Clinical trial NCT03434353
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2018-02-28; Completion date: 2021-01-26
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of the 12 week treatment regimens of inarigivir soproxil plus tenofovir alafenamide (TAF) or commercially available nucleoside/nucleotide (NUC) in adults with chronic hepatitis B (CHB), to evaluate the antiviral activity of 12 weeks of inarigivir soproxil plus TAF versus TAF alone in viremic CHB participants (Groups 1-3, 5), and to evaluate the antiviral activity of 12 weeks of inarigivir soproxil with commercially available NUC(s) in virally suppressed CHB participants (Group 4).

Detailed description:

Arms: arm 1: Viremic participants will be administered inarigivir soproxil 50 mg (2 x 25 mg capsules) once daily orally 1 hour before or 1 hour after a meal plus TAF 25 mg tablet once daily orally with food for 12 weeks followed by TAF 25 mg tablet once daily orally with food for 36 weeks. arm 2: Viremic participants will be administered TAF 25 mg tablet once daily orally with food for 48 weeks. arm 3: Viremic participants will be administered inarigivir soproxil 200 mg (2 x 100 mg tablets) once daily orally 1 hour before or 1 hour after a meal plus TAF 25 mg tablet once daily orally with food for 12 weeks followed by TAF 25 mg tablet once daily orally with food for 36 weeks arm 4: Virally suppressed participants receiving commercially available nucleoside/nucleotide (NUC) will be administered inarigivir soproxil 100 mg tablet once daily orally 1 hour before or 1 hour after a meal for 12 weeks. Participants will continue commercially available NUCs for 48 weeks. arm 5: Viremic participants will be administered inarigivir soproxil 400 mg (2 x 200 mg tablets) once daily orally 1 hour before or 1 hour after a meal plus TAF 25 mg tablet once daily orally with food for 12 weeks followed TAF 25 mg tablet once daily orally with food for 36 weeks.
Interventions: intervention 1: Inarigivir Soproxil intervention 2: TAF
Intervention descriptions: intervention 1: Administered orally once daily one hour before or one hour after a meal intervention 2: Administered orally once daily with food

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Open-Label, Active-Controlled Study to 
Evaluate the Safety and Antiviral Activity of GS-9992 Plus 
Tenofovir Alafenamide (TAF) for 12 Weeks in Chronic 
Hepatitis B (CHB) Subjects 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
Non-IND Study 
Not Applicable 
NCT03434353 
Chronic Hepatitis B 
GS-US-464-4437 
Gilead Study Director: 
Name: 
PD 
PD 
PD 
Telephone: 
Fax: 
Gilead Medical Monitor: 
Name: 
Telephone: 
Fax: 
Protocol Version/Date: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
PD 
PD 
PU 
22 August 2017 
05 December 2017 
24May2018 
11 March 2019 (Hong Kong) 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly unpublished data, is the prope1iy 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 infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
Final 
Amendment3 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 19 
1. 
INTRODUCTION .............................................................................................................................................. 23 
1.1. 
Background ............................................................................................................................................ 23 
1.2. 
GS-9992 (SB 9200) ................................................................................................................................ 24 
1. 2 .1. 
General Infonnation ............................................................................................................. 25 
1.2.2. 
Clinical Trials of GS-9992 ................................................................................................... 25 
1.2.3. 
Preclinical Phannacology and Toxicology ........................................................................... 29 
1.3. 
TAF(GS-7340) ...................................................................................................................................... 31 
1.3 .1. 
General Infonnation ............................................................................................................. 31 
1.3.2. 
Clinical Trials ofTAF .......................................................................................................... 31 
1.4. 
Rationale for This Study ........................................................................................................................ 41 
1.4.1. 
Rationale for Dose Selection ................................................................................................ 42 
1. 5. 
Risk/Benefit Assessment for the Study .................................................................................................. 45 
1.6. 
Compliance ............................................................................................................................................ 46 
2. 
OBJECTIVES ..................................................................................................................................................... 47 
3. 
STUDY DESIGN ................................................................................................................................................ 49 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
Endpoints ............................................................................................................................................... 49 
Study Design .......................................................................................................................................... 50 
Study Treatments ................................................................................................................................... 51 
Duration ofTreatment ............................................................................................................................ 51 
Biomarker Testing .................................................................................................................................. 52 
3 .5 .1. 
Biomarker Sam les to Address the Stud Ob· ectives .......................................................... 52 
4. 
SUBJECT POPULATION .................................................................................................................................. 54 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 54 
4.2. 
Groups 1-3 and 5 Inclusion Criteria ....................................................................................................... 54 
4.3. 
Groups 1-3 and 5 Exclusion Criteria ...................................................................................................... 55 
4.4. 
Group 4 Inclusion Criteria ...................................................................................................................... 56 
4.5. 
Group 4 Exclusion Criteria .................................................................................................................... 57 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 59 
5.1. 
Rando1nization and Treatinent Codes .................................................................................................... 59 
5.2. 
Description and Handling ofGS-9992 and TAF .................................................................................... 59 
5.2.1. 
Foimulation .......................................................................................................................... 59 
5.2.2. 
Packaging and Labeling ....................................................................................................... 60 
5. 2. 3. 
Storage and Handling ........................................................................................................... 60 
5.3. 
Dosage and Administrntion ofGS-9992 and TAF ................................................................................. 61 
5 .4. 
Prior and Concomitant Medications ....................................................................................................... 62 
5.5. 
Accountability for GS-9992 and TAF .................................................................................................... 63 
5.5.1. 
Investigational Medicinal Product Retum or Disposal.. ....................................................... 63 
6. 
STUDY PROCEDURES .................................................................................................................................... 64 
CONFIDENTIAL 
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Gilead Sciences, Inc. 
Amendment 3
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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................64
6.2.
Pretreatment Assessments......................................................................................................................64
6.2.1.
Screening Visit .....................................................................................................................64
6.2.2.
Baseline Assessments (Day 1)..............................................................................................65
6.3.
Post-Day 1 Assessments (Weeks, 1, 2, 4, 8, 12, 16, 24, 36, and 48,  All Visits Have Window 
of ± 3 Days)............................................................................................................................................66
6.5.
24-Week Treatment Free Assessments ( Weeks 4, 8, 12, 16, 20, and 24, All Visits Have 
Window of ± 5 Days).............................................................................................................................68
6.6.
Assessments for Early Discontinuation from the Study.........................................................................69
6.7.
Unscheduled Visits.................................................................................................................................70
6.8.
Study Procedure Details.........................................................................................................................70
6.8.1.
Medical History....................................................................................................................70
6.8.2.
Complete Physical Examination...........................................................................................70
6.8.3.
Electrocardiogram Assessment ............................................................................................70
6.8.4.
Vital Signs............................................................................................................................71
6.8.5.
Clinical Laboratory Tests/Assessments................................................................................71
6.8.6.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................73
6.9.
Sample Storage.......................................................................................................................................73
6.10.
Assessments for Premature Discontinuation from Study.......................................................................73
6.11.
Criteria for Discontinuation of Study Treatment....................................................................................73
6.12.
Resistance Surveillance and ddPCR.......................................................................................................74
6.13.
End of Study...........................................................................................................................................74
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................75
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................75
7.1.1.
Adverse Events.....................................................................................................................75
7.1.2.
Serious Adverse Events........................................................................................................75
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................76
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................76
7.2.2.
Assessment of Severity ........................................................................................................77
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................77
7.4.
Gilead Reporting Requirements.............................................................................................................78
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events and Toxicity Management...............................................................................79
7.6.
Toxicity Management ............................................................................................................................79
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................81
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................81
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................81
7.7.
Special Situations Reports......................................................................................................................81
7.7.1.
Definitions of Special Situations..........................................................................................81
7.7.2.
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 .............................................................................................................86
8.2.
Analysis Conventions.............................................................................................................................86
8.2.1.
Analysis Sets ........................................................................................................................86
8.3.
Data Handling Conventions ...................................................................................................................87
8.4.
Demographic Data and Baseline Characteristics ...................................................................................87
8.5.
Efficacy Analysis ...................................................................................................................................88
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8.5.1.
Primary Analysis..................................................................................................................88
8.5.2.
Secondary Analyses .............................................................................................................88
8.5.3.
Analysis of Other Endpoints of Interest ...............................................................................88
8.6.
Safety Analysis.......................................................................................................................................88
8.6.1.
Extent of Exposure...............................................................................................................88
8.6.2.
Adverse Events.....................................................................................................................88
8.6.3.
Laboratory Evaluations ........................................................................................................89
8.7.
Pharmacokinetic Analysis......................................................................................................................89
8.9.
Sample Size............................................................................................................................................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) 
Review and Approval...........................................................................................................91
9.1.3.
Informed Consent.................................................................................................................91
9.1.4.
Confidentiality......................................................................................................................91
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.............................................93
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 .............................................................................................94
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 ..............................................................95
9.3.4.
Study Discontinuation..........................................................................................................95
10.
REFERENCES ...................................................................................................................................................96
11.
APPENDICES ....................................................................................................................................................99
Appendix 1.
Investigator Signature Page..................................................................................................100
Appendix 2.
Study Procedures Table........................................................................................................101
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............104
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................126
LIST OF IN-TEXT TABLES
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................33
Table 1-2.
GS-US-320-0108 and G -US-320-0110: HBV DNA Outcome at Week 48 Using 
HBV DNA of < 29 IU/mL, Missing = Failure (Full Analysis Set) ........................................34
Table 1-3.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or Seroconversion at 
Week 48, Missing = Failure (Serologically Evaluable Full Analysis Set) .............................35
Table 1-4.
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
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Table 1-5.
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 1-6.
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 1-7.
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) .........................39
Table 5-1.
Disallowed Concomitant Medications....................................................................................62
Table 7-1.
GS-9992 Dose Modification and Monitoring.........................................................................80
Table 7-2.
TAF Dose Modification and Monitoring................................................................................80
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................50


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 6
11 March 2019
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Open-Label, Active-Controlled Study to 
Evaluate the Safety and Antiviral Activity of GS-9992 Plus 
Tenofovir Alafenamide (TAF) for 12 Weeks in Chronic Hepatitis B 
(CHB) Subjects 
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Non-IND Study
Not Applicable
NCT03434353
Study Centers Planned:
Approximately 15 centers in South Korea and Hong Kong
Objectives:
The primary objectives of this study are:

To evaluate the safety and tolerability of the 12 week treatment 
regimens of GS-9992 (also known as SB 9200) plus TAF or 
commercially available nucleos(t)ide (NUC)

Groups 1-3 and 5
To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF 
versus TAF alone in viremic CHB subjects as measured by the 
proportion of subjects with ≥0.5 log10 IU/mL decline from Baseline 
at Week 12 in circulating serum HBV surface antigen (HBsAg) 

Group 4
To evaluate the antiviral activity of 12 weeks of GS-9992 with 
commercially available NUC(s) in virally suppressed CHB subjects  
as measured by the proportion of subjects with ≥0.5 log10 IU/mL 
decline from Baseline at Week 12 in circulating serum HBV surface 
antigen (HBsAg) 
The secondary objectives of this study are: 
Groups 1-3 and 5

To evaluate the safety and tolerability of the 48 week treatment 
regimens as assessed by review of the accumulated safety data

To evaluate the antiviral activity of 12 weeks of GS-9992 plus 
TAF versus TAF alone in CHB subjects as measured by the 
proportion of subjects with ≥1 log10 IU/mL decline from 
Baseline at Week 12 in circulating HBsAg 


GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment3 
• 
To evaluate the propo1tion of HBeAg-positive CHB subjects 
who achieve HBeAg loss and seroconversion during 12 weeks of 
GS-9992 plus T AF versus T AF alone and after GS-9992 
discontinuation through 48 weeks 
• 
To evaluate the propo1t ion of CHB subjects who achieve HBsAg 
loss during 12 weeks of GS-9992 plus TAF versus TAF alone 
and after GS-9992 discontinuation through 48 weeks 
• 
To evaluate the incidence of drng resistance mutations during 
48 weeks of treatment 
• 
To characterize steady-state phannacokinetics of study diugs 
• 
To evaluate the change from Baseline in HBV DNA and 
quantitative HBsAg in CHB subjects during 12 weeks of 
GS-9992 plus T AF versus T AF alone and after GS-9992 
discontinuation through 48 weeks 
Group 4 
• 
To evaluate the propo1t ion of subjects experiencing HBV 
virologic breakthrough (2 consecutive visits of HBV DNA 
.:: 69 ID/mL) during 12 weeks of GS-9992 treatment 
• 
To evaluate the antiviral activity of 12 weeks of GS-9992 in 
CHB subjects as measured by the propo1t ion of subjects with 
::::l log10 ID/mL decline from Baseline at Week 12 in circulating 
HBsAg 
• 
To evaluate the propo1tion of HBeAg-positive CHB subjects 
who achieve HBeAg loss and seroconversion during 12 weeks of 
GS-9992 and after GS-9992 discontinuation through 48 weeks 
• 
To evaluate the propo1t ion of CHB subjects who achieve HBsAg 
loss during 12 weeks of GS-9992 and after GS-9992 
discontinuation through 48 weeks 
• 
To characterize steady-state phannacokinetics of study diugs 
• 
To evaluate the change from Baseline in quantitative HBsAg in 
CHB subjects during 12 weeks of GS-9992 and after GS-9992 
discontinuation through 48 weeks 
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GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
I 
I 
Final 
Amendment3 
Approximately 120 chronic, immune-active, HBV-infected adults 
without cinhosis may be enrolled; including 100 viremic subjects 
not cunently on HBV nucleos(t)ide (NUC) treatment from 
Groups 1-3 and 5, and 20 virally suppressed subjects on an NUC 
from Group 4. 
Approximately 40 viremic subjects not cmTently on HBV 
nucleos(t)ide ti·eatment will be randomized (3:1) to Group 1 and 
Group 2, below: 
• 
Group 1 (n = 30): GS-9992 50 mg once daily one hour before or 
one hour after a meal plus T AF 25 mg once daily with food for 
12 weeks then TAF 25 mg once daily with food for 36 weeks 
• 
Group 2 (n = 10): TAF 25 mg once daily with food for 48 weeks 
Approximately 40% of subjects enrolled will be HBeAg negative. 
Randomization will be sti·atified by HBeAg status (positive or 
negative) at Screening. 
Group 3 
Approximately 30 viremic subjects may be enrolled and assigned: 
• 
GS-9992 200 mg (2 x 100 mg tablets) once daily one hour 
before or one hour after a meal plus T AF 25 mg once daily with 
food for 12 weeks then TAF 25 mg once daily with food for 
36 weeks 
Approximately 40% of subjects enrolled in Group 3 will be HBeAg 
negative. 
Group 3 will not staii enrolling subjects until the ACHIEVE 
(SB-9200-HBV-201) ti·ial's independent Data Safety Monitoring 
Boai·d has deemed it safe to proceed based on review of data for the 
200 mg monotherapy coho1i. 
Group 4 
Approximately 20 virally suppressed CHB subjects taking a 
commercially available NUC(s) may be enrolled. Subjects will 
remain on their cmTent commercially available NUC(s) therapy for 
the duration of the study and receive: 
• 
GS-9992 100 mg once daily one hour before or one hour after a 
meal for 12 weeks. 
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Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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Approximately 50% of subjects enrolled in Group 4 will be HBeAg 
negative. All subjects will be followed through Week 48.
Group 5 (Hong Kong Only)
Approximately 30 viremic subjects may be enrolled and assigned:

GS-9992 400 mg (2 x 200 mg tablets) once daily one hour 
before or one hour after a meal plus TAF 25 mg once daily with 
food for 12 weeks then TAF 25 mg once daily with food for 
36 weeks
Approximately 40% of subjects enrolled in Group 5 will be HBeAg 
negative.  
Safety of GS-9992 200mg plus TAF for 12 weeks (Group 3) will be 
confirmed prior to enrollment of Group 5.
24 Week Treatment-Free Follow-up 
Subjects that meet any one of the following criteria will be followed 
for 24 weeks or until the initiation of alternative CHB therapy, 
whichever comes first:

Subjects that discontinue all HBV therapy (e.g.GS-9992 and/or 
TAF or commercially available NUC), for any reason 

Subjects with HBsAg loss confirmed at least 12 weeks apart 
should discontinue all HBV therapy following confirmation 

ALT Elevation or Flare Management
Subjects with on-treatment serum ALT elevation >2 × nadir 
or > 2 × Baseline value and ≥5 × ULN, with or without associated 
symptoms should be managed according to the guidance below. 
All on-treatment elevated serum ALT should be confirmed as soon 
as possible and ideally within 3 days of receipt of results. During the 
visit, a clinical assessment of the subject should be performed. The 
assessment should include a physical examination, evaluation of the 
subject’s mental status and the following laboratory tests: 
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, HBsAb, HBeAg and HBeAb), HDV, HAV IgM, HCV, and 
HEV.


