circulating levels of 
TFV relative to TDF at therapeutically active doses {Agarwal et al 2015, Babusis et al 2013, 
Murakami et al 2015}, an improved safety profile has been demonstrated with TAF when 
compared with TDF through 48 Weeks {Buti et al 2016, Chan et al 2016}. In HIV infection, 
switching virologically suppressed (HIV RNA < 50 copies/mL) patients from TDF-based 
antiretroviral regimens to a once-a-day, single tablet TAF-based regimen E/C/F/TAF resulted in 
noninferior efficacy (i.e. maintenance of viral suppression) and improved bone mineral density 
and renal function at Week 48 compared with those who continued taking their TDF-based 
regimen {Mills et al 2016}.
Thus, patients with CHB, particularly those with advanced age, who are currently virally 
suppressed on TDF, may benefit from switching therapy to TAF by maintaining viral 
suppression while resulting in improved safety of bone and renal parameters compared to TDF
treatment.
1.5.
Risk/Benefit Assessment for the Study
This concept is supported by recent results of a large dataset of 1733 HIV-infected, treatment 
naive subjects randomized to receive treatment with the FDC of E/C/F/TAF or E/C/F/TDF [STB; 
Stribild®]). Renal and bone parameters were significantly less affected in subjects who received 
E/C/F/TAF compared with E/C/F/TDF {Sax et al 2015}. Moreover, in a large, prospective, 
randomized (2:1) open-label switch study in 1443 virally suppressed, HIV-infected subjects 


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(959 subjects randomized to E/C/F/TAF and 477 to continue TDF-based antiretroviral regimens), 
results at Week 48 showed that viral suppression was maintained while bone and renal 
parameters were significantly improved in the E/C/F/TAF group {Mills et al 2016}. In adult 
subjects with CHB, a global Phase 3 program for TAF consisting of 2 prospective, randomized, 
active-controlled studies with 1 each in HBeAg-negative (Study GS-US-320-0108) and 
HBeAg-positive (Study GS-US-320-0110) subjects is currently ongoing. Primary endpoint data 
shows that TAF is as effective as TDF for viral suppression at Week 48. In addition, renal and 
bone safety parameters were improved with TAF treatment relative to TDF. In a pooled analysis 
of both studies, patients receiving TAF experienced significantly smaller mean percentage 
decreases from baseline in hip and spine bone mineral density at week 48 (p < 0.001), and the 
median change in estimated glomerular filtration rate (eGFRCG) from baseline to week 48 was 
less with TAF compared with TDF (-1.2 mL/min vs. -5.4 mL/min; p < 0.001). In addition, 
significantly smaller changes in biomarkers of bone turnover (bone formation markers: 
osteocalcin, bone-specific alkaline phosphatase, and procollagen type 1 N-terminal propeptide, 
and the bone resorption marker, C-type collagen sequence) and quantitative markers of proximal 
tubular function (beta-2 microglobulin to creatinine and retinol binding protein to creatinine 
ratios) were seen in TAF subjects compared with TDF subjects at Week 48.
TDF has been used in clinical practice for the treatment of CHB for many years and its use and 
safety profile is very well understood by clinicians. Moreover, in ongoing HBV studies 
GS-US-320-0108 and GS-US-320-0110, subjects on TAF have similar rates of HBV DNA 
suppression as the TDF group, with TAF meeting the primary endpoint of noninferiority to the 
TDF group at Week 48. Thus, patients with CHB who are currently virally suppressed on TDF, 
should experience no greater risk as pertains to viral suppression by switching therapy to TAF
from TDF. Moreover, throughout the study, subjects will be closely monitored at intervals that 
are above those recommended by treatment guidelines for the use of TDF, therefore subjects 
who remain on TDF therapy will benefit from additional monitoring. 
For subjects receiving TAF, adult data from the Phase 3 studies indicates that TAF is safe and 
effective. 
The benefit/risk for this study is therefore considered positive.
1.6.
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 as follows:

To evaluate the efficacy of switching to tenofovir alafenamide (TAF) 25 mg QD versus 
continued tenofovir disoproxil fumarate (TDF) 300 mg QD in virologically suppressed 
subjects with chronic HBV as determined by the proportion of subjects with HBV DNA 
≥20 IU/mL (as defined by the modified US FDA-defined snapshot algorithm) at Week 24

To compare the safety and tolerability of switching to TAF 25 mg QD versus continued TDF 
300 mg QD in virologically suppressed subjects with chronic HBV at Week 24
The key secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the percent change from baseline in hip and spine BMD at Week 24

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 24
Other secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the percent change from baseline in hip and spine BMD at Weeks 48 and 96

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Weeks 48 and 96

To compare the safety and tolerability of switching to TAF 25 mg QD versus continued TDF 
300 mg QD for virologically suppressed subjects with chronic hepatitis B at Week 48

To evaluate the efficacy of switching to TAF 25 mg QD versus continued TDF 300 mg QD 
as determined by the proportion of subjects with HBV DNA ≥20 IU/mL (as defined by the 
modified US FDA-defined snapshot algorithm) at Weeks 48 and 96

To compare the serological response (loss of HBsAg and seroconversion to anti-HBs, and 
loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Weeks 24, 48, and 96

To compare biochemical response (normal ALT and normalized ALT) of switching to TAF 
25 mg QD versus continued TDF 300 mg QD at Weeks 24, 48, and 96


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
To compare the change in fibrosis as assessed by FibroTest® after switching to TAF 25 mg 
QD versus continued TDF 300 mg QD at Weeks 48 and 96

To evaluate the comparative open-label efficacy and safety of switching to TAF 25 mg QD 
from Week 48 through Week 96 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with continued TDF 300 mg QD for 48 weeks and then switched 
to open-label TAF 25 mg QD

To evaluate the proportion of subjects with HBV DNA < 20 IU/mL and target 
detected/not detected (i.e. < LLOD) at Weeks 24, 48, and 96
The exploratory objectives of this study are as follows:
 
 
 
PPD


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3.
STUDY DESIGN
3.1.
Study Treatment Plan and Regimen
This is a randomized, double-blind, multicenter, active-controlled study to evaluate the safety 
and efficacy of TAF 25 mg QD in virologically suppressed subjects who switch from TDF to 
TAF compared to continued TDF treatment.
Approximately 300 subjects (with approximately 50% of subjects being ≥50 years old) will be 
randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD and matched placebo of TDF 
300 mg QD or Gilead-provided TDF 300 mg QD and matched placebo of TAF 25 mg QD.
At randomization, subjects will be stratified by screening HBeAg status (HBeAg-negative vs. 
HBeAg-positive) and age (≥ 50 or < 50 years).