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
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For GS-9992 Management
Based on the results of the confirmatory tests, the following 
treatment modifications for GS-9992 are recommended:
GS-9992 Dose Modification and Monitoring
Liver Toxicity
Action
Confirmed ALT ≥ 10 ULN  without 
evidence of hepatic toxicity as defined 
below
Discuss with the Medical Monitor if 
GS-9992 should be dose reduced by 50% or 
discontinued if the safety of the subject is 
of immediate concern. Subject should be 
monitored weekly or more frequently if 
clinically indicated until ALT < 5 × ULN
Confirmed ALT > 2 nadir, with 
evidence of hepatic toxicity, defined as 
any one of the following:
Total bilirubin > 2 baseline or nadir 
AND > ULN in the absence of Gilbert’s 
disease
Elevated INR > 0.5 above baseline AND 
> ULN 
Abnormal serum albumin > 1 g/dL 
decrease from baseline
Permanently discontinue GS-9992. Subject 
should be monitored weekly until ALT 
< 5 × ULN, and total bilirubin and INR 
values return to normal or baseline levels
Confirmed ALT > 2 × Baseline and 
≥5 × ULN without evidence of hepatic 
toxicity, as defined above
Continue GS-9992, ALT should be 
evaluated every 2 weeks or more frequently 
as clinically needed, until ALT < 5 × ULN
For TAF Management
Based on the results of the confirmatory tests, the following 
treatment modifications for TAF are recommended:
Liver Toxicity
Action
Confirmed ALT levels >10 ULN, with 
evidence of hepatic toxicity, defined as 
any one of the following:

Total bilirubin > 2 baseline or 
nadir AND > ULN in the absence of 
Gilbert’s disease

Elevated INR > 0.5 above baseline 
AND > ULN 

Abnormal serum albumin > 1 g/dL 
decrease from baseline
Discuss with the Medical Monitor if TAF 
should be discontinued, unless the safety of 
the subject is of immediate concern. 
Subject should be monitored weekly as 
long as ALT, total bilirubin and INR values 
remain elevated or above baseline values. 
If the ALT values remain persistently 
elevated, the investigator should discuss 
with the Medical Monitor if TAF should be 
discontinued. 
Confirmed ALT levels ≥10 ULN, 
without evidence of hepatic toxicity, as 
defined above
Continue TAF and monitor weekly until 
ALT values return to normal or baseline 
levels. If the ALT values remain 
persistently elevated, the investigator 
should discuss with the Medical Monitor if 
TAF should be discontinued.


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 11
11 March 2019
Criteria for Discontinuation of Study Drug(s)
GS-9992 and/or TAF may also be discontinued if the following 
instances are met:

A confirmed ≥ Grade 3 AE (excluding isolated ALT elevations) 
considered related to GS-9992 and/or TAF by the investigator, 
should discontinue one or both study drug(s)

A confirmed, clinically significant lab abnormality ≥ Grade 3 
(excluding isolated ALT elevations) considered related to 
GS-9992 and/or TAF by the investigator, should discontinue 
one or both study drug(s)

Intercurrent illness that would, in the judgment of the 
investigator, affect assessments of clinical status to a significant 
degree 

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

HBsAg loss confirmed at least 12 weeks apart

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study 

Discontinuation of the study at the request of Gilead, a 
regulatory agency or an institutional review board or 
independent ethics committee (IRB/IEC)
For Group 5, study treatment(s) will be held in all subjects in the 
dosing group, if ≥3 subjects experience a Grade 3 adverse event or 
≥2 subjects experience a Grade 4 or serious adverse event, in the 
same system organ class (excluding isolated ALT elevations) that is 
considered related by the investigator(s) to the Graded toxicity. 
Decisions to reinitiate continuation of dosing of study treatment(s) 
will be made by Gilead Medical Monitor upon review of all safety 
data generated by subjects dosed to date.
HBV will be managed according to local standard of care if subjects 
are discontinued from the study. Subjects that discontinue all study 
drug(s) will be followed for 24 weeks or until the initiation of 
alternative CHB therapy, whichever comes first. 


GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
Number of Subjects 
Planned: 
Target Population: 
Duration of 
Treatment: 
Diagnosis and Main 
Eligibility Criteria: 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Approximately 120 subjects 
Chronic, immune-active, viremic and virally suppressed 
HBV-infected adults 
Final 
Amendment3 
Group 1: GS-9992 plus TAF for 12 weeks then TAF for 36 weeks 
Group 2: T AF for 48 weeks 
Group 3: GS-9992 plus TAF for 12 weeks then TAF for 36 weeks. 
Group 4: GS-9992 for 12 weeks 
Group 5: GS-9992 plus TAF for 12 weeks then TAF for 36 weeks 
Male and non-pregnant female subjects, ages 18-70 years, inclusive, 
with chronic HBV infection may be eligible for the study. 
Refer to Section 4 of the protocol for detailed Inclusion and 
Exclusion criteria. 
After consent is obtained, Screening assessments will be completed 
within 45 days prior to the Baseline/Day 1 visit. 
All subjects will complete the following study visits: Screening, 
Baseline/Day 1, Post-Day lvisits at the end of Weeks 1, 2, 4, 8, 12, 
16, 24, 36, and 48. Subjects that discontinue all HBV therapy 
(GS-9992 and/or TAF or commercially available NUC) should 
complete Treatment-Free follow up visits at the end of Weeks 4, 8, 
12, 16, 20, and 24, or until the initiation of alternative CHB therapy, 
whichever comes first. 
Screening assessments include: 
• 
Review of inclusion/exclusion criteria 
• 
Obtain medical histo1y (including HBV disease and treatment 
histo1y) 
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
Review concomitant medications

Complete physical examination

Vital signs

Body weight and height

12-lead ECG (Subjects must rest quietly in the supine position 
for a minimum of 5 minutes prior to the recording)

Sample Collection for:
Safety laboratory tests (hematology, chemistry, and 
coagulation)
Serology testing to exclude HCV, HDV, and HIV infection
Quantitative plasma HBV DNA
Quantitative serum HBsAg, 
 
 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg 
is negative] and HBsAg [reflex HBsAb if HBsAg is 
negative])
HBV viral sequencing samples (resistance surveillance)
Estimated creatinine clearance (using the Cockcroft-Gault 
method)
Other screening laboratory tests: urinalysis, urine drug 
screen, and serum β-hCG (females of child bearing potential 
only) 
Record any serious adverse events and all adverse events related to 
protocol mandated procedures occurring after signing of the consent 
form.
Day 1 (Baseline) assessments include:

Review of inclusion/exclusion criteria and confirm medical 
history 

Complete Physical Examination including body weight

Vital signs

12-lead ECG (Subjects must rest quietly in the supine position 
for a minimum of 5 minutes prior to the recording)

Review adverse events prior to study drug administration, report 
AEs related to protocol mandated procedures and all SAEs. After 
drug administration, report all AEs and SAEs.
Review Concomitant Medications
CCI


GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
CONFIDENTIAL 
• 
Sample Collection For: 
Final 
Amendment3 
-
Safety laborato1y tests (hematology, chemistry, and 
coagulation) 
-
HBV genotype for Groups 1-3 and 5 only; for Group 4 
historic HBV genotype should be documented in EDC, if 
available 
-
Quantitative plasma HBV DNA 
-
-
titative sernm HBsAg, 
-
Qualitative HBV serology (HBeAg [ reflex HBeAb if HBeAg 
is negative] and HBsAg [ reflex HBsAb if HBsAg is 
negative]) 
-
Collection of PBMC, whole blood, sernm, and plasma 
samples for biomarker analysis (PBMC sample collection is 
only required at the sites that have access to PBMC 
processing laborato1y) 
-
Sernm sample for HBV viral sequencing (resistance 
surveillance) or ddPCR (Group 4) 
-
Other laborato1y tests: urinalysis, urine drng screen and 
pregnancy test for child bearing potential only) 
• 
Estimated creatinine clearance (using Cockcroft-Gault method) 
• 
Randomization 
• 
Drng Administi·ation of GS-9992 and/or TAF 
-
Dispense study drng as directed by IWRS 
-
Instrnct the subject on the packaging, storage, and 
administi·ation of study diugs 
-
Observe the subject taking the first dose of study di·ug(s) 
Post-Day 1 assessments include: 
• 
Vital signs 
• 
Weight at Weeks 12 and 48 
• 
Review adverse events 
• 
Review concomitant medications 
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GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
CONFIDENTIAL 
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Amendment3 
• 
Complete Physical Examination (Week 12) 
• 
Symptom-directed physical examination 
• 
12-lead ECG (Subjects must rest quietly in the supine position 
for a minimum of 5 minutes prior to the recording) (Week 12) 
• 
Sample collection for: 
I 
-
Safety laborato1y tests (hematology and chemistiy ; 
coagulation on Week 12 only) 
-
Quantitative plasma HBV DNA 
-
Qualitative HBV serology (HBeAg [ reflex HBeAb if HBeAg 
is negative] and HBsAg [ reflex HBsAb if HBsAg is 
negative]) at Weeks 12, 24, 36, and 48 
-
Collection of PBMC, whole blood, semm, and plasma 
samples for biomarker analysis at Weeks 1, 4, 12, 24, 48 
(PBMC sample collection is only required at the sites that 
have access to PBMC processing laborato1y). 
-
Semm sample for HBV viral sequencing (resistance 
surveillance) or ddPCR (Group 4) 
-
Single plasma PK sample will be collected at each on-study 
ti·eatment visit. 
On Weeks 2 and 8, the sample will be collected between 
15 minutes and 4 hours post-dose. In-clinic dose of 
GS-9992 required. 
All PK samples will be collected anytime on all other 
on-ti·eatment visit. 
Single PK blood samples will only be collected through 
Week 12 for Group 4 
-
Urine pregnancy test (females of child bearing potential 
only) 
-
Urinalysis 
-
Estimated creatinine clearance (using Cockcroft-Gault 
method) at Weeks 12 and 48 
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Gilead Sciences, Inc. 
CONFIDENTIAL 
I 
Final 
Amendment3 
• 
Perfonn study chug accountability (GS-9992 Weeks 1-12, 
TAF Weeks 1-48) 
• 
Dispense study chug GS-9992 Weeks 1-8 (Groups 1, 3, 4, and 5), 
TAF Weeks 4-48 (Group 1, 2, 3, and 5) as outlined in 
Appendix 2. 
Treatment-Free assessments include: 
• 
Complete Physical examination at Week 4 
• 
Symptom-directed physical examination 
• 
Review adverse events at Week 4 and collect SAEs through the 
end of study 
• 
Review concomitant medications 
• 
Vital signs 
• 
Sample collection for: 
-
Safety laborato1y tests (hematology and chemistry) 
-
Quantitative plasma HBV DNA 
-
Quantitative sernm HBsAg, 
-
Qualitative HBV serology (HBeAg [ reflex HBeAb if HBeAg 
is negative] and HBsAg [reflex HBsAb ifHBsAg is 
negative]) to be collected at Weeks 12 and 24 
-
Collection of PBMC, whole blood, senun, and plasma 
samples for biomarker analysis at Weeks 4, 8, 12, and 24 
(PBMC sample collection is only required at the sites that 
have access to PBMC processing laborato1y). 
-
Sernm sample for HBV viral sequencing (resistance 
smveillance) or ddPCR (Group 4) 
-
Urine pregnancy test (females of child bearing potential only 
at Week 4) 
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GS-9992 
Protocol GS-US-464-4437 
Gilead Sciences, Inc. 
Test Product, Dose, and 
Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for Evaluation: 
Safety: 
Antiviral Activity: 
Phaimacokinetics: 
CONFIDENTIAL 
Final 
Amendment3 
• 
Group 1: GS-9992 (also known as SB 9200) 50 mg (2 x 25 mg) 
capsules are administered orally once daily one hour before or 
one hour after a meal for first 12 weeks. 
• 
Group 3: GS-9992 200 mg (2 x 100mg) tablets are administered 
orally once daily one hour before or one hour after a meal for 
first 12 weeks. 
• 
Group 4: GS-9992 100 mg tablet is administered orally once 
daily one hour before or one hour after a meal for first 12 weeks. 
• 
Group 5: GS-9992 400 mg (2 x 200mg) tablets are administered 
orally once daily one hour before or one hour after a meal for 
first 12 weeks. 
• 
Groups 1, 3 and 5: TAF 25 mg tablet is administered orally once 
daily for 48 weeks with food 
T AF 25 mg tablet for Group 2 is administered orally once daily for 
48 weeks with food 
Safety will be evaluated by assessment of clinical laborato1y tests 
and adverse events collected through end of treatment. Prima1y 
safety analysis will be evaluated through four weeks after last dose 
of GS-9992. 
Antiviral Activity will be evaluated using scheduled assessments of 
quantified sennn HBsAg levels. Primaiy antiviral activity analysis 
will be evaluated through Week 12. 
A single PK blood sample will be collected at each on-treatment 
visit through 48 weeks for Groups 1-3 and 5. Single PK blood 
samples will only be collected through Week 12 for Group 4. 
For all groups on Weeks 2 and 8, the sample will be collected 
between 15 minutes and 4 hours post-dose. PK sample can be 
collected at any time on all other on-treatment visits. 
The PK of GS-9992 (and its metabolites), TAF, and TFV 
(if applicable) will be assessed. 
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Statistical Methods:
The primary efficacy endpoint is the proportion of subjects with 
≥0.5 log10 IU/mL decline in HBsAg from baseline at Week 12. It 
will be summarized in all randomized/enrolled and treated subjects 
for all groups. The 2-sided 95% confidence interval of the 
proportion difference (Group 1 – Group 2, Group 3 – Group 2, 
Group 5 – Group 2) will be constructed by using stratum-adjusted 
Mantel-Haenszel (MH) proportions, stratified by the randomization 
stratification factor HBeAg status (positive, negative). 
The secondary endpoints may include the proportion of subjects 
with ≥ 1 log10 IU/mL decline in HBsAg from baseline at Week 12, 
the proportion of HBeAg-positive CHB subjects who achieve 
HBeAg loss and seroconversion, and the proportion of CHB subjects 
who achieve HBsAg loss, the change from baseline in HBV DNA 
(Groups 1-3 and 5) and HBsAg, the proportion of subjects with drug 
resistant mutations (Groups 1-3 and 5) and the proportion of subjects 
experiencing HBV virologic breakthrough (Group 4).
All continuous efficacy endpoints will be summarized using an 
8-number summary (n, mean, standard deviation [SD], median, 
1st quartile [Q1], 3rd quartile [Q3], minimum, and maximum). All 
categorical efficacy endpoints will be summarized by number and 
percentage of subjects who meet the endpoint. 
Safety will be evaluated by treatment group by the number and 
percentage of subjects with adverse events or laboratory 
abnormalities for categorical values or by the 8-number summary 
(n, mean, SD, median, Q1, Q3, minimum, maximum) for continuous 
data.
Due to the exploratory nature of this study, the sample size was not 
determined by any formal power calculation. The number of subjects 
in each treatment group was decided based on clinical experience.
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
λz
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration versus time curve of the drug
AUC
area under the plasma concentration-time curve
°C 
degrees Celsius
°F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase (previously serum glutamic pyruvic transaminase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase 
AUC
area under the concentration versus time curve
AUCinf
area under the concentration versus time curve extrapolated to infinite time, calculated as 
AUClast + (Clast/λz)
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
bpm
beats per minute
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CHB
Chronic hepatitis B
CI
confidence interval
CK
creatine kinase
Clast
last observed quantifiable concentration of the drug
CLcr
creatinine clearance
Cmax
maximum observed concentration of drug
CPK
creatine phosphokinase
CRO
contract (or clinical) research organization 
CSR
clinical study report
CTA
clinical trial application
Ctau
observed drug concentration at the end of the dosing interval
DDI
drug-drug interaction
ddPCR
digital droplet PCR
DNA
deoxyribonucleic acid
EASL
European Association for the Study of the Liver (EASL)
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment


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EudraCT
European Clinical Trials Database
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FU
follow-up
G
Genomics
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
HBV
hepatitis B virus
HBcrAg
hepatitis B core-related antigen
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV RT
HBV reverse transcriptase 
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HIV, HIV-1
human immunodeficiency virus, type 1
HLGT
high-level group term
HLT
high-level term
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
Identification
IEC
independent ethics committee
IFN
interferon
IND
investigational new drug (application)
IRB
institutional review board
IUD
intrauterine device
LDL
low-density lipoprotein
LLT
lower-level term
LLOQ
lower limit of quantitation
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MM
medical monitor


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NDA
new drug application
NOAEL
no-observed-adverse-effect-level
NOD-2
nucleotide-binding oligomerization domain-containing protein 2 
NUC
nucleos(t)ide
PD
pharmacodynamic(s)
PEG
pegylated interferon-α
PI
principal investigator
PHH
primary human hepatocytes
PK
pharmacokinetic(s)
PR interval
electrocardiographic interval occurring between the onset of the P wave and the 
QRS complex representing time for atrial and ventricular depolarization, respectively
PT
preferred term
PTM
placebo to match
PTT
partial thromboplastin time
PVE
Pharmacovigilance & Epidemiology
QA
quality assurance
QD
one a day 
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave, representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RBC
red blood cell
RIG-I
retinoic acid-inducible gene 1
RNA
ribonucleic acid
RT
reverse transcriptase 
SADR
serious adverse drug reaction
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TAF
Tenofovir Alafenamide 
TEAE
treatment-emergent adverse event
TE
treatment-emergent 
Tlast
time (observed time point) of Clast
TFV
tenofovir 
Tmax
the time (observed time point) of Cmax
TQT
thorough QT


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t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
ULN
upper limit of normal
US, USA
United States, United States of America
Vz/F
apparent volume of distribution of the drug
WBC
white blood cell
WHO
World Health Organization


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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 {World 
Health Organization (WHO) 2015}. 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 patients with CHB in the absence of effective treatment {Terrault 2016, 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) 2015}. In 2013, an estimated 686,000 deaths were due to 
HBV infection and associated complications, placing it among the top 20 causes of mortality 
worldwide {G. B. D. Mortality Causes of Death Collaborators 2015, Ott 2012}. 
The loss of HBsAg is the accepted endpoint for anti-HBV therapy and has been associated with 
improvements in liver histology, including the reversal of cirrhosis, a decreased risk of HCC, and 
prolonged survival {Benias 2011, European Association for the Study of the Liver (EASL) 2017, 
Fattovich 1998, Kim 2013, Liaw 2012, Lok 2009}. Recent treatment guidelines, Terrault 2016, 
EASL 2017 {European Association for the Study of the Liver (EASL) 2017, Terrault 2016} and 
APASL 2016 {Sarin 2016}, acknowledge the importance of HBsAg clearance in CHB. HBsAg 
clearance is associated with definitive remission of the activity of CHB and an improved long 
term outcome {European Association For The Study Of The Liver 2009}; recent data show that 
the risk of HCC is lower if HBsAg clearance occurs before 50 years of age {Yuen 2008}. Loss 
of HBsAg is thus a primary goal of CHB therapy.
Nucleos(t)ide analogues are the standard of care for CHB, providing durable on-treatment 
suppression of viral replication and resulting in long-term clinical benefits with a reduced risk of 
liver complications {Dienstag 2003, Liaw 2011, Lok 2013}. With potent oral antivirals (NUCs), 
the yearly incidence of HBsAg loss is low but cumulative as duration of NUC treatment 
increases. As a result, continuous long-term use is advised for most patients. More, treatment 
with oral nucleos(t)ide inhibitors rarely results in clearance of HBsAg {Kwon 2011}. Therefore, 
new therapies that enhance rates of HBsAg loss after a finite treatment course are needed. 
A finite course of subcutaneously injected pegylated interferon-α (PEG) given in CHB patients, 
can result in responses equivalent to a clinical cure of the virus in approximately 5% of treated 
patients {Ghany 2009, Perrillo 2009}. However, these rates vary dramatically depending on 
patient characteristics and virus subtype. Additionally, PEG has notable barriers to patient 
acceptance including the subcutaneous route of administration and a significant adverse effect 


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profile; fatigue, malaise, cytopenias, depression and induction of autoimmunity. These adverse 
effects have been associated with early drug discontinuation. In light of the relatively low 
response rates and barriers to use of PEG, orally administered immunomodulatory regimens with 
fewer side effects than exogenous interferons are needed. An ideal therapy would be oral and 
more tolerable than current therapies, more broadly applicable and associated with higher 
long-term viral eradication rates (as measured by HBsAg clearance).
The host immune response to HBV infection plays a pivotal role in whether acute infection is 
resolved or becomes chronic. Individuals who are able to clear HBV infection spontaneously 
following an acute infection display a vigorous, polyclonal HBV-specific CD8+ and 
CD4+ T cell response {Rehermann 2005}. In contrast, CHB is associated with a limited and 
dysfunctional CD8+ T cell response as well as impaired NK cell antiviral function {Peppa 2010, 
Rehermann 2005}. Various mechanisms have been identified which may play a role in immune 
dysfunction in CHB, including inefficient T cell priming, persistent antigen presentation leading 
to T cell "exhaustion", immunosuppressive cell types (e.g. T regulatory cells and myeloid 
derived suppressor cells) and cytokines (e.g. IL-10 and TGF-β), NK cell-mediated killing of 
antiviral T cells, as well as intrahepatic regulation of T cell metabolism by arginase 1 and 
indoleamine 2,3-dioxygenase 1 (IDO1) {Debes 2015, Maini 2010, Peppa 2013, Protzer 2012}.
GS-9992, also known as SB 9200, is a dinucleotide prodrug being developed as an oral antiviral 
agent for the treatment of chronic hepatitis infections. GS-9992 has a dual mechanism of action 
involving: (a) selective activation of the host cytosolic proteins – retinoic acid-inducible gene 1 
(RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), which 
are involved in recognition of viral nucleic acids that result in the stimulation of interferon (IFN) 
production and induction of antiviral state in infected cells, and (b) direct inhibition of viral 
replication by blocking the access of the viral polymerase to the viral nucleic acid template. This 
is due to the interaction of GS-9992 with the nucleotide-binding domain of RIG-I and NOD-2 
that sterically hinders the axis of viral polymerase to the viral ribonucleic acid (RNA) template. 
The stimulation of IFN production by GS-9992 also causes the induction of these innate immune 
responder genes, RIG-I and NOD-2, by a feed-back loop and further potentiates the antiviral 
activity.
1.2.
GS-9992 (SB 9200)
GS-9992, also known as SB 9200, is being developed for use in combination with approved 
antiviral agents for HBV. Upon oral administration, the prodrug GS-9992 is converted to the 
active dinucleotide metabolite (SB 9000) by esterases. It is to be noted that GS-9992 is a mixture 
of 2 isomers, designated as Rp-SB 9000 and Sp-SB 9000. Both isomers have been shown to have 
similar activity. There is no evidence of any interconversion of the isomers in vitro or in vivo, 
but both prodrug isomers are converted to the active form at the same rate. In vitro studies using 
liver microsomes from different species and in vivo studies in both rodents and woodchucks 
have demonstrated that GS-9992 is not subject to Phase 1 metabolism or Phase 2 conjugation 
reactions and is eliminated predominately in the urine as the intact dinucleotide. Currently, there 
is no evidence that GS-9992 would have any drug-to-drug interactions with currently approved 
oral direct-acting antivirals (DAAs) for HBV.


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1.2.1.
General Information
Please refer to the SB 9200 Investigator’s Brochure for further information on GS-9992 
(SB 9200), including:

In Vitro Anti-Hepatitis B Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.2.2.
Clinical Trials of GS-9992
Phase 1 Clinical Studies
The completed Phase 1 study (SB12-9200-101) evaluated the safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of GS-9992 up to 900 mg in treatment-naive HCV-infected adults. The 
study was conducted in 2 parts: 1) a single ascending dose under fed or fasting conditions (Part 
A) and 2) a placebo-controlled multiple ascending dose under fasting conditions (Part B).
In Part A, single ascending doses of GS-9992 at doses of 100 to 800 mg were given as 
monotherapy. For subjects in whom GS-9992 was detectable (200, 400, and 800 mg GS-9992), 
no clear difference in the time to maximum analyte concentration (Tmax) for the parent compound 
GS-9992 was observed following dosing in either the fed or fasted conditions. Due to the sparse 
data available, it was not possible to conclude whether food had any effect on either maximum 
analyte concentration (Cmax) or area under the concentration versus time curve (AUC) for 
GS-9992 and its metabolites. The parent compound was rapidly cleared from the plasma with a 
mean half-life (t1/2) ranging from 1.16 to 1.42 hours. The metabolites Sp-SB 9000 and 
Rp-SB 9000 remained in the circulation much longer with a mean t1/2 ranging from 5.88 to 
19.3 hours and 2.62 to 8.84 hours, respectively. 
In Part B, multiple ascending doses of GS-9992 at doses of 200 to 900 mg were given QD as 
monotherapy for up to 7 days. There was a lack of measurable GS-9992 concentrations at the 
lowest dose level tested (200 mg). Based on dose-normalized area under the analyte 
concentration versus time curve from time zero to the last quantifiable time point (AUC0-t) and 
Cmax, the exposure of GS-9992 appeared to increase in a dose proportional manner when 
GS-9992 was increased from 400 to 900 mg on Days 1 and 7.
Based on dose-normalized AUC0-t and Cmax, taking into consideration the high intersubject 
variability in the exposure of the metabolites Sp-SB 9000 and Rp-SB 9000, increases in AUC0-t 
and Cmax appeared to be dose proportional when GS-9992 oral doses were increased from 
200 to 900 mg. GS-9992 was rapidly (t1/2 approximately 1 hour) cleaved into 2 metabolites via 
an esterase mediated process. The t1/2 of the metabolites were between 5 and 9 hours, an 
important distinction as it is the metabolites that contribute to the antiviral activity in the liver. 


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For the parent compound, the t1/2 was relatively short and ranged from 0.684 hours to 
1.07 hours, while the t1/2 was slightly longer for the metabolites. Mean plasma Sp-SB 9000 t1/2 
ranged from 4.65 to 8.90 hours on Days 1 and 7. Mean plasma Rp-SB 9000 t1/2 ranged from 
4.31 to 5.94 hours on Days 1 and 7. Mean peak GS-9992 plasma concentrations and the area 
under the analyte concentration versus time curve from time zero extrapolated to 24 hours 
(AUC0-24) were consistently higher on Day 7 (mean Cmax range: 0.885 to 6.66 ng/mL and mean 
AUC0-24 range: 0.770 to 13.7 ng•h/mL) compared with Day 1 (mean Cmax range: 
0.531 to 3.75 ng/mL and mean AUC0-24 range: 0.512 to 7.91 ng•h/mL). The time to peak 
plasma of GS-9992 concentration levels was similar after single or multiple oral doses of 
GS-9992 administration with median Tmax ranging from 1.00 to 1.51 hours on Day 1 and 
1.00 to 1.28 hours on Day 7.
Mean peak plasma Sp-SB 9000 concentrations across all dose levels were comparable between 
Day 7 (range: 7.13 to 16.5 ng/mL) and Day 1 (range: 7.76 to 22.0 ng/mL). The time to peak 
plasma Sp-SB 9000 concentration levels appeared slightly longer after single administration 
compared with multiple administrations with median Tmax ranging from 4.32 to 7.51 hours on 
Day 1 and from 1.50 to 4.23 hours on Day 7. Mean peak plasma concentrations across all dose 
levels were comparable between Day 7 (range: 4.85 to 14.7 ng/mL) and Day 1 
(range: 4.32 to 12.6 ng/mL). For the metabolites, based on the mean accumulation factor R 
(AUC) across dose levels for Sp-SB 9000 (i.e., from 1.39 to 1.61) and Rp-SB 9000 
(i.e., 1.24 to 1.51), a low to moderate accumulation of Sp-SB 9000 and Rp-SB 9000 was 
observed following repeated QD oral dosing of GS-9992 for 7 days.
There were no relationships between GS-9992 or its metabolites and AUC0-t, the area under the 
plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-τ), or 
the minimum drug concentration after dosing (Cmin) and maximum suppression of HCV RNA. A 
significant relationship between GS-9992 Cmax at steady state and maximum suppression of HCV 
RNA on Day 7 was observed (p = 0.015) after exclusion of 2 subjects with extreme Cmax values 
for GS-9992. GS-9992 was generally well tolerated in both parts of the study. The most 
frequently reported treatment-emergent adverse event (TEAE) following multiple dosing with 
GS-9992 was headache (12 events reported by 10 subjects). Headache was mild and self-limited. 
Diarrhea, nausea, ALT increase, AST increase, and insomnia were reported for 2 subjects each. 
The ALT/AST elevations on treatment were less than 5 × the upper limit of normal (ULN), all 
occurred after treatment had been completed and no subject had hyperbilirubinemia.
Phase 2 Clinical Studies
GS-9992 (SB 9200) is currently being evaluated in the ACHIEVE trial (SBP-9200-HBV-201), a 
double-blind, placebo-controlled Phase 2 study in HBV treatment-naïve patients to identify the 
optimal dose of GS-9992 as both monotherapy and in combination with tenofovir DF 300mg 
daily. Enrollment was completed in South Korea, Taiwan, Hong Kong, and Canada. GS-9992 
doses were administered one hour before or one hour after meals with approximately 240 ml of 
water. 
Preliminary safety data from all cohorts in the ACHIEVE trial evaluating GS-9992 25mg, 50mg, 
100mg, and 200mg for 12 weeks are provided below. Primary end points were safety and 
antiviral response defined by reduction in HBV DNA at Week 12. 


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Preliminary Safety
In the Ph 2 study (SBP-9200-HBV-201 [ACHIEVE]) in CHB patients at doses between 25 and 
200 mg dosed daily for 12 weeks, all TEAEs were mild to moderate, and the majority were 
judged as unrelated to study drug administration by the investigator. There were no flu-like 
events, IFN-like side effects or non-specific immune side effects. At 200 mg there was a single 
SAE of hospitalization for knee pain which was considered unrelated by the investigator. Three 
placebo and 6 active patients had ALT flares as defined by elevation of ALT >5 X ULN or 2X 
nadir, which were considered AEs of special interest. ALT flare was the only Grade 3 laboratory 
abnormality noted with the exception of one subject who had a Grade 3 triglyceride elevation, 
which was not confirmed with repeat testing. No ALT flare was associated with a significant 
increase in bilirubin or INR or a decrease in albumen. No subjects with ALT flare met Hy’s law 
defined as ALT >3xULN AND total bilirubin >2xULN. In the active arm, flares were associated 
with a reduction in HBV DNA and were considered immune flares. One patient who’s ALT went 
above 10X ULN had inarigivir dosing discontinued at Week 4, with a switch to tenofovir 
disoproxil fumarate as per protocol. In  2 placebo patients, one ALT flare was secondary to a 
reversion from HBeAg negative to positive with an increase in HBV DNA by 1 log10 and the 
second flare was consistent with natural fluctuations of ALT in HBV patients. There were no 
other Grade 3 or 4 changes in hematology or biochemistry at the time of the flares. Additional 
data per Cohort are provided below
In Cohort 1 (25mg) there were Male 12: Female 8, mean age 40.5 years with 18 Asians and 
2 Caucasians. 11 were HBeAg-positive and 9 HBeAg-negative, genotype A 2, B 9, C 7 and D 2. 
Baseline viral burden was higher in HBeAg+ (mean HBV DNA 7.1 log10; mean quantitative 
HBsAg 4.38 log10) compared to the HBeAg- patients (mean HBV DNA 5.5 log10; mean 
quantitative HBsAg 3.18 log10). There were no clinical, hematological or biochemical SAEs and 
no interferon-like side effects. 11 patients had treatment-emergent AEs and there was no notable
difference in the number or type of AEs between GS-9992 or placebo patients with the most 
common (20%) being non-specific GI complaints of constipation, abdominal pain, nausea and 
diarrhea. All AEs were graded mild to moderate. Three patients had ALT flares > 200 IU. 
Two placebo patients had viral flares including an HBeAg-neg reversion to HBeAg-pos; the 
other flare was immune related at week 4 in a patient on GS-9992 who had an associated 
2.32 log10 reduction in HBV DNA and a 1.01 log10 reduction in HBsAg. All 3 patients were 
dose-reduced to every other day. 
In Cohort 2 (50mg), all subjects were Asian. Subjects administered GS-9992 50mg were 
primarily HBeAg positive (68.8%, n=11) and male (87.5%, n=14). The average age was 
39.7 years old (SD = 11.80, range 19-61), and the average BMI at baseline was 
23.88 (SD = 4.440, range 17.0-31.1). The median treatment duration was 12.10 weeks with range 
(0.3-12.3) weeks and the average daily dose was 46.21 mg (SD: 5.117; range [35-50]). 
Two subjects had dose modifications due to adverse event and 1 due to the subject decision. 
Eleven subjects (68.8%) had at least one TEAE. The most commonly reported (>1 subjects) 
TEAE were headache (n=2), fatigue (n=2), ALT (n=2) and AST elevations (n=2). Four subjects 
(25.0%) had at least one TEAE related to study treatment.  Two subjects had at least 1 TEAE 
leading to discontinuation of the study treatment. One subject discontinued study treatment, 