Treatment Arm A: approximately 150 subjects administered TAF 25 mg QD and matched 
placebo of Tenofovir DF (TDF) 300 mg QD

Treatment Arm B: approximately 150 subjects administered Gilead-provided TDF 300 mg 
QD and matched placebo of TAF 25 mg QD
The duration of double blind treatment is 48 weeks. All subjects who complete 48 weeks of 
treatment are eligible for participation in the open label TAF 25 mg extension period for an 
additional 48 weeks (through Week 96). During the double-blind period, subjects with a 
confirmed creatinine clearance by Cockcroft Gault Method (eGFRCG) < 50 ml/min, and > 20% 
decline in eGFR by CKD-EPI (cystatin C) compared to baseline 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 during the double blind phase of the study will have 
the study drug permanently discontinued. Subjects with confirmed eGFRCG < 50 mL/min will 
not undergo dose modification to every other day during the open-label TAF 25 mg extension 
period, nor will treatment be permanently discontinued for confirmed eGFRCG < 30 mL/min 
during the open-label extension period.
Subjects who permanently discontinue study drug (either prematurely or at the end of study 
[Week 96]) 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 appropriate 
alternative, HBV therapy, whichever occurs first. Use of appropriate, alternative HBV therapy is 
strongly encouraged.
Subjects with HBsAg loss, and 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 prior to Week 24 are not permitted to discontinue
study drug prior to the Week 24 visit. Subjects with HBsAg loss with confirmed seroconversion
will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule 
(Appendix 2) through Week 96/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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The primary analysis will occur at Week 24 with the primary efficacy endpoint being the 
proportion of subjects with HBV DNA ≥20 IU/mL, as determined by the modified US FDA-
defined snapshot algorithm.
An external, independent, multidisciplinary DMC will review the progress and safety of this 
study. The committee will convene after the last subject enrolled completes Week 24 of the 
study. However, Gilead will defer to the DMC for any decision to convene earlier or more 
frequently. At each meeting, the DMC will review routine safety and DXA data and will make 
recommendations regarding modification of the study treatment.
Subjects with a history of or current diagnosis of compensated cirrhosis (i.e. those with cirrhosis 
without laboratory or clinical evidence of decompensated liver disease) 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, a Fibrotest score ≥0.75, 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. The change in fibrosis as assessed by Fibrotest® will be performed in all 
subjects participating in the trial at Baseline, and Weeks 24, 48, and 96/ED.
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 biomarkers with study drug response, including efficacy and/or 
adverse events and to increase knowledge and understanding of the biology of chronic hepatitis 
B and related diseases. The specific analyses will include, but will not be limited to, the 
biomarkers 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.

Fasting Urine Biomarkers including, but not limited to, retinol binding protein (RBP) and
beta-2 microglobulin 

Fasting Serum Bone Biomarkers including, but not limited to, C-type collagen sequence 
(CTX) and procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected from all subjects in a fasted state at Baseline and 
Weeks 4, 12, 24, 48, 72, and 96/ED. Samples may be stored by Gilead Sciences for a period of 
15 years at the end of the study.


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3.2.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3.
End of Study
End of Study is defined as when the last subject has completed 96 weeks of treatment, or when 
the last subject has completed 96 weeks of treatment and up to 24 weeks of treatment free 
follow-up if appropriate, alternative anti-HBV treatment is not initiated after completing 
96 weeks of study treatment.
3.4.
Post Study Care
Once a subject has completed their study participation, the long-term care of the participant will 
return to the responsibility of their primary treating physicians.
PPD
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 300 subjects (with approximately 50% of subjects being ≥50 years old) will be 
randomized in a 1:1 ratio (A:B) to receive either TAF 25 mg QD and matched placebo of TDF 
300 mg QD or Gilead-provided TDF 300 mg QD and matched placebo of TAF 25 mg QD. 
4.2.
Inclusion 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; consent must 
be obtained prior to initiation of study procedures
2) Adult male and non-pregnant, non-lactating female subjects, ≥18 years of age 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 5).
3) Documented evidence of chronic HBV infection previously (e.g., documented HBsAg 
positive for more than 6 months)
4) Maintained on TDF 300 mg QD for at least 48 weeks, and as monotherapy for CHB for at 
least 24 weeks prior to screening and with viral suppression (HBV DNA < LLOQ) for a 
minimum of 12 weeks prior to Screening, and including a Screening HBV DNA value of
< 20 IU/mL (by central laboratory)
5) Estimated creatinine clearance ≥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)
6) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
7) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
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 5.
3) Co-infection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5) Current evidence of, or recent (≤5 years) history 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 > 5 × ULN
e) Albumin < 3.0 mg/dL
f)
INR > 1.5 × ULN (unless stable on anticoagulant regimen)
g) Total bilirubin > 2.5 × ULN
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator
9) Malignancy within 5 years prior to Screening, with the exception of specific cancers that are 
cured by surgical resection (e.g. basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible.
10) Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic 
agents, or agents capable of modifying renal excretion
11) Known hypersensitivity to study drugs, metabolites, or formulation excipients


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12) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
13) 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.
14) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
15) Use of any prohibited medications as described in Section 5.4. Subjects on prohibited 
medications who are otherwise eligible will need a wash out period of at least 30 days prior 
to the Baseline visit.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
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. Eligible subjects (n = 300) will be randomized 1:1 to receive either blinded TAF 
25 mg and TDF matched placebo (n = 150) or TDF 300 mg and TAF matched placebo (n = 150) 
for 48 weeks. Subjects will be stratified by HBeAg status (HBeAg-negative [and anti-HBe 
positive] vs. HBeAg-positive) and age (> 50 years vs. < 50 years). At Week 48, all subjects will 
be switched to open-label TAF 25 mg QD for an additional 48 weeks (through Week 96/ED). 
For the entire duration of the study, subjects and investigators 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 IXRS system 
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.
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 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) and TDF
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.
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.
5.2.2.
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 packing 
material. Each bottle is enclosed with a white, continuous thread, child-resistant polypropylene 
screw cap with an induction-sealed and aluminum-faced liner.