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GS-9992, due to a TEAE of elevated ALT > 10 ULN and switched to tenofovir with resolution. 
The second patient withdrew from the study and discontinued study treatment at Week 2 due to a 
TEAE of a mild headache.
Two subjects (12.3%) had a Grade 3 ALT increase. Overall, 4 subjects (25.0%) had ALT 
> 3xULN, 2 subjects (12.5%) had ALT > 5ULN and 1 subject (6.3%) had ALT 10xULN. 
Two subjects (12.5%) had AST > 3xULN and no subjects had abnormal alkaline phosphatase or 
total bilirubin values.  Subjects administered placebo were 50% HBeAg positive (n=2) and male 
(n=2) with an average age of 34.5 (SD = 11.62, range 18-45), and an average BMI at baseline of 
22.50 (SD = 1.224, range 20.8-23.6).  The median treatment duration on study was 12.08 weeks 
with range (12.0-12.1) weeks. No subjects had dose modification or dose reduction. Three 
subjects (75%) had at least one TEAE and 1 subject (25%) had at least one TEAE related to 
study treatment. No TEAE was reported in >1 subject, however, ALT and AST elevations was 
also reported in 1 PBO subject. No TEAE leading to discontinuation of study treatment were 
observed in the placebo arm. Two subjects (50.0%) had ALT > 3xULN and no subjects had 
abnormal AST, abnormal alkaline phosphatase or total bilirubin values. 
In Cohort 3 (100mg), 19 subjects were Asian. Subjects administered GS-9992 100mg were 
primarily HBeAg positive (76.5%, n=13) and male (58.8%, n=10), with an average age of 
36.7 years old (standard deviation = 7.48, range 23-51) and an average BMI at baseline of 
26.28 (standard deviation (SD) = 5.043, range 18.2-33.9). The median treatment duration was 
12.10 weeks with range (11.7-12.6) weeks and the average daily dose was 94.29 mg (SD: 8.809; 
range [74-100]). One subject (5.9%) had a dose reduction due to elevated ALT. Ten subjects 
(58.8%) had at least one TEAE and 3 subjects (17.6%) had at least one TEAE related to study 
treatment. The most commonly reported (>1 subject) TEAE was headache (n=2), influenza-like 
illness (n=2), and upper respiratory infection (n=2). No TEAE leading to discontinuation of 
study treatment were observed. One subject (5.9%) had Grade 3 ALT elevation and 1 subject 
(5.9%) had a transient Grade 3 hypertriglyceridaemia. Five subjects (29.4%) had ALT > 3xULN 
and 2 subjects (11.8%) had ALT > 5xULN. Three subjects (17.6%) had AST > 3xULN. No 
subjects had abnormal alkaline phosphatase or total bilirubin values. Of 3 subjects administered 
placebo two were HBeAg positive and one was male with an average age of 44.3 (standard 
deviation = 15.95, range 31-62) and average BMI at baseline of 23.14 (SD = 4.089, range 18.5-
26.2). The median duration on study was 12.10 weeks (range 11.9-12.3 weeks). No subject had a 
dose modification or dose reduction.  Two subjects (66.7%) had at least one TEAE and none 
were related to study treatment. No TEAE was reported in >1 subject, however, influenza-like 
illness was also reported in 1 PBO subject. No TEAE leading to discontinuation of study 
treatment were observed. No subjects had increase in ALT, AST, abnormal alkaline phosphatase 
or total bilirubin values.
In Cohort 4 (200mg), the preliminary demographics of first 15 subjects (12 active and 3 placebo) 
enrolled showed all were Asian and included equal proportion of HBeAg positive and negative 
CHB patients. Majority were female (60%, n=9), with an average age of 50.4 years old (range 
24-64). These 15 subjects all completed 12 weeks of treatment with GS-9992 200 mg
monotherapy. No subjects required dose modification or discontinuation. Eight of 15 subjects 
(73.3%) had at least one TEAE and none had a TEAE considered related to study treatment by 
the investigators. The most commonly reported (>1 subject) TEAE in the subjects was influenza 


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like illness (n=2) in 1 subject on active and 1 subject on placebo. 2 subjects had a clinically 
significant laboratory abnormality noted: 1 subject had an ALT elevation >5xULN at Week 2 
that decreased to <5xULN by Week 5 while on treatment and 1 subject had a transient increase 
in AST >2x nadir at Week 4 that resolved by Week 6 on treatment. There was also, 1 SAE of a 
bilateral knee pain that required hospitalization for surveillance reported; the SAE was not 
considered related to study drug by the investigator. No other notable safety events have been 
observed.
Preliminary Efficacy
Cohort 1, at week 12, mean change in HBV DNA was -0.58 log10 IU/mL in GS-9992 compared 
to +0.37 log10 IU/mL  in placebo patients (p = 0.014). HBV DNA reduction was greater in 
GS-9992 - treated HBeAg-negative patients (mean -0.86 log10 IU/mL) compared to HBeAg-
positive patients (mean -0.37 log10 IU/mL). Overall 5 of 16 patients (31%) had a maximal 
>0.5 log10 IU/mL reduction in HBsAg (range 0.52 – 1.01 log10 IU/mL).
Cohort 2, at week 12, mean change in HBV DNA was -0.61 log10 IU/mL in HBeAg positive and 
-1.05 log10 IU/mL in HBeAg negative subjects administered GS-9992 compared to +0.33 log10
in placebo patients.  Change in mean HBV RNA decline at week 12 was -0.46 log10 IU/mL in 
HBeAg positive and -3.15 log10 IU/mL in HBeAg negative subjects administered GS-9992 
compared to +0.0.48 log10 IU/mL in placebo patients. 
Cohort 3, at week 12, mean change in HBV DNA was -0.55 log10 IU/mL in HBeAg positive and 
-2.26 log10 IU/mL in HBeAg negative subjects administered GS-9992 compared to +0.25 log10
in placebo patients.  Change in mean HBV RNA decline at week 12 was -0.49 log10 IU/mL in 
HBeAg positive and -3.2 log10 IU/mL in HBeAg negative subjects administered GS-9992 
compared to +0.04 log10 IU/mL in placebo patients.
Additional details on GS-9992 are provided in the Investigator’s Brochure (IB) for SB 9200.
1.2.3.
Preclinical Pharmacology and Toxicology
The in vitro and in vivo studies conducted to date indicate that orally administered GS-9992 
should be well tolerated. In a dose-range finding study in monkeys, GS-9992 was administered 
orally at 500 mg/kg/day for 4 consecutive days and the compound was clinically well tolerated 
with no overt toxicity except for up to a 2-fold elevation in alanine aminotransferase (ALT) and a 
6 fold elevation in aspartate aminotransferase (AST) levels, which were reversible following 
cessation of dosing. In a 2-week repeat-dose toxicity and toxicokinetic study in monkeys, GS 
9992 produced no adverse effects in the toxicological endpoints evaluated in this study at oral 
doses up to and including 360 mg/kg/day. Clinical chemistry changes on Day 10 and at 
termination consisted of increased ALT (up to 301%) and increased triglycerides (up to 118%) in 
males administered 360 mg/kg/day. These findings had generally resolved by the recovery 
interval. No changes were observed in females administered 360 mg/kg/day. In a single dose 
cardiovascular study in cynomolgus monkeys, oral administration of GS-9992 produced no 
effects on cardiovascular function at doses up to and including 500 mg/kg. Safety pharmacology 
studies in rats to evaluate pulmonary and central nervous system (CNS) function also 


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demonstrated no effects of GS-9992, at doses as high as 500 mg/kg, on any respiratory or 
neurophysiological endpoints.
Long-term toxicity was evaluated in a 13-week repeat-dose study with a 4-week recovery period. 
In this study, the potential subchronic toxicity of GS-9992 in cynomolgus monkeys was 
evaluated. In addition, the study included an evaluation of reversibility, progression, or delayed 
appearance of any observed changes following the 4-week postdose observation period. Animals 
were administered GS-9992 at 0, 90, 180, and 360 mg/kg once daily (QD). Dose-limiting 
toxicity (DLT) was observed at 360 mg/kg/day. Although several of the clinical chemistry and 
histopathological findings were reversible, the constellation of microscopic findings in the liver 
at the terminal and recovery necropsy, in conjunction with the increased liver enzyme values, 
were considered adverse in females at ≥ 90 mg/kg/day and males at ≥ 180 g/kg/day.
Accordingly, oral administration of GS-9992 produced adverse effects in females at all dose 
levels evaluated and males at doses ≥ 180 mg/kg/day. Although no observed adverse effect level 
(NOAEL) could be established for females in this study; the NOAEL for males was determined 
to be 90 mg/kg/day. A second study was conducted in cynomolgus monkeys that were 
administered GS-9992 daily at doses of 0, 15, 30, or 60 mg/kg/day for 13 weeks with a 4-week 
recovery period for the high dose group. 
Assessment of toxicity was based on mortality, clinical observations, body weight, 
ophthalmoscopic, and electrocardiographic examinations; and clinical and anatomic pathology. 
The liver was the primary target organ with a constellation of microscopic findings. At doses of 
≥ 30 mg/kg/day, there were dose-dependent findings of hepatocyte enlargement, hepatocyte 
vacuolar degeneration, mixed leukocyte infiltration/inflammation, and increased pigmentation 
and hypertrophy of Kupffer cells. Additional microscopic findings at 60 mg/kg/day included 
individual hepatocyte necrosis, increased mitotic figures, multinucleated hepatocytes, and bile 
duct hyperplasia. Following the recovery period, the findings at 60 mg/kg/day were reversing, 
although incomplete. These microscopic findings were supported by the alterations in the clinical 
chemistry parameters. The constellation of microscopic findings in the liver at the terminal and 
recovery necropsies, in conjunction with increased serum enzyme values and decreased serum 
albumin and fibrinogen values (changes generally associated with hepatocellular injury), were 
considered adverse in both sexes at ≥ 30 mg/kg/day. Accordingly, oral administration of GS 
9992 produced adverse effects in both sexes at ≥ 30 mg/kg/day; therefore, the NOAEL was 
determined to be 15 mg/kg/day. 
In a GLP 39-week oral gavage toxicity study, cynomolgus monkeys were administered inarigivir 
at doses of 0, 5, 10, 15, or 20 mg/kg/day for 39 weeks or at doses of 30 or 60 mg/kg three times 
weekly for 39 weeks. In animals that survived their scheduled termination, the oral 
administration of SB 9200 once daily at doses of 5, 10, 15, and 20 mg/kg/day or tri-weekly at 30 
mg/kg/day was well tolerated and did not result in any signs of overt toxicity. Microscopic 
changes in animals administered tri-weekly at 30 mg/kg/day were noted in the liver, which 
included minimal hepatocellular single cell necrosis and minimal mixed cell infiltrate in 7/8 
animals, and minimal intracellular hemosiderin pigment in 1/8 animals. However, there were no 
adverse events found in animals administered doses at or lower than 20mg/kg/day, therefore the 


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NOAEL in this study was judged to be 20 mg/kg/day. This study is still in the reporting phase 
and the toxicokinetic parameters have not yet been reported. However, the microscopic findings 
in the liver at 30 mg/kg dosed TIW was consistent with previous studies and lack of findings at 
20 mg/kg/day was similar to the results in the 13 week study in cynomolgus monkeys where no 
findings were observed at the 15 mg/kg/day dose level.
Additional details of the nonclinical studies for GS-9992 are provided in the Investigator’s
Brochure (IB) for SB 9200.
1.3.
TAF (GS-7340)
Vemlidy®, (GS-7340) (2:1) is a novel oral prodrug of tenofovir (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. 
For further information on TAF (GS-7340), please refer to the current Investigator’s Brochure 
for TAF.
1.3.1.
General Information
Please refer to the TAF (GS-7340) Investigator’s Brochure for further information on TAF, 
including:

In Vitro Anti-Hepatitis B Virus Activity

Nonclinical Pharmacokinetics and In Vitro Metabolism

Nonclinical Pharmacology and Toxicology

Clinical Experience
1.3.2.
Clinical Trials of TAF
Overall, approximately 2403 subjects have been enrolled in the TAF clinical program, of which 
approximately 1856 subjects have received Vemlidy single agent (439 healthy volunteers, 
1331 CHB infected subjects, and 86 HIV-1 infected subjects). 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, and a comprehensive Phase 1 program that also included evaluations of TAF 
and TFV PK in subjects with impaired renal or hepatic function (additional information is 
provided in the IB).
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.
TAF clinical studies which are currently ongoing are listed below:


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
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(ongoing)

GS-US-320-4018, 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 mg QD in Subjects with Chronic Hepatitis B who are Virologically 
Suppressed (ongoing)

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 (NUC) in Virologically Suppressed Chronic Hepatitis B 
(CHB) Subjects with Renal Impairment and/or Hepatic Impairment (ongoing)
Please refer to the latest version of the Investigator’s Brochure for TAF for further information 
on the clinical program.
An overview of the ongoing 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, non-inferiority, 
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, non-inferiority, 
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.


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In both of these similarly designed non-inferiority 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 NUC
treatment status (treatment naive vs treatment experienced) at screening. In both studies, all 
subjects completing at least 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).
Table 1-1.
Clinical Studies to Support Efficacy for the TAF Marketing 
Applications
Study
Study Design
Treatment Regimen 
(Number of Subjects)
Primary Endpoint
Analysis
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%).


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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%
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 non-inferiority to the TDF group.
Table 1-2.
GS-US-320-0108 and G -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. 


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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.
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 1-3. 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 1-3.
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.


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Safety of TAF in CHB Subjects
The principal sources of safety data for TAF are presented 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.
Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-4 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 1-4.
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:
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
Any AE with an onset date on or after the study drugs start date for those who had not discontinued study drug permanently, or
Any AEs leading to study drug discontinuation
Source: TAF Week 48 ISS, Table 6


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Common Adverse Events
Table 1-5 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 1-5.
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 1-6 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 1-6.
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
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 1-7 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 


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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.
Table 1-7.
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 (i.e., 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’ mea
ns low.
Source: TAF Week 48 ISS, Table 20


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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 
(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 post baseline 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:


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
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
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.
Please refer to the latest version of the Investigator’s Brochure for TAF for further information 
on the clinical program.
1.4.
Rationale for This Study
Given the low rate of HBsAg loss with currently available therapies and the treatment burden
associated with life-long treatment to maintain viral suppression, there is a need to identify new 
therapies that may provide durable HBsAg loss with a finite treatment duration. The primary
objective is to evaluate the safety, tolerability and efficacy of GS-9992 in association with an 
oral nucleotide (NUC) HBV polymerase inhibitor (TAF or other commercially available NUC) 
for the treatment of CHB subjects, while also evaluating the changes in HBV specific immune 
responses following treatment with GS-9992.
This Phase 2 study will be conducted in subjects with CHB, who are currently not receiving 
treatment for CHB (can be either treatment naïve or previously treated) or are virally-suppressed 
on a commercially available oral NUC. Viremic subjects with CHB generally have a rapid 
decline in viremia in response to beginning antiviral treatment. The decrease in viral burden may 
allow for an increased responsiveness to immune stimulation and forms the basis for the design 
of Groups 1-3 and 5 in this study. To further evaluate GS-9992 ability to improve immune 
response, an additional group, Group 4, will enroll virally-suppressed CHB subjects on a 
commercially available NUC.  The immune responsiveness of CHB patients has been shown to
improve in patients who are on chronic suppressive antiviral therapy with less antigen burden.  
Virally-suppressed patients will have lower levels of HBV virions and proteins, including 
HBsAg, within the serum as well as lower expression of HBV antigens within infected 
hepatocytes.  Therefore Group 4 will evaluate the potential maximal efficacy benefits of 
GS-9992 in virally-suppressed CHB subjects.


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Further, the safety data with GS-9992 in treatment naive subjects and in virally-suppressed 
subjects was evaluated in a Phase 1b study SBP-9200-101 and in the ongoing Phase 2 study 
SBP-9200-HBV-201. Both studies support the evaluation of GS-9992 in these populations. 
Subjects will be stratified by HBeAg status. HBeAg status has been shown in prior studies of 
TDF (GS-US-174-0102 and GS-US-174-0103) to be a predictor of eventual HBsAg loss with 
TDF treatment irrespective of HBV genotype. 
1.4.1.
Rationale for Dose Selection
GS-9992 for Groups 1-4
In a 3-month, repeat-dose toxicology study conducted in rat (50, 150, and 250 mg/kg/day) and 
monkey (15, 30, and 60 mg/kg/day), the NOAEL was determined to be 250 mg/kg for the rat and 
15 mg/kg for the monkey. Thus, monkey was considered to be the most sensitive species and 
was used to designate the minimum recommended starting dose (MRSD) for clinical studies. The 
NOAEL in humans corrected for body surface area (equation 1) using the NOAEL from monkey 
(15 mg/kg) and the mean body weight of the monkeys in that dose group (2.9 kg) resulting in a 
human equivalent dose (HED) for the human equivalent NOAEL of 3.43 mg/kg. To allow for a 
10-fold safety margin, a dose of 0.34 mg/kg was selected as the MRSD. This is equivalent to a 
dose of 24 mg to a 70 kg human. Thus, the starting dose for the clinical study in HBV patients is 
proposed to be 25 mg (or 0.36 mg/kg).  
Equation 1: HED = (animal dose in mg/kg * body weight in kg)0.33
The MRSD chosen for the proposed clinical study is 25 mg to be incrementally increased up to 
400 mg. These doses are expected to be effective against HBV in patients, based upon 
nonclinical studies. A dose of 9 mg/kg administered to a woodchuck model of hepatitis for 
4 weeks was efficacious against hepatitis B infection as assessed by a decline in HBV DNA. In a 
subsequent study, a dose of 15 mg/kg/day for 12 weeks resulted in dose and time-related decline 
in HBV viral DNA that was at or near baseline values at the end of the study. In a transgenic 
HBV mouse model, a dose of 10 mg/kg produced statistically significant decline in HBV DNA. 
By correcting for body surface area, the human equivalent efficacious dose calculated from 
woodchuck efficacy studies ranged from 2.5 to 5 mg/kg (mean body weight 2.8 kg). The human 
equivalent efficacious dose calculated from the murine efficacy studies was 0.62 mg/kg (mean 
body weight of 0.034 kg). Since the proposed doses in the clinical study range from 25 mg up to 
400 mg or 0.36 to 5.76 mg/kg in a 70 kg patient, it is reasonable to expect that this dose range 
will be therapeutically effective in HBV patients. 
In the ongoing Phase 2 ACHIEVE trial, all subjects in Cohorts 1,2, 3, and 4 (n = 20/ cohort) have 
completed treatment with GS-9992 (SB 9200) 25 mg, 50mg, 100mg, and 200mg once daily 
monotherapy for 12 weeks. There were no clinical, hematological or biochemical SAEs and all 
AEs were graded mild to moderate in severity. 
There were no interferon-like side effects, except for 3 subjects with mild AE of flu-like 
symptoms in Cohort 3, 1 of the 3 subjects was administered placebo. There were no dose 
proportional increases in the number or severity of treatment-emergent adverse events reported. 


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Overall, 6 subjects experienced an ALT flare >200 IU/mL, 2 subjects were on placebo; no 
subjects have met Hy’s law.  
GS-9992 50 mg and 100 mg monotherapy for 12 weeks demonstrated a mean change in HBV 
DNA of -0.61 log10 IU/mL and -0.55 log10 IU/mL in HBeAg positive subjects, respectively, and 
-1.05 log10 IU/mL and -2.26 log10 IU/mL in HBeAg negative subjects, respectively. The mean 
change in HBV RNA decline at week 12 was -0.46 log10 IU/mL and -0.49 log10 IU/mL in 
HBeAg positive and -3.15 log10 IU/mL and -3.2 log10 IU/mL in HBeAg negative subjects 
administered GS-9992 50 mg and 100 mg, respectively.  
The safety and efficacy results from the Phase 2 ACHIEVE trial support further evaluation of the 
50 mg and 100 mg dose of GS-9992 in combination with a NUC in this study. The 200mg 
GS-9992 monotherapy for 12 weeks is currently being evaluated in Cohort 4 in the ACHIEVE 
trial. Safety of the 200mg GS-9992 monotherapy has been confirmed by ACHIEVE trial's 
independent Data Safety Monitoring Board.  To date, no safety concerns have been observed. 
GS-9992 for Group 5 (400 mg)
GS-9992 (aka inarigivir and SB 9200), developed by Spring Bank Pharmaceuticals, is a prodrug 
of SB 9000, which consists of two diastereomers Rp-9000 and Sp-9000 for the treatment of 
hepatitis B virus (HBV) infection. In vitro and in vivo studies have established that both forms of SB 
9200 have antiviral activity against HBV and HCV ribonucleic acid (RNA) viruses. Upon oral 
administration, both prodrug SB 9200 isomers are equivalently converted to their active dinucleotide 
metabolites SB 9000 by esterases. Phase 1 clinical testing is complete, and a 12-week Phase 2 study 
(SBP-9200-HBV-201) is currently ongoing in HBV-infected patients. The safety and 
pharmacokinetic profile of SB 9200 and its active diastereomer metabolites have been 
extensively characterized in healthy subjects and patients. Both the pharmacokinetic properties 
and accumulated pre-clinical and clinical safety of all active moieties of SB 9200 support 
extended administration of 400 mg in the target patient population (reference SB 9200 IB). 
In vitro binding studies showed dose-dependent binding of SB 9200 and SB 9000 to RIG-1 and 
equipotent activity of Rp and Sp isomers of SB 9000. Additionally, in vitro, SB 9000 
demonstrated a dose dependent reduction in viral replication in either primary human 
hepatocytes or HepG2.2.1.5 cells infected with HBV with EC50 ranging from 0.2 uM to 2 uM
depending on treatment duration. To connect the inarigivir concentrations that were seen to be 
active in vitro to the clinical setting it is necessary to consider that inarigivir and SB 9000 are 
found to concentrate in the liver at levels greater than 20-fold as compared to the plasma as was 
shown in rat distribution studies and when inarigivir levels were measured in the rat following 
repeated administration. The plasma Cmax values of SB 9000 observed in the DDI study (SBP-
9200-HBV-202) at 400 mg were 11.19 ng/ml and assuming similar concentrative activity of SB 
9000 in the liver of humans as was observed in the rat there would be liver concentrations of SB 
9000 of approximately 405 nM at the time of maximal concentration. Anti-viral activity of SB 
9000 was observed in vitro in various test systems at concentrations below and above this value.
In vivo pharmacology studies following IP injection of 100 mg/kg/day showed significant reduction 
of viral DNA load in the liver of transgenic mice, with antiviral activity similar to that of adefovir. 


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The minimally effective dose in this model was 1 mg/kg. Similar studies conducted with oral SB 
9200 showed the minimal effective dose to be between 1 and 10 mg/kg. Other, in vivo studies in 
naturally infected (WHV) woodchucks showed induction of RIG-1 in liver biopsies after 12 weeks 
treatment, with dose-dependent activity following 12 weeks of 15 and 30 mg/kg/day resulting in 
reduced surface antigen and serum WHV DNA; delayed viral relapse at higher dose; elevated IFN, 
RIG-1, NOD2; and significant reductions in hepatic viral DNA, RNA, cccDNA. Although the 
pharmacokinetics of SB 9000 were not measured in the pharmacology studies, the lowest doses of 
SB 9200 shown to have efficacy in these pharmacology models were 10 mg/kg/day in the mouse and 
15mg/kg in the woodchuck, on the basis of body surface area, the human equivalent doses of either 
the mouse or the woodchuck would be adequately covered by a 400 mg/day dose in humans.
The pre-clinical and clinical profile of inarigivir supports its exploration as a potential treatment 
option for patients with HBV at 400 mg. The pre-clinical toxicology studies have consistently 
indicated that the monkey is the more sensitive species and that the liver is the sole target organ 
of inarigivir mediated toxicity. The exposure parameters Cmax and AUC(0-t) at the identified 
NOAEL in the longest term completed GLP toxicology study are 3.5 and 1.7-fold higher 
respectively than those observed when 400 mg was administered in the clinic. In all of the 
clinical studies conducted so far where doses between 25 and 900 mg have been administered 
daily for durations between 7 days and 12 weeks, the safety profile has been acceptable and there 
have been no changes in liver safety parameters that were independently associated with 
inarigivir, instead the changes in liver enzyme levels to date have been correlated with immune 
flares consistent with an ongoing HBV infection.  
The clinical safety of a 400 mg daily dose of inarigivir in HCV patients has been tested in two 
different studies for durations of either 7 or 12 days and demonstrated a benign safety profile in each 
case. Additionally, inarigivir has been shown to be well tolerated at doses more than 2-fold greater 
than the target dose of 400 mg QD for 7 consecutive days. In the ongoing ACHEIVE Ph 2 study 
(SBP-9200-HBV-201), HBV patients have been administered up to 200 mg daily for 12 weeks with a 
similar benign safety profile as was observed in the shorter-term studies. The clinical 
pharmacokinetics of inarigivir and its primary active metabolites Sp-9000 and Rp-9000 have 
demonstrated predictable and linear PK over a dose range of 25-900 mg. Accumulation of its active 
metabolites is minimal following multiple dose administration and the change in exposure with dose 
is consistent with dose proportionality. In the Ph1 study (SB12-9200-101), a statistically significant 
relationship between SB 9200 Cmax at steady-state and maximum suppression of HCV RNA on Day 
7 was observed (p=0.015). In the HCV trial (SB12-9200-101), the peak individual viral load drop 
was observed to improve from 1.5 to 1.9 log10 when the dose of SB 9200 increased from 200 to 400 
mg. Further dose increases did not result in response increases. In the ongoing Ph 2 study (SBP-
9200-HBV-201) in CHB patients, at doses between 25 and 100 mg there was an observed dose 
response in anti-viral clinical activity without an as yet observed plateau, indicating that higher doses 
could have increased levels of efficacy. This observation parallels with the observed dose 
proportionality of the plasma pharmacokinetics of inarigivir. Based on these observations it is 
proposed that a 400 mg daily dose administered to patients with HBV would lead to plasma and liver 
levels of inarigivir consistent with increased activity on the hepatitis B virus infection as well as a 
benign safety profile. To further ensure safety of the administration of GS-9992 400 mg plus TAF for 
12 weeks in Group 5, safety data of 200mg GS-9992 plus TAF through Week 12 in all subjects 
enrolled in Group 3 will be confirmed by the Medical Monitor prior to enrollment of Group 5. 


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TAF
TAF 25 mg (Vemlidy®) is the marketed dose approved for the treatment of chronic hepatitis B 
infection in adults. 
1.5.
Risk/Benefit Assessment for the Study
GS-9992
GS-9992 is a new class of pharmaceuticals known as small molecule nucleic acid hybrids. 
GS-9992 is being developed to provide patients with CHB with a finite duration, curative 
treatment option and for beneficial antiviral response. GS-9992 has a dual mechanism of action 
involving: (a) selective activation of the host cytosolic proteins – retinoic acid-inducible gene 1 
(RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), which 
are involved in recognition of viral nucleic acids that result in the stimulation of interferon (IFN) 
production and induction of antiviral state in infected cells, and (b) direct inhibition of viral 
replication by blocking the access of the viral polymerase to the viral nucleic acid template. This 
is due to the interaction of GS-9992 with the nucleotide-binding domain of RIG-I and NOD-2 
that sterically hinders the axis of viral polymerase to the viral ribonucleic acid (RNA) template. 
The stimulation of IFN production by GS-9992 also causes the induction of these innate immune 
responder genes, RIG-I and NOD-2, by a feed-back loop and further potentiates the antiviral 
activity.
This stimulation results in the induction the innate immune response critical to achieve 
hepatitis B surface antigen (HBsAg) loss. The loss of HBsAg is the gold standard endpoint for 
anti-HBV therapy and allows for cessation of treatment {EASL 2012, Liaw 2012, Lok 2009}. 
Loss of serum HBsAg is associated with improvement in both the rates of liver cirrhosis and the 
development of hepatocellular carcinoma in patients with CHB, and in increased survival rate 
{Idilman 2012, Kim 2013, Moucari 2009, Simonetti 2010}. While HBsAg loss is the ultimate 
goal of treatment, it occurs at a very low rate and over several years: less than 10% of patients 
achieve clearance of HBsAg with the therapeutic options currently available. Thus, new 
treatment options that enhance rates of HBsAg loss are needed. Through these effects on the 
innate and adaptive response and immune effectors and HBV-specific T cell and B cell
responses, activation of retinoic acid inducible gene (RIG-I) and nucleotide-binding and 
oligomerization domain 2 (NOD2), may provide a novel component of treatment for patients 
with chronic HBV infection. The warnings and precautions for GS-9992 that may be relevant to 
a human population include observations of elevated AST and ALT in monkey studies and in the 
Phase 1 study (SB12-9200-101) in treatment-naïve HCV-infected adults. GS-9992 up to 900 mg 
was generally well tolerated in the study. The most frequently reported treatment-emergent 
adverse event (TEAE) following multiple dosing with GS-9992 was headache (12 events 
reported by 10 subjects). Headache was mild and self-limited. Diarrhea, nausea, ALT increase, 
AST increase, and insomnia were reported for 2 subjects each. The ALT/AST elevations on 
treatment were less than 5 × the upper limit of normal (ULN), all occurred after treatment had 
been completed and no subject had hyperbilirubinemia (see full details in the SB 9200 IB). 