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Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice −Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
TAF, TDF, and their matched placebo tablets should be stored at controlled room temperature of 
25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage 
conditions are specified on the label. Until dispensed to the subjects, all bottles of study drugs 
should be stored in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.
5.3.
Dosage and Administration of Tenofovir Alafenamide (TAF) and TDF
Subjects will be randomly assigned (1:1) to receive one of the following treatments in a blinded 
fashion:

Treatment Arm A: approximately 150 subjects administered TAF 25 mg QD and matched 
placebo of Tenofovir DF (TDF) 300 mg QD

Treatment Arm B: approximately 150 subjects administered Gilead-provided TDF 300 mg 
QD and matched placebo of TAF 25 mg QD
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 or without food. 
Subjects taking TDF 300 mg QD with food prior to randomization should continue to take study 
drug with food; subjects taking TDF 300 mg QD without food prior to randomization should 
continue to take study drug without food during the study period.
Study drug should be administered after assessing adverse events and concomitant medication(s).


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5.4.
Prior and Concomitant Medications
Concomitant/previous medications taken within 30 days of screening, up to and including the 
date of the last study visit, need to be recorded in the source documents and eCRFs.
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:

Investigational agents or devices for any indication

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
Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e., P-gp) with study drug(s) may result in PK interactions.
Examples of representative medications which are prohibited from 21 days prior to Day 1 
through the end of treatment are listed below:
Table 5-1.
Disallowed Concomitant Medications
Medication Class
Prohibited Medications
Medications to be used with caution
Anticonvulsants
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin: may lower 
concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle 
(i.e., silymarin), Chinese herb 
sho-saiko-to (or Xiao-Shai-Hu-Tang)
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.


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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) bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP 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 bottles

Record the date, subject number, subject initials, the IMP bottle number dispensed

Record the date, quantity of used and unused IMP 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 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. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
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 3.1.
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 randomization to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment 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 with 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 hip and spine. The Baseline DXA scan can be performed at any time during the
Screening period to ensure the results are received prior to the first dose of the study drug 
and therefore should be completed at least 14 days prior to the Baseline visit

Blood sample for:
plasma HBV DNA (must be < 20 IU/mL at time of Screening to be eligible)
Serum chemistry and liver function tests, hematology, serum HBsAg (quantitative), 
HBV serology (qualitative HBsAg and HBeAg), ruling out 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 (i.e., 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 and drug screen
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
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 (including HBV disease 
and treatment history)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

Review concomitant medications

Review adverse events 


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
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 (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 
 and vitamin D assessment

Serum 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), 
 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI)

Complete the “Fracture Risk Assessment” (FRAX®) eCRF
6.3.
Treatment Assessments
6.3.1.
Double Blind Visits (Visit Window ± 3 days)
6.3.1.1.
Week 4

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications
PPD
PPD
PPD


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
Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

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), 
 

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), 
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

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
virology (resistance surveillance), 

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), 
PPD
PPD
PPD
PPD


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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 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 (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 
6.3.1.4.
Week 24 (visit window is – 14 days)

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

DXA scan of hip and spine (within −14 days of the expected visit date)

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
PPD
PPD


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
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 (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 

Health Related Quality of Life (HRQoL) Surveys (SF-36, WPAI and CLDQ) 
6.3.1.5.
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

Fasting blood sample for 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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 
PPD
PPD
PPD
PPD


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6.3.1.6.
Week 48 (visit window is −6 weeks)

Complete physical examination with 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 hip and spine (within −6 weeks of the expected visit date)

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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 

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), 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36, WPAI)

Retrieve blinded study drug and dispense open label study drug
PPD
PPD
PPD


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6.3.2.
Open Label Visits (Visit Window ± 7 days)
6.3.2.1.
Week 60

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 open label study drugs

Fasting blood sample for 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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg) virology 
(resistance surveillance), 

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), 
6.3.2.2.
Week 72

Complete physical examination with vital signs (blood pressure, pulse, respiration rate and 
temperature) and body weight

DXA scan of hip and spine (within ± 14 days of the expected visit date)

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense open label study drugs
PPD
PPD


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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

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
serum HBsAg (quantitative), HBV serology (qualitative HBeAg and HBsAg), virology 
(resistance surveillance),

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), 
6.3.2.3.
Week 96

Complete physical examination with 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 hip and spine (within ± 14 days of the expected visit date)

Review concomitant medications

Review adverse events 

Perform study drug accountability (no study drug will be dispensed at Week 96 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 (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 
 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®
PPD
PPD
PPD
PPD


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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), 

Health Related Quality of Life (HRQoL) Surveys (CLDQ, SF-36 and WPAI)
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 24 visit, will be followed off treatment every 4 weeks for
12 weeks and then per the original study visit schedule through Week 96/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 appropriate, alternative 
HBV therapy, whichever occurs first.
6.4.3.
Treatment-Free 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
 
 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine for urinalysis
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (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 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
PPD
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The ED Visit should be performed within 72 hours (i.e., visit window is ± 3 days) of the last 
study drug dose.

Complete physical exam with 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 visit date and is
done only if not done within the past 12 weeks of the ED visit

Review concomitant medications

Review adverse events 

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 (only collected if not done in the last 12 weeks)

Fasting urine sample for renal biomarkers (only collected if not done in the last 12 weeks)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (qualitative HBsAg and HBeAg), virology 
(resistance surveillance), 
 

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), 

Health Related Quality of Life (HRQoL) Surveys (SF-36, WPAI and CLDQ) are done only if 
not done within the past 24 weeks of the ED visit
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. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Unacceptable toxicity, 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
PPD
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
Subjects with confirmed creatinine clearance of < 30 mL/min during the double blind phase 
of the study will have their study drug permanently discontinued

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 24 are not permitted to discontinue 
study drug prior to the Week 24 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

Therapeutic failure 

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.7.
Other Evaluations
6.7.1.
Bone and Renal Markers
The following biological specimens will be collected in this study and will be used to evaluate 
the association of exploratory biomarkers with study drug response, including efficacy and/or 
adverse events and to increase knowledge and understanding of the biology of chronic 
hepatitis B and related diseases. The specific analyses will include, but will not be limited to, the 
biomarkers listed below. 

Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) urine 
Biomarkers including, but not limited to, retinol binding protein (RBP) and
beta-2 microglobulin 

Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) serum 
Bone Biomarkers including, but not limited to, C-type collagen sequence (CTX) and 
procollagen type 1 N-terminal propeptide (P1NP)
These specimens will be collected from all subjects at Baseline and Weeks 4, 12, 24, 48, 72, and 
96 or ED. 
 
 
PPD


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6.8.
Resistance Surveillance and Virologic Rebound Management
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for potential resistance 
mutations may be attempted for any subject with HBV DNA > 69 IU/mL at Baseline and for 
subjects who experience viremia (HBV DNA ≥69 IU/mL) at Weeks 24, 48, and 96/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 serum sample for potential resistance surveillance will be collected at 
each study visit. 
In the event of unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be asked 
to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound 
occurring within the first 12 weeks of the study, the next scheduled visit will used for follow up. 
For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 
within 2-3 weeks after the date of the original test that resulted with HBV DNA virologic 
rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for 
resistance testing will be obtained. For unscheduled visits, the subject will be required to bring 
their supply of study drug with them and be assessed for adherence by pill count, and if 
necessary, the subject will be re-counseled on adherence to study medication.


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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

Persistent or significant disability/incapacity


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
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 without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, 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 (eg, 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 (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.5. 
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 (eg, 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 (eg, 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, (eg., 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 4). 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 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
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 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 30-days after last administration of study IMP must be reported to the CRF/eCRF database 
as instructed.
All AEs should be followed up until resolution or until the adverse event 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 occurs 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 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after 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.
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 to:
Gilead DSPH:
Fax: 
Email: 
Medical Monitor:
Phone:
Fax:
Email:

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.

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.
PPD
PPD
PPD
PPD
PPD
PPD


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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 associated 
with any study IMP. 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 3.

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restarted at full dose or modified dose that is 
dependent upon discussion with the Gilead Sciences Medical Monitor.

Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

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.


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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.
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.


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7.5.5.
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
7.5.5.1.
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.
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). 


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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.
7.5.5.2.
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:

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. 
7.5.6.
Management of Ocular Safety
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. In the TAF HIV program, there is one 
report of SAEs of Grade 1 visual impairment and Grade 2 autoimmune uveitis in a 13 year-old 
female subject from Uganda in Study GS-US-292-0106. Onset of both events was Day 14 and 
both were considered related to study drug (E/C/F/TAF) by the investigator. The SAE of 
autoimmune uveitis resolved on Day 166, and the visual impairment was ongoing at Day 418 of 
study drug treatment.


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Across the TAF HBV Phase 3 Safety Population, eye disorders were uncommon and balanced 
between the treatment groups. None were indicative of posterior uveitis, and none resulted in 
permanent discontinuation of study drug. Nonetheless, if any subject participating in this study 
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).
7.5.7.
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, serum 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.
During the double-blind period, 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.
During the open-label TAF 25 mg extension period, subjects who meet the above eGFR criteria 
(i.e. confirmed CLCr ≥ 30 mL/min to < 50 mL/min and > 20% reduction from baseline in eGFR 
by CKD-EPI equation) are not required to undergo dose modification to every other day dosing 
of study drug, and subjects with confirmed CLCr < 30 mL/min are not required to permanently 
discontinue study drug.


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All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis are recommended to 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.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports of 
adverse events associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE and AE in an infant following exposure from breastfeeding.
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 and 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).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.
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.


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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 (eg, 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 Gilead DSPH 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:
 and Fax: 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
 or email 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
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 Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead 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.
PPD
PPD
PPD
PPD


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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 as follows:

To evaluate the efficacy of switching to tenofovir alafenamide (TAF) 25 mg QD versus 
continued tenofovir disoproxil fumarate (TDF) 300 mg QD in virologically suppressed 
subjects with chronic HBV as determined by the proportion of subjects with HBV DNA 
≥20 IU/mL (as defined by the modified US FDA-defined snapshot algorithm) at Week 24

To compare the safety and tolerability of switching TAF 25 mg QD versus continuing TDF 
300 mg QD in virologically suppressed subjects with chronic HBV at Week 24
The key secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the percent change from baseline in hip and spine bone mineral density 
(BMD) at Week 24

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Week 24
Other secondary objectives of this study are as follows: 

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the percent change from baseline in hip and spine bone mineral density 
(BMD) at Weeks 48 and 96

To compare the safety of switching to TAF 25 mg QD versus continued TDF 300 mg QD as 
determined by the change from baseline in estimated creatinine clearance by Cockcroft-Gault 
method (eGFRCG) at Weeks 48 and 96

To compare the safety and tolerability of switching to TAF 25 mg QD versus continued TDF 
300 mg QD in virologically suppressed subjects with chronic hepatitis B at Week 48

To evaluate the efficacy of switching to TAF 25 mg QD versus continued TDF 300 mg QD 
as determined by the proportion of subjects with HBV DNA ≥20 IU/mL (as defined by the 
modified US FDA-defined snapshot algorithm) at Weeks 48 and 96

To compare the serological response (loss of HBsAg and seroconversion to anti-HBs, and 
loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) of switching to 
TAF 25 mg QD versus continued TDF 300 mg QD at Weeks 24, 48, and 96


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
To compare biochemical response (normal ALT and normalized ALT) of switching to TAF 
25 mg QD versus continued TDF 300 mg QD at Weeks 24, 48, and 96

To compare the change in fibrosis as assessed by FibroTest® for switching to TAF 25 mg QD
versus continued TDF 300 mg QD at Weeks 48 and 96

To evaluate the comparative open-label efficacy and safety of switching to TAF 25 mg QD 
from Week 48 through Week 96 in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with continued TDF 300 mg QD for 48 weeks and then switched 
to open-label TAF 25 mg QD

To evaluate the proportion of patients with HBV DNA < 20 IU/mL and target detected/not 
detected (i.e. < LLOD) at Weeks 24, 48, and 96
The exploratory objectives of this study are as follows:
 
 
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with HBV DNA ≥20 IU/mL
(as determined by the modified US FDA-defined snapshot algorithm) at Week 24.
8.1.3.
Secondary Endpoint
The secondary efficacy endpoints are:

The proportion of subjects with HBV DNA ≥20 IU/mL (as determined by the modified 
US FDA-defined snapshot algorithm) at Weeks 48 and 96

The proportion of subjects with HBV DNA < 20 IU/mL and target detected/not detected
(i.e. < LLOD) at Weeks 24, 48 and 96, as determined by the modified US FDA-defined 
snapshot algorithm

The proportion of subjects with HBeAg loss and proportion with seroconversion to anti-HBe 
at Weeks 24, 48, and 96
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
The proportion of subjects with HBsAg loss and proportion with seroconversion to anti-HBs 
at Weeks 24, 48, and 96

The proportion of subjects with normal ALT and proportion with normalized ALT 
(by central laboratory and AASLD criteria) at Weeks 24, 48, and 96

The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48 and 96
The key secondary safety endpoints are:

The percent change from baseline in hip bone mineral density (BMD) at Week 24 

The percent change from baseline in spine bone mineral density (BMD) at Week 24

The change from baseline in eGFRCG (measured by Cockcroft-Gault method) at Week 24
The secondary safety endpoints are:

The percent change from baseline in hip bone mineral density (BMD) at Weeks 48 and 96

The percent change from baseline in spine bone mineral density (BMD) at Weeks 48 and 96

The change from baseline in eGFRCG (measured by Cockcroft-Gault method) at 
Weeks 48 and 96
8.1.4.
Other Endpoints of Interest

The change from baseline in serum markers of bone turnover at Weeks 24, 48, and 96

The change from baseline in urine markers of renal tubular dysfunction at 
Weeks 24, 48, and 96

The effect of treatment on health related to quality of life (via SF-36, CLDQ and WPAI 
questionnaires) at Weeks 24, 48 and 96
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
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.


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8.2.1.2.
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.
8.2.1.3.
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.
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.
8.2.1.5.
DEXA
8.2.1.5.1.
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.
8.2.1.5.2.
Spine DXA Analysis Set
The Spine DXA Analysis Set includes 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.
8.3.
Data Handling Conventions
For key secondary safety endpoints, an analysis will be performed using the last observation 
carried forward (LOCF) method to impute missing data.
For other categorical secondary efficacy endpoints, missing data will be handled using a 
missing = failure approach except for the endpoints of HBV DNA ≥ 20 IU/mL and HBV DNA 
< 20 IU/mL.
For the remaining endpoints, values for missing data will not be imputed, unless specified 
otherwise.
8.4.
Multiplicity Adjustments
To control type I error for the assessment of the primary efficacy endpoint and key secondary 
safety endpoints, the hypothesis testing will be performed in a sequential order. The primary 
hypothesis of non-inferiority of TAF 25 mg QD vs. TDF 300 mg QD with respect to the 
proportion of subjects with HBV DNA ≥ 20 IU/mL (as defined by the modified US FDA-defined 


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snapshot algorithm) at Week 24 will be tested first. The non-inferiority test will be performed 
using a two-sided, 0.05 alpha level. If non-inferiority is established, then multiplicity adjustments 
will be performed for the following endpoints using a fallback procedure {Wiens et al 2005} in 
the sequential order given below with a pre-specified two-sided alpha level:
a) Percentage change from baseline in Hip BMD at Week 24 (alpha = 0.02)
b) Percentage change from baseline in Spine BMD at Week 24 (alpha = 0.01)
c) Change from baseline in Creatinine clearance (eGFRCG) at Week 24 (alpha = 0.02)
d) Superiority test for proportion of subjects with HBV DNA ≥ 20 IU/mL at Week 24 
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8.5.
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, HBV DNA 
level, years positive for HBV, ALT level (≤ ULN, > ULN), previous TDF use and other oral 
nucleoside/nucleotide treatment experience, previous interferon experience, and HBV genotype 
by history.
8.6.
Efficacy Analysis
8.6.1.
Primary Analysis
The primary analysis will be performed when the last subject has completed Week 24 
assessments or discontinued prematurely. The primary analysis will consist of a non-inferiority 
evaluation of efficacy of TAF versus TDF, with respect to the proportion of subjects with HBV
DNA ≥20 IU/mL at Week 24 (as defined by the modified FDA snapshot Algorithm). It will be 
concluded that TAF is not inferior to the TDF if the upper bound of the two-sided 
95% confidence interval of the difference between treatment arms (TAF arm – TDF arm) in the 
response rate is less than 6% (i.e., a margin of 6% is applied to non-inferiority assessment). The 
95% confidence interval will be constructed using the normal approximation method based on 
stratified Mantel-Haenszel proportions, where stratification factors are HBeAg status 
(HBeAg positive or negative) and age (≥50 or < 50 years).
8.6.1.1.
Modified US FDA-Defined Snapshot Alogrithm
The US FDA-defined snapshot algorithm, developed for HIV-1 clinical trials, has been modified 
for use in HBV {U. S. Department of Health and Human Services et al 2015} using on-treatment 
HBV DNA values of < 20 IU/mL and ≥20 IU/mL.
The analysis window at Week 24 is defined as from Study Day 126 to Study Day 209, inclusive.
All HBV DNA data collected on-treatment will be used in the snapshot algorithm. Virologic 
outcome will be defined as the following categories: 

HBV DNA < 20 IU/mL: this includes subjects who have the last available on-treatment 
HBV DNA < 20 IU/mL in the Week 24 analysis window

HBV DNA ≥20 IU/mL: this includes subjects who
1) Have the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 24 analysis 
window, or
2) Do not have on-treatment HBV DNA data available in the Week 24 analysis window and


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a) Discontinue study drug prior to or in the Week 24 analysis window due to lack of 
efficacy, or
b) Discontinue study drug prior to or in the Week 24 analysis window due to reason
other than lack of efficacy and have the last available on-treatment HBV DNA 
≥20 IU/mL

No Virologic Data in the Week 24 Analysis Window: this includes subjects who do not
have on-treatment HBV DNA data available in the Week 24 analysis window for any of the 
following reasons:
1) Discontinuation of study drug prior to or within the Week 24 analysis window due to 
reasons other than lack of efficacy and the last available on-treatment HBV DNA value is 
< 20 copies/mL, or
2) Missing data within the window but who are on study drug treatment
8.6.2.
Analyses of Secondary Endpoints
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 may 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, 
may be used to compare the treatment groups, in an exploratory manner. Missing data will be 
handled by the missing = failure approach except for the endpoints of HBV DNA ≥20 IU/mL
and HBV DNA < 20 IU/mL.
8.7.
Safety Analysis
All safety data collected on or after the date that IMP was first dispensed up to the date of last 
dose of IMP will be summarized by treatment group (according to the IMP received). Data for 
the pretreatment and treatment-free follow-up periods will be included in data listings.
8.7.1.
Key Secondary Safety Analyses
The percent change from baseline in hip and spine BMD at Weeks 24 and 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 in eGFRCG at Weeks 24 and 48 will be analyzed using a 2-sided 
Wilcoxon rank sum test to compare the 2 treatment groups. The details are provided in the SAP.