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To minimize potential risks in the proposed study, patients will be required to have adequate 
hematologic function at study entry and sufficient hepatic reserve (F0-F2). The protocol will 
follow patient laboratory and vital sign changes routinely and allows for more frequent 
monitoring based on clinically significant changes. Also, specific parameters that would lead to 
dose interruption or discontinuation are included in Section 6.11. 
In summary, the goal of the GS-9992 program is to address a major unmet need for CHB 
patients, namely to enhance rates of serum HBsAg loss with a finite duration treatment regimen. 
Study GS-US-464-4437 will investigate the efficacy of 50 mg, 200 mg, and 400 mg of GS-9992
administered orally once daily to patients with CHB currently not on treatment and 100 mg of 
GS-9992 in virally suppressed patients on a commercially available NUC. Patient safety will be 
carefully monitored by periodic safety assessments, and by implementation of stringent pre-
defined stopping rules. 
In view of the potential for developing GS-9992 as a finite-duration, curative treatment for CHB, 
the existing safety data and the GS-US-464-4437 study design defined to carefully monitor 
patient safety, the benefit/risk balance for this study is considered positive.
TAF
TAF 25 mg (Vemlidy®) has been approved globally for the treatment of CHB in adults. 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.
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:

To evaluate the safety and tolerability of the 12 week treatment regimens of GS-9992 plus 
TAF or commercially available NUC

Groups 1-3 and 5
To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in 
viremic CHB subjects as measured by the proportion of subjects with ≥0.5 log10 IU/mL 
decline from Baseline at Week 12 in circulating serum HBV surface antigen (HBsAg) 

Group 4
To evaluate the antiviral activity of 12 weeks of GS-9992 with commercially available 
NUC(s) in virally suppressed CHB subjects as measured by the proportion of subjects with 
≥0.5 log10 IU/mL decline from Baseline at Week 12 in circulating serum HBV surface 
antigen (HBsAg)
The secondary objectives of this study are: 

Groups 1-3 and 5

To evaluate the safety and tolerability of the 48 week treatment regimens as assessed by 
review of the accumulated safety data

To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in 
CHB subjects as measured by the proportion of subjects with ≥1 log10 IU/mL decline from 
Baseline at Week 12 in circulating HBsAg  

To evaluate the proportion of HBeAg-positive CHB subjects who achieve HBeAg loss and 
seroconversion during 12 weeks of GS-9992 plus TAF versus TAF alone and after GS-9992 
discontinuation through 48 weeks

To evaluate the proportion of CHB subjects who achieve HBsAg loss during 12 weeks of 
GS-9992 plus TAF versus TAF alone and after GS-9992 discontinuation through 48 weeks 

To evaluate the incidence of drug resistance mutations during 48 weeks of treatment

To characterize steady-state pharmacokinetics of study drugs

To evaluate the change from Baseline in HBV DNA and quantitative HBsAg in CHB 
subjects during 12 weeks of GS-9992 plus TAF versus TAF alone and after GS-9992 
discontinuation  through 48 weeks


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• 
Group 4 
• 
To evaluate the propo1iion of subjects experiencing HBV virologic breakthrough 
Final 
Amendment3 
(2 consecutive visits of HBV DNA 2::: 69 IU/mL) during 12 weeks of GS-9992 treatment 
• 
To evaluate the antiviral activity of 12 weeks of GS-9992 in CHB subjects as measured by 
the propo1i ion of subjects with ~l log10 IU/mL decline from Baseline at Week 12 in 
circulating HBsAg 
• 
To evaluate the propo1iion of HBeAg-positive CHB subjects who achieve HBeAg loss and 
seroconversion during 12 weeks of GS-9992 and after GS-9992 discontinuation through 
48 weeks 
• 
To evaluate the propo1iion of CHB subjects who achieve HBsAg loss during 12 weeks of 
GS-9992 and after GS-9992 discontinuation though 48 weeks 
• 
To characterize steady-state phan nacokinetics of study mugs 
• 
To evaluate the change from Baseline in quantitative HBsAg in CHB subjects during 
12 weeks of GS-9992 and after GS-9992 discontinuation through 48 weeks 
I 
I 
I 
I 
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3.
STUDY DESIGN
3.1.
Endpoints
Groups 1-3 and 5
The primary efficacy endpoint of this study is the proportion of subjects with ≥0.5 log10 IU/mL 
decline in HBsAg from Baseline at Week 12.
Group 4
The primary efficacy endpoint of this study is the proportion of subjects with ≥0.5 log10 IU/mL 
decline in HBsAg from Baseline at Week 12 in virally suppressed CHB subjects.
The secondary endpoints of this study are:
Groups 1-3 and 5

Proportion of subjects with ≥1 log10 IU/mL decline in HBsAg from Baseline at Week 12

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion through 
48 weeks of treatment

Proportion of subjects who achieve HBsAg loss through 48 weeks of treatment

Proportion of subjects with drug resistance mutations during 48 weeks of treatment

Change from Baseline in HBV DNA and quantitative HBsAg through 48 weeks of treatment
Group 4

Proportion of subjects experiencing HBV virologic breakthrough (2 consecutive visits of 
HBV DNA ≥69 IU/mL) during 12 weeks of GS-9992 treatment

Proportion of subjects with ≥ 1 log10 IU/mL decline in HBsAg from Baseline at Week 12 in 
circulating HBsAg

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion during 
12 weeks of GS-9992 and after GS-9992 discontinuation through 48 weeks

Proportion of subjects who achieve HBsAg loss during 12 weeks of GS-9992 and after 
GS-9992 discontinuation through 48 weeks

Change from Baseline in quantitative HBsAg during 12 weeks of GS-9992 and after 
GS-9992 discontinuation through 48 weeks


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3.2. 
Study Design 
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This is a randomized, open label study to evaluate the antiviral activity of GS-9992 plus T AF or 
commercially available NUC. Subjects will be randomized in a 3:1 ratio to Group 1 and Group 2. 
Randomization will be stratified by HBeAg positive or negative status with approximately 
40% of subjects enrolled with HBeAg negative status. 
Groups 3, 4, and 5 treatment will be assigned. Group 3 will not staii enrolling subjects until the 
ACHIEVE (SB-9200-HBV-201) trial's independent Data Safety Monitoring Board has deemed 
it safe to proceed based on review of data for the 200 mg monotherapy coho1i. 
Group 5 will not staii enrolling subjects until safety of the first 12 weeks of the combination 
treatment in Group 3 has been confnmed by the Medical Monitor. 
Figure 3-1. 
Week 
Group 1 
n=30 
Group 2 
n=10 
Group 3 
n=30 
G roup 4 
n=20 
Group S 
n= 30 
0 
H 
Study Schema 
12 
GS-9992 50 mg QO 
TAF 25 mg QO 
TAF 25 mg QO 
GS-999 2 200 m g QD 
TAF 25 mg QO 
GS-9992 100 mg Q D + 
Commercially available 
NUC 
GS-9992 400 mg Q D (2 X 
200mg 0D) 
TAF 25 mg QO 
48 
TA F 25 mg 
TA F 25 mg 
C ommercial NUC" 
TAF 25 mg 
*Group 4: Subjects who discontinue NUCs should be followed in Treabnent-Free Follow-up 
24 Week Treatment-Free Follow-up 
FU 24 
Subjects that meet any one of the following criteria will be followed for 24 weeks or until the 
initiation of alternative CHB therapy, whichever comes first: 
• 
Subjects that discontinue all HBV therapy (e.g. GS-9992 and/or TAF or commercially 
available NUC), for any reason 
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
Subjects with HBsAg loss confirmed at least 12 weeks apart should discontinue all HBV 
therapy  following confirmation 
3.3.
Study Treatments
Approximately 120 chronic, immune-active, HBV-infected adults without cirrhosis will be 
enrolled; including 100 viremic subjects not currently on HBV nucleos(t)ide (NUC) and 
20 virally suppressed subjects on a commercially available NUC.
Approximately 40 viremic subjects will be randomized (3:1) to Group 1 and Group 2, below:
Groups 1 and 2: Subjects will be randomized (3:1) to the following:

Group 1: Approximately 30 subjects will be administered GS-9992 50 mg (2 × 25 mg
capsules) once daily one hour before or one hour after a meal plus TAF 25 mg once daily
with food for 12 weeks then TAF 25 mg once daily with food for 36 weeks.

Group 2: Approximately 10 subjects will be administered TAF 25 mg once daily with food 
for 48 weeks
Randomization will be stratified by HBeAg status (positive or negative) at screening with 
approximately 40% of HBeAg negative subjects enrolled.
Group 3: Approximately 30 viremic subjects will be administered GS-9992 200 mg (2 x 
100 mg) once daily one hour before or one hour after  a meal plus TAF 25 mg once daily with 
food for 12 weeks then TAF 25 mg once daily with food for 36 weeks.
Approximately 40% of subjects enrolled in Group 3 will be HBeAg negative.
Group 4: Approximately 20 virally suppressed subjects currently being treated with a 
commercially available NUC(s) for CHB will be administered GS-9992 100 mg tablet once daily 
one hour before or one hour after a meal for 12 weeks.
Approximately 50% of subjects enrolled in Group 4 will be HBeAg negative. Subjects will 
remain on their current commercially available NUC(s) therapy for the duration of the study. All 
subjects will be followed through Week 48. 
Group 5 (Hong Kong): Approximately 30 viremic subjects may be enrolled and assigned:
GS-9992 400 mg (2 x 200 mg tablets) once daily one hour before or one hour after a meal plus 
TAF 25 mg once daily with food for 12 weeks then TAF 25 mg once daily with food for 36 
weeks.
3.4.
Duration of Treatment
The duration of study treatment is 48 Weeks. Groups 1, 3, and 5 consist of 12 weeks treatment of 
GS-9992 and TAF followed by TAF only treatment for 36 weeks, and Group 2 is 48 Weeks of 


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T AF only treatment. Group 4 consist of 12 weeks of ti·eatment of GS-9992 and subjects will 
remain on their cmTent commercially available NUC therapy for the duration of the study. All 
subjects will be followed through Week 48. 
All groups include a screening period of up to 45 days. 
3.5. 
3.5.1. 
Bio marker Testing 
Biomarker Samples to Address the Study Objectives 
Biological specimens will be collected in this study and will be used to evaluate the association 
of explorato1y systemic and/or tissue specific biomarkers with study diug response, including 
efficacy and/or adverse events and to increase knowledge and understanding of the biology of 
chronic hepatitis B or related diseases and/or the validation of a companion diagnostic for 
GS-9992. Plasma samples will be collected to measure cytokines and whole blood will be 
collected to measure potential changes in ti·anscript levels and immune cell subsets 
-
-
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3.6. 
End of Study 
The end of this study will be last subject's last observation. 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of approximately 120 subjects will enrolled in the study, aged 18-70 years inclusive, with 
chronic hepatitis B including viremic subjects not currently on HBV oral antiviral (Groups 1-3
and 5) and  virally suppressed subjects on an NUC (Group 4).
4.2.
Groups 1-3 and 5 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures.
2) Aged 18 to 70 years of age, inclusive, based on the date of screening visit.
3) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at screening and a negative urine test at Baseline before dosing.
4) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception until 90 days
after the last dose of GS-9992 and as described in Appendix 4. 
5) Chronic hepatitis B infection defined as, HBsAg or HBV DNA positivity for at least 
6 months prior to the Baseline visit, or medical records indicating a chronic HBV infection, 
and meeting the following criteria. 
a) Screening HBV DNA ≥ 2 × 104 IU/mL for HBeAg-positive subjects
b) Screening HBV DNA ≥ 2 × 103 IU/mL for HBeAg-negative subjects
c) Screening serum ALT level 35 U/L (males) or > 25 U/L (females) and ≤5 ULN 
(by central laboratory range).
6) Subjects not taking any prescribed HBV NUC treatment for at least 3 months prior to the 
Baseline visit.
7) Screening ECG without clinically significant abnormalities, including QTcF interval 
(QT corrected using Fridericia’s formula) < 450 msec for males and < 470 msec for females.
8) Must be willing and able to comply with all study requirements.


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4.3.
Groups 1-3 and 5 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) Co-infection with HCV, HIV, or HDV.
3) Extensive bridging fibrosis or cirrhosis as defined clinically, by imaging or by the following:
a) Metavir ≥ 3 or Ishak fibrosis score ≥ 4 by a liver biopsy within 5 years of screening, or, 
in the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and APRI > 1, or
c) Historic FibroScan with a result > 9 kPa within ≤ 6 months of screening (if available)
If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available)
If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or 
(c, if available). In the event of discordance between (b) and (c), the FibroScan results will 
take precedence.
4) Evidence of hepatocellular carcinoma on imaging (e.g., ultrasound, CT scan, or MRI) 
performed within 3 months prior to the Baseline visit.
5) Any history of, or current evidence of, clinical hepatic decompensation (e.g., ascites, 
encephalopathy or variceal hemorrhage).
6) Abnormal hematological and biochemical parameters at Screening, including:

Hemoglobin < 12 g/dL for males and < 11 g/dL for females

Absolute neutrophil count < 1000 cells/mm3

White blood cell count < 2500 cell/uL

Platelets < 100,000/mm3

AST or ALT > 5 × ULN

Total Bilirubin > 2.5 × ULN

Albumin < 3.5 g/dL

INR > 1.5 × ULN (unless stable on anticoagulant regimen)

Creatinine clearance < 50 mL/min


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7) Received solid organ or bone marrow transplant.
8) Significant immunodeficiency disorder, autoimmune, cardiovascular, pulmonary, or 
neurological disease in the opinion of the investigator.
9) Chronic liver disease of a non-HBV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis, steatohepatitis).
10) Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are not eligible.
11) Currently on or have received therapy with an approved or investigational 
immunomodulators (e.g. systemic corticosteroids) or biologics (e.g., monoclonal antibody, 
IFN) within 3 months or any other investigational agents within 30 days of Screening.
12) Subjects on prohibited concomitant medications (reference Table in Section 5.4). 
13) Known hypersensitivity to study drugs, metabolites, or formulation excipients.
14) Current alcohol or substance abuse judged by the investigator that will potentially interfere 
with subject compliance.
15) 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.
4.4.
Group 4 Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures.
2) Aged 18 to 70 years of age, inclusive, based on the date of screening visit.
3) Females of childbearing potential (as defined in Appendix 4) must have a negative serum 
pregnancy test at screening and a negative urine test at Baseline before dosing.
4) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception until 90 days 
after the last dose of GS-9992 and as described in Appendix 4.


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5) Documented evidence of chronic HBV infection (e.g. HBsAg positivity) for more than 
6 months with detectable HBsAg at Screening.
6) Have at least one prior documented result of HBV DNA ≤ lower limit of quantitation 
(LLOQ) from the local lab 6 or more months prior to Screening.
7) HBV DNA ≤20 IU/mL at Screening by Central Lab.
8) Have been on a commercially available HBV NUC treatment(s) (tenofovir alafenamide, 
tenofovir disoproxil fumurate, entecavir, adefovir, lamivudine, telbivudine, either as single 
agents or in combination) for less than 2 years, with no change in regimen for 3 months prior 
to screening.
9) Screening ECG without clinically significant abnormalities and with QTcF interval 
(QT corrected using Fridericia’s formula) ≤450 msec for males and ≤ 470 msec for females.
10) Must be willing and able to comply with all study requirements.
4.5.
Group 4 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) Co-infection with HCV, HIV, or HDV.
3) Extensive bridging fibrosis or cirrhosis as defined clinically, by imaging or by the following:
a) Metavir ≥ 3 or Ishak fibrosis score ≥ 4 by a liver biopsy within 5 years of screening, or, 
in the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and APRI > 1, or
c) Historic FibroScan with a result > 9 kPa within ≤ 6 months of screening (if available)
If liver biopsy is available, the liver biopsy result supersedes (b) and/or (c, if available)
If an appropriate liver biopsy is not available, fibrosis will be evaluated by (b) and/or 
(c, if available). In the event of discordance between (b) and (c), the FibroScan results will 
take precedence.
4) Evidence of hepatocellular carcinoma on imaging (e.g., ultrasound, CT scan, or MRI) 
performed within 3 months prior to the Baseline visit.
5) Any history of, or current evidence of, clinical hepatic decompensation (e.g., ascites, 
encephalopathy or variceal hemorrhage).


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6) Abnormal hematological and biochemical parameters at Screening, including:
a) Hemoglobin < 12 g/dL (for males) or <11 g/dL (for females)
b) White Blood cell count < 2500 cells/mm3
c) Neutrophil count < 1000 cell/mm3
d) ALT > 3x ULN 
e) INR > 1.5 X ULN (unless stable on an anticoagulant regimen)
f)
Albumin < 3.5 g/dL
g) Total bilirubin >1.5x ULN
h) Platelet Count < 100,000/uL
i)
Estimated creatinine clearance (CrCl) < 50 mL/min 
7) Received solid organ or bone marrow transplant 
8) Significant immunodeficiency disorder, autoimmune, cardiovascular, pulmonary, or 
neurological disease in the opinion of the investigator.
9) Chronic liver disease of a non-HBV etiology (e.g., hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, cholangitis, steatohepatitis).
10) 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). Subjects under evaluation for 
possible malignancy are not eligible
11) Received prolonged therapy with immunomodulators (e.g. corticosteroids) or biologics 
(e.g. monoclonal antibody, interferon) within 3 months of screening
12) Use of any prohibited concomitant medications as described in Section 5.4
13) Known hypersensitivity to study drug or formulation excipients
14) Use of another investigational agent within 90 days of screening, unless allowed by the 
Sponsor
15) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
16) Believed by the Study Investigator to be inappropriate for study participation for any reason 
not otherwise listed


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Treatment Codes
The randomization will be performed via an Interactive Web Response System (IWRS), whereby 
study treatment will be assigned to subjects according to the randomization schedule. A unique 
subject number will be provided during randomization. Groups 1 and 2 will be randomized in a 
3:1 ratio to receive either GS-9992 and TAF or TAF alone. Groups 3 and 5 will be enrolled
based on HBeAg status and receive GS-9992 and TAF. Group 4 will be enrolled based on 
HBeAg status and receive GS-9992.
5.2.
Description and Handling of GS-9992 and TAF
5.2.1.
Formulation
5.2.1.1.
GS-9992
GS-9992 is provided in capsule formulation containing 25 mg strengths. The current 
composition of the capsules includes Active Pharmaceutical Ingredient (API) GS-9992 and the 
following excipients: lactose and sodium stearyl fumarate.
GS-9992 tablets, 100 mg, are blue, round, film-coated tablets.  In addition to the active 
ingredient, each film-coated tablet contains the following ingredients: lactose anhydrous, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, sodium stearyl 
fumarate, colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, 
Fd&C Blue #1/Brilliant Blue FcF aluminum lake, and Fd&C Blue #2 Indigo Carmine aluminum 
lake.
GS-9992 tablets, 200 mg, are blue, oval, modified capsule shape, film-coated tablets.   In 
addition to the active ingredient, each film-coated tablet contains the following ingredients: 
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, 
sodium stearyl fumarate, colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, Fd&C Blue #1/Brilliant Blue FcF aluminum lake, and Fd&C Blue #2 
Indigo Carmine aluminum lake.
5.2.1.2.
Tenofovir Alafenamide [TAF] Tablets
TAF 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is equivalent to 
25 mg of tenofovir alafenamide. 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.


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5.2.2.
Packaging and Labeling
5.2.2.1.
GS-9992
GS-9992 capsules, 25 mg are packaged in white, high density polyethylene (HDPE) bottles. 
Each bottle contains 17 capsules, silica gel desiccant and packing material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.
GS-9992 tablets, 100 mg are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 17 tablets, silica gel desiccant and packing material. Each bottle is enclosed with 
a white, continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner.
GS-9992 tablets, 200 mg are packaged in white, high density polyethylene (HDPE) bottles. Each 
bottle contains 35 tablets, silica gel desiccant and packing material. Each bottle is enclosed with 
a white, continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner.
Study drug to be distributed to centers in the 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.
5.2.2.2.
TAF
TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, silica gel desiccant and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.
Study drug to be distributed to centers in the 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
GS-9992
GS-9992 capsules, 25 mg, GS-9992 tablets, 100 mg and GS-9992 tablets, 200mg, should be 
stored at 2°C to 8°C (36°F to 46°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. 


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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.
TAF
TAF 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 GS-9992 and TAF
Study drug(s) are to be taken at the same time each day (i.e., 24 hour window between TAF 
doses and 24 hour window between GS-9992 doses, if applicable).
Groups 1 and 2: Subjects will be randomly assigned (3:1) the following treatments:

Group 1 (n = 30): GS-9992 50 mg (2 × 25 mg capsules) once daily one hour before or 
one hour after  a meal plus TAF 25 mg once daily with food for 12 weeks then TAF 25 mg 
once daily with food for 36 weeks.

Group 2 (n = 10): TAF 25 mg once daily with food for 48 weeks
Groups 3,4, and 5 will be assigned:

Group 3 (n = 30): GS-9992 200 mg (2 x 100 mg tablets) once daily one hour before or 
one hour after a meal plus TAF 25 mg once daily with food for 12 weeks then TAF 25 mg 
once daily with food for 36 weeks.

Group 4 (n = 20): GS-9992 100 mg tablet once daily one hour before or one hour after a meal
for 12 weeks. Subjects will remain on their current commercially available NUC(s) therapy 
for the duration of the study. All subjects will be followed through Week 48.

Group 5 (n=30): GS-9992 400 mg (2 x 200 mg tablets) once daily one hour before or one 
hour after a meal plus TAF 25 mg once daily with food for 12 weeks then TAF 25 mg once 
daily with food for 36 weeks.


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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 Screening 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)

Antiretroviral regimens that contain pharmacokinetic boosters (i.e. ritonavir or cobicistat) for 
the treatment of HIV.

Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e., P-gp and/or inhibitors of OATP 1B1/1B3) with study drug(s) may result in 
PK interactions.

Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or immunomodulating 
agents are prohibited for a minimum of 3 months prior to screening period and during the 
study.
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 
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Hematopoietic Growth Factor*
Eltrombopag
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Lipid Regulating Agents*
Gemfibrozil
*
For subjects receiving GS-9992 in combination with TAF (Groups 1, 3 and 5 only)
Should subjects have a need to initiate treatment with any excluded concomitant medication, 
including herbal/natural products/therapies, and over the counter medications, the 


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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 GS-9992 and TAF
The investigator is responsible for ensuring adequate accountability of all used and unused 
IMP capsules. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition of capsules and/or tablets). All used and unused IMP capsules and/or tablets dispensed 
to subjects must be returned to the site.
GS-9992 and TAF accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits.

Record the date, subject number and the IMP kit number dispensed.

Record the date, quantity of used and unused IMP capsules and/or tablets, along with the 
initials of the person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
At the beginning 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. 


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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
Entry into screening does not guarantee enrollment into the study. In order to manage the total 
trial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any 
site or trial-wide at any time.
6.2.
Pretreatment Assessments
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements. 
6.2.1.
Screening Visit
Subjects will be screened within 45 days before randomization/enrollment to determine 
eligibility for participation in the study. 

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment history)

Review concomitant medications

Complete physical examination

Vital signs

Body weight and height

12-lead ECG (Subjects must rest quietly in the supine position for a minimum of 5 minutes 
prior to the recording)

Sample Collection for:
Safety laboratory tests (hematology, chemistry, and coagulation)
Serology testing to exclude HCV, HDV, and HIV infection


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Quantitative plasma HBV DNA
Quantitative serum HBsAg, 
 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative])
HBV viral sequencing samples (resistance surveillance)
Estimated creatinine clearance (using the Cockcroft-Gault method)
Other screening laboratory tests: urinalysis, urine drug screen, and serum β-hCG 
(females of child bearing potential only) 
Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form.
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 or enrollment 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 (eCRF). All 
other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF. 
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Baseline Assessments (Day 1)
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. 

Review of inclusion/exclusion criteria and confirm medical history 

Complete Physical Examination including body weight

Vital signs

12-lead ECG (Subjects must rest quietly in the supine position for a minimum of 5 minutes 
prior to the recording)

Review adverse events prior to study drug administration, report AEs related to protocol 
mandated procedures and all SAEs. After drug administration, report all AEs and SAEs.

Review Concomitant Medications
CCI


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Sample Collection For: 
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Safety laborato1y tests (hematology, chemistry, and coagulation) 
Final 
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HBV genotype for Groups 1-3 and 5 only, for Group 4 historic genotype should be 
documented in EDC if available 
-
Quantitative plasma HBV DNA 
-
Quantitative sernm HBsAg, 
-
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[ reflex HBsAb if HBsAg is negative]) 
-
Collection of PBMC, whole blood, sernm, and plasma samples for biomarker analysis 
(PBMC sample collection is only required at the sites that have access to PBMC 
processing laborato1y). 
-
Sernm sample for HBV viral sequencing (resistance surveillance) or ddPCR (Group 4) 
-
Other laborato1y tests: urinalysis, urine dmg screen and pregnancy test for child bearing 
potential only) 
• 
Estimated creatinine clearance (using Cockcroft-Gault method) 
• 
Randomization 
• 
Drng Administr·ation of GS-9992 and TAF 
-
Dispense study diug as directed by IWRS 
-
Instruct the subject on the packaging, storage, and adininistration of study di11gs 
-
Observe the subject taking the first dose of study dmg(s) 
6.3. 
Post-Day 1 Assessments (W'eeks, 1, 2, 4, 8, 12, 16, 24, 36, and 48, All Visits 
Have Window of :I: 3 Days) 
• 
Vital signs 
• 
Weight at Weeks 12 and 48 
• 
Review adverse events 
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• 
Review concomitant medications 
• 
Complete Physical Examination (Week 12) 
• 
Symptom-directed physical examination 
• 
12-lead ECG (Subjects must rest quietly in the supine position for a minimum of 5 minutes 
prior to the recording) (Week 12) 
• 
Sample collection for: 
I 
I 
-
Safety laborato1y tests (hematology and chemistiy; coagulation on Week 12 only) 
-
Quantitative plasma HBV DNA 
-
Quantitative sernm HBsAg, 
-
Qualitative HBV serology (HBeAg [reflex HBeAb ifHBeAg is negative] and HBsAg 
[reflex HBsAb ifHBsAg is negative]) at Weeks 12, 24, 36, and 48 
-
Collection of PBMC, whole blood, sernm, and plasma samples for biomarker analysis at 
Weeks 1, 4, 12, 24, 48 (PBMC sample collection is only required at the sites that have 
access to PBMC processing laborato1y). 
-
Sernm sample for HBV viral sequencing (resistance surveillance) or ddPCR (Group 4) 
-
Single plasma PK sample will be collected at each on- study ti·eatment visit. 
On Weeks 2 and 8, the sample will be collected between 15 minutes and 4 homs 
post-dose. In-clinic dose of GS-9992 required. 
All PK samples will be collected anytime on all other on-tl'eatment visit. 
Single PK blood samples will only be collected through Week 12 for Group 4 
-
Urine pregnancy test (females of child bearing potential only) 
-
Urinalysis 
-
Estimated creatinine clearance (using Cockcroft-Gault method) at Weeks 12 and 48 
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• 
Perfo1m study drng accountability (Groups 1, 3, and 5: GS-9992 Weeks 1-12, TAF Weeks 1-
48; Group 2 TAF Weeks 1-48; and Group 4: GS-9992 Weeks 1-12) 
• 
Dispense study diu g GS-9992 Weeks 4-8 (Groups 1, 3, 4, and 5), TAF Weeks 4-36 
(Group 1, 2, 3 and 5) as outlined in Appendix 2. 
6.5. 
24-Week Treatment Free Assessments ( Weeks 4, 8, 12, 16, 20, and 24, All 
Visits Have Window of± 5 Days) 
Subjects that meet the criteria for the treatment free follow-up (Section 3.2) will be followed for 
24 weeks or until the initiation of alternative CHB therapy, whichever comes first. 
The following assessments will be completed: 
• 
Complete Physical examination at Week 4 
• 
Symptom-directed physical examination 
• 
Review adverse events at Week 4 and collect SAEs through the end of study 
• 
Review concomitant medications 
• 
Vital signs 
• 
Sample collection for: 
-
Safety laborato1y tests (hematology and chemistiy) 
-
Quantitative plasma HBV DNA 
-
Quantitative sernm HBsAg, 
-
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative]) to be collected at Weeks 12 and 24 
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Collection of PBMC, whole blood, serum, and plasma samples for biomarker analysis at 
Weeks 4, 8, 12, and 24 (PBMC sample collection is only required at the sites that have
access to PBMC processing laboratory).
Serum sample for HBV viral sequencing (resistance surveillance) or ddPCR (Group 4)
Urine pregnancy test (females of child bearing potential only at Week 4) 
6.6.
Assessments for Early Discontinuation from the 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 6.5 Post-Treatment Assessments). 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
Criteria for study treatment discontinuation and Toxicity Management can be found in 
Section 6.11 and Section 7.6.
The Early Discontinuation (ED) Visit should be performed within 14 days from notification of
study discontinuation. The following assessments will be performed at the ED visit:

Vital signs

Review AEs and concomitant medications

Complete Physical Examination 

Body Weight

12-lead ECG (Subjects must rest quietly in the supine position for a minimum of 5 minutes 
prior to the recording)

Sample collection for: 
Safety Laboratory Tests (hematology, chemistry, and urinalysis)
Quantitative plasma HBV DNA 
Quantitative serum HBsAg, 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative])
Estimated creatinine clearance (using the Cockcroft-Gault method)
CCI


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Sernm sample for HBV viral sequencing (resistance surveillance) or dd.PCR (Group 4) 
-
Single Plasma PK sample 
-
Urine pregnancy test (females of child bearing potential only) 
-
Collection of PBMC, whole blood, sernm, and plasma samples for biomarker analysis 
(PBMC sample collection is only required at the sites that have access to PBMC 
processing laborato1y). 
• 
GS-9992 and T AF accountability, as applicable 
I 
6.7. 
Unscheduled Visits 
The assessments at the unscheduled visits are at the investigator's discretion. 
6.8. 
6.8.1. 
Study Procedure Details 
Medical History 
Medical histo1y will include details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is cmTently ongoing; histo1y of prior and cmTent use of nicotine or 
nicotine-containing products, alcohol and illegal mugs; and histo1y of cmTent and prior (within 
previous 30 days) medication; and all prior medication adininistered to treat HBV. 
6.8.2. 
Complete Physical Examination 
A complete physical examination must include source documentation of general appearance, and 
the following body systems: Head, neck and thyroid, eyes, ears, nose, throat, mouth and tongue; 
chest ( excluding breasts); respirato1y; cardiovascular; lymph nodes, abdomen; skin, hair, nails; 
musculoskeletal; neurological. At the screening visit, the Complete Physical Examination will 
include documentation of subject height. 
6.8.3. 
Electrocardiogram Assessment 
Subjects should rest quietly in the supine position for a minimum of 5 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete. 
There should be no environmental distractions (including TV, radio, video games, and 
conversation) while the subjects are resting prior to and during the recordings. 
Electrocardiograms will be recorded using the site's standard ECG equipment. All ECGs will be 
obtained using instnnnents that analyze data using the same algorithms and produce the same 
data for interpretation. Electrode placement will be perfo1med according to the method of 
Wilson, Goldberger, and Einthoven with a check to confmn that the a VR lead is not inve1ted. 
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The investigator or other qualified individuals at the study center will review ECGs to assess for
changes in ECG intervals and morphology as compared with pretreatment ECGs. ECG interval
measurements output by the machine will be used for bedside safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP.
QTc interval will be reported using Fridericia’s correction: QTcF=QT/RR0333
6.8.4.
Vital Signs
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and oral temperature. Subject body weight will be obtained at: Screening, Baseline, 
Weeks 12 and 48, and ED. 
Blood pressure will be measured using the following standardized process:
Subject should sit for ≥5 minutes with feet flat on the floor and measurement arm supported so 
that the midpoint of the manometer cuff is at heart level.
Use a mercury sphygmomanometer or automatic blood pressure device with an appropriately 
sized cuff with the bladder centered over the brachial artery.
Measure and record the blood pressure to the nearest 2 mmHg mark on the manometer or to the 
nearest whole number on an automatic device.
6.8.5.
Clinical Laboratory Tests/Assessments
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Appendix 2.
6.8.5.1.
Blood Sampling
Blood samples will be collected for the following laboratory analyses:

Hematology: 
Hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, white blood cell
(WBC) count with differential (absolute and percentage), including lymphocytes, 
monocytes, neutrophils, eosinophils, basophils, and mean corpuscular volume (MCV),
and 

Coagulation panel 
Prothrombin time, partial thromboplastin time [PTT] and international normalized ratio 
[INR])


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
Chemistry: 
Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total 
cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, 
total protein, albumin, lactic acid dehydrogenase (LDH), creatine kinase (CK), 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine (see below), 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, and lipase (reflex 
amylase testing is performed in subjects with total lipase >1.5 × upper limit of normal 
[ULN])

Serum pregnancy test (females of childbearing potential only)

Follicle-stimulating hormone (FSH) testing (For female subjects post-menopausal for less 
than two years, if FSH < 40 mIU/ mL a serum pregnancy test will be required)
6.8.5.2.
Urine Samples
Urine samples will be collected for urinalysis and drug screen assessments and urine pregnancy 
as applicable.
6.8.5.3.
Creatinine Clearance
Creatinine Clearance
Weight will be collected at screening and upon admission calculate creatinine clearance (CLcr) 
for inclusion criteria.
Creatinine clearance is calculated by the Cockcroft-Gault equation {Cockcroft 1976} using 
actual bodyweight (BW).
Male:
CLcr (mL/min) = [140 −age (years)] × BW(kg)
72 Scr
Female:
CLcr (mL/min) = [140 −age (years)] × BW(kg) 0.85
72 Scr
Scr = serum creatinine (mg/dL)
6.8.5.4.
HIV, HDV, and HCV Reflex Testing
In the event of a positive result for serology and/or antigen testing for HIV, HDV or HCV 
serology, reflex tests will automatically be performed.
Co-infection with HIV, HDV, or HCV is exclusionary.