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8.7.2.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP administration data. 
Exposure data will be summarized by treatment group.
8.7.3.
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 
IMP up to the date of last dose of IMP. 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
8.7.4.
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 4.


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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 IMP or after the subject has been 
discontinued from treatment will be included in a data listing.
8.8.
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.
8.9.
Sample Size
With respect to the primary efficacy endpoint of proportion of suppressed subjects with 
HBV DNA ≥20 IU/mL (current assay LLOQ), as determined by the modified US FDA-defined 
snapshot algorithm, at Week 24, when the sample sizes are 150 (TAF 25 mg arm) and 150 
(TDF 300 mg arm), a two-group, large-sample normal approximation test of proportions with a 
one-sided 0.025 significance level will have 97% power to establish non-inferiority of TAF to 
TDF. It is assumed that both treatment arms will have subjects who have HBV DNA ≥ 20 IU/mL 
(as defined by the modified US FDA-defined snapshot algorithm) at a rate of 1.8% at Week 24 
(based on the rates of suppressed subjects having HBV DNA ≥ 29 IU/mL [the LLOQ of assay 
during those studies] after 24 weeks of treatment from the combined data of studies GS-US-174-
0102 and GS-US-174-0103 with the ratio of HBeAg- to HBeAg+ subjects assumed to be 2:1), 
with a non-inferiority margin of 6%.
The proposed sample size (n = 150 for the TAF 25 mg arm, n = 150 for the TDF 300 mg arm) 
also provides > 99% power to detect a 1.21% difference in the percentage change from baseline 
in hip BMD at Week 24 (assuming a 0.99% [SD 2.09%] change from baseline in TAF 25 mg 
arm and −0.22% [SD 1.89%] change from baseline in the TDF 300 mg arm, with a two-sided 
α = 0.05); a > 99% power to detect a 1.69% difference in the percentage change from baseline in 
spine BMD at Week 24 (assuming a 1.50% [SD 2.80%] change from baseline in the TAF 25 mg 
arm and −0.19% [SD 3.00%] change in the TDF 300 mg arm, with a two-sided α = 0.05); 
a 68% power to detect a 3.6 mL/min difference in the change from baseline in eGFRCG at 
Week 24 (assuming a +1.6 mL/min [SD 13.0] change from baseline in the TAF 25 mg arm and 
−2.0 mL/min [SD 12.4] change from baseline in the TDF 300 mg arm, with a two-sided 
α = 0.05). These assumptions were derived from an HIV switch study (GS-US-292-0109) due to 
the unavailability of switch data from TAF HBV studies.


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8.10.
Data Monitoring Committee
An external, independent, multidisciplinary DMC will convene and review the progress and 
safety of this study after the last subject enrolled completes 24 weeks of the study. However, 
Gilead will defer to the DMC for any decision to convene earlier or more frequently. At each
meeting, the DMC will review routine safety and DXA data and will make recommendations 
regarding modification of the study treatment.
The DMC’s specific activities will be defined by a mutually agreed 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 treatment.


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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, 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 subinvestigators 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 subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Ethics Committee (EC) 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/EC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC/EC 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/EC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial 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 
investigator must use the most current IRB/IEC/EC approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 


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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/IEC/EC. 
 
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/IEC/EC, 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 for further details. 
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, 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);

Documentation of the reason(s) a consented subject is not enrolled
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
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. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. 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 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 


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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
At the start of the study, the study monitor will evaluate the 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. 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 IRB/IEC/EC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC/EC
in accordance with local requirements and receive documented approval from all necessary 
bodies before modifications can be implemented.


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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.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with 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.


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Gilead Sciences, Inc.
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9.3.3.
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.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
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10.
REFERENCES
Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et al. Twenty-eight day safety, 
antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of 
chronic hepatitis B infection. J Hepatol 2015;62 (3):533-40.
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.
Buti M, Gane E, Seto WK, Chan HLY, Chuang WL, Stepanova T, et al. Tenofovir alafenamide 
versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-
negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, 
non-inferiority trial. Lancet 2016.
Centers for Disease Control (CDC), Division of Viral Hepatitis. Viral Hepatitis Surveillance 
United States, 2013.  2013.
Chan HLY, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide 
versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic 
hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority 
trial. Lancet 2016.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection [published version]. J 
Hepatology 2012;57:167-85.
Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on 
disease progression and prognostic factors. J Hepatol 2008;48 (2):335-52.
Foran JA. Principles for the Selection of Doses in Chronic Rodent Bioassays. Environ Health 
Perspect 1997;105 (1):18-20.
G. B. D. Mortality Causes of Death Collaborators. Global, regional, and national age-sex specific 
all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a 
systematic analysis for the Global Burden of Disease Study 2013. Lancet 
2015;385 (9963):117-71.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
2015;1 (4):505-27.
Kitrinos KM, Corsa A, Liu Y, Flaherty J, Snow-Lampart A, Marcellin P, et al. No detectable 
resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with 
chronic hepatitis B. Hepatology 2014;59 (2):434-42.


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
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Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. 
Hepatol International 2012;6:531-61.
Lok AS, McMahon BJ. AASLD Practice Guideline Update: Chronic hepatitis B: update 2009. 
Hepatology 2009;50 (3):661-2.
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.
Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching 
from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral 
regimens for virologically suppressed adults with HIV-1 infection: a randomised, 
active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet 
Infect Dis 2016;16 (1):43-52.
Murakami E, Wang T, Park Y, Hao J, Lepist EI, Babusis D, et al. Implications of Efficient 
Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus 
Therapy [Accepted Manuscript]. Antimicrob Agents Chemother 2015;59 
(6):3563-9.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: 
new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 
2012;30 (12):2212-9.
Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency 
virus activity and cellular metabolism of a potential prodrug of the acyclic
nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), 
Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother 1998;42 
(3):612-7.
Ruane PJ, Dejesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, et al. Antiviral 
Activity, Safety, and Pharmacokinetics/Pharmacodynamics of Tenofovir 
Alafenamide as 10-Day Monotherapy in HIV-1-Positive Adults. J Acquir Immune 
Defic Syndr 2013;63 (4):449-55.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.
Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al. Tenofovir alafenamide versus 
tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and 
emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-
blind, phase 3, non-inferiority trials. Lancet 2015;385:2606-15.


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Final
Gilead Sciences, Inc.
Original
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Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management of chronic 
hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an 
expert panel on behalf of the European Society of Pediatric Gastroenterology, 
Hepatology and Nutrition. J Hepatol 2013;59 (4):814-29.
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.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2015.
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Revision 1. November 2015.
Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 2005;15 (6):929-42.
World Health Organization (WHO). Guidelines for the Prevention, Care and Treatment of 
Persons with Chronic Hepatitis B Infection. 2015a.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015b.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


PPD
PPD
PPD
Tenofovir Alafenamide (T AF), GS-7340 
Protocol GS-US-320-4018 
Gilead Sciences, lnc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Original 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Switching 
from Tenofovir Disoproxil Fumarate (TDF) 300 rng QD to Tenofovir Alafenarnide (T AF) 25mg 
QD in Subjects with Chronic Hepatitis B who arc Virologically Suppressed 
GS-US-320-4018, Original, 30 September 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including aJI 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 Qjlead 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 
Stte Number 
CONFIDENTIAL 
Page 104 
30 September 2016 


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Appendix 2.
Study Procedures Table
Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24k
36
48k
60
72
96
EDg
Informed Consent
x
Inclusion/Exclusion Criteria
x
x
Medical History (including HBV disease and treatment history)
x
x
Concomitant Medications
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
Complete Physical Examination with weight and vital signs
x
x
x
x
x
x
x
Height 
x
Body Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signsa
x
x
x
x
x
x
x
x
x
x
x
x
x
Symptom driven Physical Examination
x
x
x
x
x
x
Health Related Quality of Life (CLDQ, SF-36, WPAI)m
x
x
x
x
x
Serum Chemistry and Liver Testsb
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
Fasting metabolic panelc
x
x
x
x
x
x
x
x
x
Pregnancy testing (women of child-bearing potential only)
serum
urine (+ve test to be confirmed with serum)
x
x
x
x
x
x
x
x
x
x
x
x
Estimated Creatinine Clearance by Cockcroft-Gault method (eGFRCG)
x
x
x
x
x
x
x
x
x
x
x
x
x
HBV serology (qualitative HBsAg and HBeAg) and quantitative HBsAgi
x
x
x
x
x
x
x
x
x
x
x
HCV, HDV, HIV Testing
x
α-fetoprotein (AFP)
x
Urinalysis
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine drug screen
x
DXA scans (Hip & Spine)d
x
x
x
x
x
x
ECGe
x
x
x
x
Plasma HBV DNA levels
x
x
x
x
x
x
x
x
x
x
x
x
x
Randomization
x
Study Drug Accountability
x
x
x
x
x
x
x
x
x
Study Drug Dispensation
x
x
x
x
x
x
x
x
x
FibroTest®
x
x
x
x
x
Serum Cystatin Cl
x
Fasting Blood for Bone Biomarkerf
x
x
x
x
x
x
x
x
Fasting Urine for Renal Biomarkerf
x
x
x
x
x
x
x
x


Tenofovir Alafenamide (TAF), GS-7340
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Final
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Study Procedures
Screening
(45 days)
Baseline
(Day 1)
Blinded (± 3 days)
Open Label (± 7 days)
Follow Uph
Week
4
8
12
24k
36
48k
60
72
96
EDg
Fracture Risk Assessment (FRAX)
x
Virology (Sequence analysis of HBV pol/RT for resistance surveillance)j
x
x
x
x
x
x
x
x
x
x
x
Vitamin D
x
a
Vital signs include blood pressure, pulse, respiration rate and temperature
b
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. At Baseline, Weeks 24, 48, 72, 96, and 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: PT/INR will be done at Screening and then as a reflex only test for ALT flares.
c
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). At Baseline, Weeks 12, 24, 36, 48, 60, 72, and 96/ED analyses of glucose will be done as part of the 
fasting metabolic assessments and not as part of the chemistry panel.
d
The Baseline DXA can be performed at any time during the Screening period, but should be completed at least 14 days prior to the Baseline visit to ensure results are received prior to 
the first dose of study drug. The Week 24 DXA window is −14 days only and the Week 48 DXA window is −6 weeks only. DXA required for Early Discontinuation (ED) visit if not 
done within the last 12 weeks and should be done within ±14 days of the expected ED visit date
e
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording.
f
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
g
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
h
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to anti-HBs on or after the Week 24 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the original study visit schedule through Week 96/ED. 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 appropriate, alternative HBV
therapy, whichever occurs first. Initiation of appropriate, alternative HBV therapy is highly encouraged.
i
HBeAb and HBsAb reflex testing will be performed as needed.
j
Resistance sequence analysis may be performed at BL for subjects with HBV DNA ≥69 IU/mL and may be attempted for viremic (HBV DNA ≥ 69 IU/mL) at Wks 24, 48, and 96/ED. 
As it may not be known at the time of the visit whether a subject is viremic or if it will be their last study visit, a virology sample will be collected as each visit. In the event of 
unconfirmed virologic rebound (HBV DNA ≥ 20 IU/mL), subjects will be asked to return to the clinic for a scheduled or unscheduled blood draw. For virologic rebound occurring 
within the first 12 weeks of the study, the next scheduled visit will used for follow up. For virologic rebound occurring after Week 12, the subject will return for an unscheduled visit 
2-3 weeks after the date of the original test that resulted with HBV DNA virologic rebound for confirmation of virologic rebound. At this follow up visit, a serum blood sample for 
resistance testing will be obtained. For unscheduled visits, the subject will be required to bring their supply of study drug with them and be assessed for adherence by pill count, and if 
necessary, the subject will be re-counseled on adherence to study medication.
k
The visit window for Week 24 visit is -14 days only. The visit window for Week 48 visit is −6 weeks only.
l
Serum Cystatin C will be done when eGFRCG falls < 50 ml/min during blinded period of study.
m
Health Related Quality of Life surveys required for Early Discontinuation (ED) visit if not done within the last 24 weeks of the expected ED visit date
PPD


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Final
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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
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
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
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
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


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


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
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
—
—
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%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


Tenofovir Alafenamide (TAF), GS-7340
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Final
Gilead Sciences, Inc.
Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>ULN  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
Adult and Pediatric
1 Year
3.0 to  <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year 
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L                
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L                 
2.0 t o <2.5 mmolL
2.0 mEq/L                         
<2.0 mmolL
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L           
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L             
6.5 to 7.0 mmol/L
7.0 mEq/L                  
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
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


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 111
30 September 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL                        
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL              
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL                     
1.51 to < 1.74 mmolL
< 6.1 mg/dL                           
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
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


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 112
30 September 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(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               
Adult and Pediatric           
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 113
30 September 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
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
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
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
LDL (Fasting)
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
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 114
30 September 2016
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
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 115
30 September 2016
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 116
30 September 2016
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 (eg, malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years 
(with repeat testing at same 
visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences (eg, malignant 
hypertension) OR
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening 
consequences 
(eg, tamponade) OR Urgent 
intervention indicated


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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30 September 2016
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, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Embolic event 
(eg, pulmonary embolism, 
life-threatening thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 118
30 September 2016
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Bronchospasm (acute)
FEV1 or peak flow reduced 
to 70% to 80%
FEV1 or peak flow 50% to 
69%
FEV1 or peak flow 25% to 
49% 
Cyanosis OR FEV1 or peak 
flow 25% OR Intubation
Dyspnea or Respiratory 
Distress
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social 
& functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
Respiratory failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiratory rate for 
age
Nasal flaring OR Intercostal 
retractions OR Pulse 
oximetry 90% to 95%
Dyspnea at rest causing 
inability to perform usual 
social & functional activities 
OR Pulse oximetry 90%
Respiratory failure with 
ventilatory support indicated
OCULAR/VISUAL
Grade 1
Grade 2
Grade 3
Grade 4
Uveitis
Asymptomatic but detectable 
on exam
Symptomatic anterior uveitis 
OR Medical intervention 
indicated
Posterior or pan-uveitis OR 
Operative intervention 
indicated
Disabling visual loss in 
affected eye(s) 
Visual Changes 
(from baseline)
Visual changes causing no or 
minimal interference with 
usual social & functional 
activities
Visual changes causing 
greater than minimal 
interference with usual social 
& functional activities
Visual changes causing 
inability to perform usual 
social & functional activities
Disabling visual loss in 
affected eye(s)


Tenofovir Alafenamide (TAF), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 119
30 September 2016
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), GS-7340
Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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30 September 2016
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight 
loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated 
[eg, tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated (eg, 
diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
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), GS-7340
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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 (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (eg, 
IV fluids)
Life-threatening 
consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (eg, sepsis, 
circulatory failure, 
hemorrhage)
Proctitis 
(functional- symptomatic)
Also see Mucositis/Stomatitis 
for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability 
to perform usual social/
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences (eg, 
hypotensive shock)


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Protocol GS-US-320-4018
Final
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Alteration in Personality-
Behavior or in Mood 
(eg, agitation, anxiety, 
depression, mania, psychosis)
Alteration causing no or 
minimal interference with 
usual social & functional 
activities 
Alteration causing greater 
than minimal interference 
with usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional activities 
Behavior potentially harmful 
to self or others 
(eg, suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, 
OR coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting


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Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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30 September 2016
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & functional 
activities
Symptoms causing inability 
to perform usual social & 
functional activities
Symptoms causing inability 
to perform basic self-care 
functions OR Hospitalization 
indicated (other than ER 
visit) OR Headache with 
significant impairment of 
alertness or other neurologic 
function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic 
self-care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & functional 
activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & functional 
activities 
Sensory alteration or 
paresthesia causing inability 
to perform usual social & 
functional activities
Disabling sensory alteration 
or paresthesia causing 
inability to perform basic 
self-care functions
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)


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Protocol GS-US-320-4018
Final
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase from 
Previous Level of Control to 
Any of These Levels
NA
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality (eg, 
severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated with 
a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


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


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Protocol GS-US-320-4018
Final
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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain 
(pain without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no or 
minimal limitation of use of 
limb
Pain/tenderness limiting use 
of limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than 
ER visit) indicated for 
management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm 
(or 2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (eg, upper 
arm/thigh)
Erythema OR Induration OR 
Edema involving 50% 
surface area of the extremity 
segment (eg, upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile abscess 
OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 48 h 
treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h 
treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


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Protocol GS-US-320-4018
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back of 
neck, breasts, abdomen)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to 
initiate medication OR 
Modification of current meds 
to regain glucose control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & functional 
activities OR Thyroid 
suppression therapy indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & functional 
activities OR Thyroid 
replacement therapy indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences
(eg, myxedema coma)
Lipoatrophy (eg, fat loss from 
the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(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 
(eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other than 
HIV infection)
Localized, no systemic 
antiμbial treatment indicated 
AND Symptoms causing no 
or minimal interference with 
usual social & functional 
activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than 
simple incision and drainage) 
indicated
Life-threatening 
consequences 
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of TAF have demonstrated that there is no 
reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies in 
animals (rats and rabbits) of TAF have demonstrated no adverse effect on fertility orembryo-fetal 
development. However, there are no clinical studies of TAF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires using at least an acceptable
effective contraceptive measure. They must have a negative serum pregnancy test at Screening
and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. At minimum, a
pregnancy test will be performed at the end of relevant systemic exposure. In the event of a
delayed menstrual period (over one month between menstruations), a pregnancy test must be
performed to rule out pregnancy. This is even true for women of childbearing potential with
infrequent or irregular periods. They must also agree to one of the following from Screening
until the end of relevant systemic exposure.


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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below.
Intrauterine device (IUD) with a failure rate of < 1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and
had confirmation of surgical success 3 months after procedure)
Barrier methods (one female barrier and one male barrier must be used in combination)
■
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
■
Male barriers: Male condom (with or without spermicide)
Hormonal methods
■
Oral contraceptives (either combined or progesterone only)
■
Injectable progesterone
■
Implants of levonorgestrel
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use
condoms when engaging in intercourse of reproductive potential.


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4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects she is pregnant during the study must report the information to 
the investigator. Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome 
are outlined in Section 7.6.2.1.