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6.8.6. 
Adverse Events/Concomitant Medications/Protocol Restrictions 
Final 
Amendment 3 
Evaluation for AEs, review of concomitant medications, and review of protocol resti·ictions will 
occur at the times shown in Appendix 2. See Section 7 for more infonnation regarding AEs and 
Section 5.4 for more info1mation about concomitant medications. 
6.10. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study dosing (for example, as a result of an AE), eve1y attempt should 
be made to keep the subject in the study and continue to perfonn the required study-related 
follow-up and procedures (see Section 6.11, 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. 
6.11. 
Criteria for Discontinuation of Study Treatment 
GS-9992 and/or TAF may be discontinued if the following instances are met: 
• 
A confinned Grade 3 AE ( excluding isolated ALT elevations) considered related to 
GS-9992 and/or TAF by the investigator, should discontinue one or both study diug(s) 
• 
A confomed, clinically significant lab abno1mality Grade 3 (excluding isolated ALT 
elevations) considered related to GS-9992 and/or TAF by the investigator, should discontinue 
one or both study diug(s) 
• 
IntercmTent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
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 
• 
HBsAg loss confomed at least 12 weeks apa1t 
• 
Subject requests to discontinue for any reason 
• 
Subject noncompliance 
• 
Pregnancy during the study 
• 
Discontinuation of the study at the request of Gilead, a regulato1y agency or an institutional 
review board or independent ethics committee (IRB/IEC) 
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For Group 5, study treatment(s) will be held in all subjects in the dosing group, if ≥3 subjects 
experience a Grade 3 adverse event or ≥2 subjects experience a Grade 4 or serious adverse event, 
in the same system organ class (excluding isolated ALT elevations) that is considered related by 
the investigator(s) to the Graded toxicity. Decisions to reinitiate continuation of dosing of study 
treatment(s) will be made by Gilead Medical Monitor upon review of all safety data generated by 
subjects dosed to date.
Refer to Section 7.6 for additional discontinuation criteria for Toxicity Management. 
HBV will be managed according to local standard of care if subjects are discontinued from the 
study. Subjects that discontinue all HBV therapy should be followed for 24 weeks or until the 
initiation of alternative CHB therapy, whichever comes first.
6.12.
Resistance Surveillance and ddPCR
Sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) to assess the incidence 
of resistance mutations will be attempted for any subject with viremia (HBV DNA ≥ 69 IU/mL) 
at Week 48 or at early discontinuation at or after Week 24. 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.
For Group 4, if subject has HBV DNA ≥ 69 IU/mL, a sequence analysis may be conducted if
applicable. If HBV DNA < 20 IU/mL, ddPCR will be conducted.
6.13.
End of Study
The end of this study will be last subject’s last observation.
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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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 7.7.1)

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 
eCRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.2.
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 each 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease,
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (e.g., venipuncture)


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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 3). 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 (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 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 (i.e., 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 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
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 PVE.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.


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• 
Site personnel must record all SAE data in the eCRF database and transmit the SAE 
infonnation to Gilead PVE within 24 hours of the investigator's knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If it is not possible to record and submit the SAE info1mation electronically, because the 
eCRF database cannot be accessed or is not available (including at study staii), record the 
SAE on the paper serious adverse event repo1i fo1m and submit by e-mail or fax within 
24 hours of the investigator's knowledge of the event to: 
GileadPVE: 
Fax: 
E-mail: 
PPD 
PPD 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ied via a paper fonn because the eCRF database has been locked, no 
finiher action is necessa1y. 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, and other 
documents ai·e 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 infonnation may be requested to ensure the timely completion of accurate safety 
repo1is. 
• 
Any medications necessaiy for tr·eatinent of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn. 
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 regulato1y agencies repo1is of SAEs, serious adverse dmg 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 regulato1y 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
cmTent regulations. 
Assessment of expectedness for SAEs will be dete1mined by Gilead using reference safety 
info1mation specified in the Investigator's Brochure or relevant local label as applicable. 
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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.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events and Toxicity Management
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, and urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to 
investigational medicinal product interruption or discontinuation must be recorded as an AE, 
as well as an SAE, if applicable. In addition, laboratory or other abnormal assessments 
(e.g., ECG, X-rays, and 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 (i.e., anemia) not the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 3). For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying conditions; this may or may not be in agreement with the grading of the 
laboratory abnormality.
7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines below.
ALT Elevation or Flare Management
Subjects with on-treatment serum ALT elevation > 2 × nadir or > 2 × Baseline value and
≥5 × ULN, with or without associated symptoms should be managed according to the guidance 
below. 
All on-treatment elevated serum ALT should be confirmed as soon as possible and ideally within 
3 days of receipt of results. During the visit, a clinical assessment of the subject should be 
performed. The assessment should include a physical examination, evaluation of the subject’s 
mental status and the following laboratory tests: 

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, HBsAb, HBeAg and HBeAb), HDV, 
HAV IgM, HCV, and HEV.


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For GS-9992 Management
Based on the results of the confirmatory tests, the following treatment modifications for GS-9992
are recommended:
Table 7-1.
GS-9992 Dose Modification and Monitoring
Liver Toxicity
Action
Confirmed ALT ≥10 × ULN without evidence of 
hepatic toxicity as defined below
Discuss with the Medical Monitor if GS-9992 should be
dose reduced by 50% or discontinued if the safety of the 
subject is of immediate concern. Subject should be 
monitored weekly or more frequently if clinically 
indicated until ALT < 5 × ULN
Confirmed ALT > 2 × nadir, with evidence of hepatic 
toxicity, defined as any one of the following:

Total bilirubin > 2 × baseline or nadir AND > ULN 
in the absence of Gilbert’s disease

Elevated INR > 0.5 above baseline AND > ULN 

Abnormal serum albumin > 1 g/dL decrease from 
baseline
Permanently discontinue GS-9992. Subject should be 
monitored weekly until ALT < 5 × ULN, and total 
bilirubin and INR values return to normal or baseline 
levels 
Confirmed ALT > 2 × Baseline and ≥ 5 × ULN without 
evidence of hepatic toxicity, as defined above
Continue GS-9992, ALT should be evaluated every 
2 weeks or more frequently as clinically needed, until 
ALT < 5 × ULN
For TAF Management
Based on the results of the confirmatory tests, the following treatment modifications for TAF are 
recommended:
Table 7-2.
TAF Dose Modification and Monitoring
Liver Toxicity
Action
Confirmed ALT levels ≥ 10 × ULN, with evidence of 
hepatic toxicity, defined as any one of the following:

Total bilirubin > 2 × baseline or nadir AND > ULN 
in the absence of Gilbert’s disease

Elevated INR > 0.5 above baseline AND > ULN 

Abnormal serum albumin > 1 g/dL decrease from 
baseline
Discuss with the Medical Monitor if TAF should be 
discontinued, unless the safety of the subject is of 
immediate concern.
Subject should be monitored weekly as long as ALT, 
total bilirubin and INR values remain elevated or above 
baseline values.
If the ALT values remain persistently elevated, the 
investigator should discuss with the Medical Monitor if 
TAF should be discontinued.
Confirmed ALT levels ≥ 10 × ULN, without evidence of 
hepatic toxicity, as defined above
Continue TAF and monitor weekly until ALT values 
return to normal or baseline levels. If the ALT values 
remain persistently elevated, the investigator should 
discuss with the Medical Monitor if TAF should be 
discontinued.


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Specific toxicity discontinuation criteria in Section 6.11 supersede below general toxicity 
guidelines, and in general, where discrepancy is present, the more conservative criteria apply. 
The Gilead Medical Monitor should be consulted prior to study drug discontinuation when 
medically feasible.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue investigational medicinal product at the discretion of the investigator.
7.6.2.
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 (except ALT 
evaluations) 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.
7.6.3.
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.
7.7.
Special Situations Reports
7.7.1.
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.


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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 is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
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 Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email:
 and Fax: 
. 
PPD
PPD


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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 PVE 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 PVE, 
fax number
 or email 
. 
Refer to Appendix 4 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.7.2.2.
Reporting Other Special Situations
All special situations reports (SSRs) will be recorded in the eCRF database within the timelines
outlined in the eCRF completion guideline.
Electronic Special Situations Report (eSSR) Reporting Process:
Site personnel record all SSR data in the eCRF database and from there transmit the SSR
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event
throughout the duration of the study, including the protocol–required post treatment follow-up 
period. Detailed instructions can be found in the eCRF completion guidelines.
If for any reason it is not possible to record the SSR information electronically, i.e., the eCRF
database is not functioning, record the SSR on the paper serious adverse event reporting form
and submit within 24 hours to: Gilead PVE: Email: 
Fax:
As soon as it is possible to do so, any SSR reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
If an SSR has been reported via a paper form because the eCRF database has been locked, no
further action is necessary. 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 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:

To evaluate the safety and tolerability of the 12 week treatment regimens of GS-9992 plus 
TAF or commercially available NUC

Groups 1-3 and 5
To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in
viremic CHB subjects as measured by the proportion of subjects with ≥0.5 log10 IU/mL 
decline from Baseline at Week 12 in circulating serum HBV surface antigen (HBsAg) 

Group 4
To evaluate the antiviral activity of 12 weeks of GS-9992 with commercially available 
NUC(s) in virally suppressed CHB subjects as measured by the proportion of subjects with 
≥0.5 log10 IU/mL decline from Baseline at Week 12 in circulating serum HBV surface 
antigen (HBsAg) 
The secondary objectives of this study are: 
Groups 1-3 and 5

To evaluate the safety and tolerability of the 48 week treatment regimens as assessed by 
review of the accumulated safety data

To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in 
CHB subjects as measured by the proportion of subjects with ≥1 log10 IU/mL decline from 
Baseline at Week 12 in circulating HBsAg  

To evaluate the proportion of HBeAg-positive CHB subjects who achieve HBeAg loss and 
seroconversion during 12 weeks of GS-9992 plus TAF versus TAF alone and after GS-9992
discontinuation through 48 weeks

To evaluate the proportion of CHB subjects who achieve HBsAg loss during 12 weeks of 
GS-9992 plus TAF versus TAF alone and after GS-9992 discontinuation through 48 weeks 

To evaluate the incidence of drug resistance mutations during 48 weeks of treatment

To characterize steady-state pharmacokinetics of study drugs


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• 
To evaluate the change from Baseline in HBV DNA and quantitative HBsAg in CHB 
subjects during 12 weeks of GS-9992 plus TAF versus TAF alone and after GS-9992 
discontinuation through 48 weeks 
Group 4 
• 
To evaluate the propo1iion of subjects experiencing HBV virologic breakthrough 
(2 consecutive visits of HBV DNA 2::: 69 IU/mL) during 12 weeks of GS-9992 treatment 
• 
To evaluate the antiviral activity of 12 weeks of GS-9992 in CHB subjects as measured by 
the proportion of subjects with ~l log10 IU/mL decline from Baseline at Week 12 in 
circulating HBsAg 
• 
To evaluate the propo1iion of HBeAg-positive CHB subjects who achieve HBeAg loss and 
seroconversion during 12 weeks of GS-9992 and after GS-9992 discontinuation through 
48 weeks 
• 
To evaluate the propo1iion of CHB subjects who achieve HBsAg loss during 12 weeks of 
GS-9992 and after GS-9992 discontinuation through 48 weeks 
• 
To characterize steady-state phan nacokinetics of study diugs 
• 
To evaluate the change from Baseline in quantitative HBsAg in CHB subjects during 
12 weeks of GS-9992 and after GS-9992 discontinuation through 48 weeks 
I 
I 
I 
I 
8.1.2. 
Primary Endpoint 
Groups 1-3 and 5 
The prima1y efficacy endpoint of this study is the propo1iion of subjects with~ 0.5 log10 IU/mL 
decline in HBsAg from Baseline at Week 12. 
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Group 4
The primary efficacy endpoint of this study is the proportion of subjects with ≥0.5 log10 IU/mL 
decline in HBsAg from Baseline at Week 12 in virally suppressed CHB subjects.
8.1.3.
Secondary Endpoint
The secondary endpoints of this study are:
Groups 1-3 and 5

Proportion of subjects with ≥1 log10 IU/mL decline in HBsAg from Baseline at Week 12

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion through 
48 weeks of treatment

Proportion of subjects who achieve HBsAg loss through 48 weeks of treatment

Proportion of subjects with drug resistance mutations during 48 weeks of treatment

Change from Baseline in HBV DNA and quantitative HBsAg through 48 weeks of treatment
Group 4

Proportion of subjects experiencing HBV virologic breakthrough (2 consecutive visits of 
HBV DNA ≥69 IU/mL) during 12 weeks of GS-9992 treatment

Proportion of subjects with ≥1 log10 IU/mL decline in HBsAg from Baseline at Week 12

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion through 
48 weeks

Proportion of subjects who achieve HBsAg loss through 48 weeks

Change from Baseline in quantitative HBsAg through 48 weeks 
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis is the full analysis set (FAS), defined as all 
subjects who were randomized to Group 1 or 2, or enrolled in Group 3 or 4 or 5 and who took at 
least 1 dose of any study drug. Subjects will be analyzed according to the randomized or enrolled 
treatment assignment. 


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8.2.1.2. 
Safety 
Final 
Amendment3 
The prima1y analysis set for safety analysis is the safety analysis set (SAS), defined as all 
subjects who took at least 1 dose of any study diu g. Subjects will be analyzed according to the 
treatment actually received. 
8.2.1.3. 
Phaimacokinetics 
The phaimacokinetics (PK) analysis set will include all subjects who were randomized to 
Group 1 or 2, or emolled in Group 3 or 4 or 5 and took at least 1 dose of any study diug and have 
at least 1 nonmissing concentration value repo1ted by the PK laboratory. 
8.2.1.4. 
Biomai·kers 
The prima1y analysis set for biomai·ker analysis is the biomarker analysis set, defined as all 
subjects who were randomized to Group 1 or 2 or emolled in Group 3 or 4 or 5 and who took at 
least 1 dose of any study diug and have at least 1 nonmissing biomarker value for each 
respective biomai·ker. 
8.3. 
Data Handling Conventions 
For the primaiy efficacy endpoint and the categorical secondaiy efficacy endpoints, missing data 
will be handled using a missing = failure approach. 
For the diug resistant mutations endpoint, a missing = excluded approach will be employed. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be summarized by treatment group and overall 
using standard descriptive methods. 
Demographic summai·ies will include age, sex, race and ethnicity. 
Baseline data will include a summaiy of body weight, height, body mass index, HBeAg status, 
HBeAb status, HBsAg (log10 ID/mL), HBV DNA (log10 ITJ/mL), ALT, HBV genotype, previous 
HBV treatment experience, and additional endpoints as necessaiy. 
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8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint, i.e. the proportion of subjects with ≥ 0.5 log10 IU/mL decline in 
HBsAg from baseline at Week 12, will be evaluated for all groups in the FAS. The 2-sided 
95% confidence interval (CI) of the proportion difference (Group 1 – Group 2, Group 3 − 
Group 2, Group 5 − Group 2) will be constructed by using stratum-adjusted Mantel-Haenszel 
(MH) proportions, stratified by the randomization stratification factor HBeAg status (positive, 
negative).
8.5.2.
Secondary Analyses
Continuous secondary endpoints will be summarized using conventional descriptive statistics
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group. 
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint by treatment group.
8.5.3.
Analysis of Other Endpoints of Interest
Continuous endpoints will be summarized using conventional descriptive statistics (n, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group. 
Categorical endpoints will be summarized by number and percentage of subjects who meet the 
endpoint by treatment group.
8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests and adverse events. Primary 
safety analysis will be evaluated through four weeks after last dose of GS-9992.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug(s) will be generated from the study drug(s) 
administration data. Exposure data will be summarized by treatment group
8.6.2.
Adverse Events
Clinical and laboratory adverse events (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.


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Summaries (number and percentage of subjects) of treatment-emergent (TE) AEs (by SOC and 
PT) will be provided by treatment group: 
• 
All TEAEs 
• 
TEAEs of Grade 3 or higher 
• 
TEAEs of Grade 2 or higher 
• 
All TE treatment-related AEs 
• 
TE ti·eatment-related AEs of Grade 3 or higher 
• 
TE ti·eatment-related AEs of Grade 2 or higher 
• 
All TE SAEs 
• 
All TE ti·eatment-related SAEs 
• 
All TEAEs leading to premature discontinuation of any study drng 
• 
All TEAEs leading to temponuy inte1n1ption of any study drng 
All AEs collected dming the study will be presented in the data listings. 
8.6.3. 
Laboratory Evaluations 
Selected laborato1y 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 laborato1y abnonnalities will be defined using the grading scheme in Appendix 3. 
fucidence of ti·eatment-emergent laborato1y abnonnalities will be summarized. All laborato1y 
abnonnalities will be included in the listings of laboratory data. 
8.7. 
Pharmacokinetic Analysis 
P asma concenu-at10ns o t e stu y ug over trme w1 
e summan ze usmg 
descriptive statistics. Plasma concenti·ations will be plotted in semi-logarithmic and linear 
fo1mats as mean± standard deviation. Details of phaimacokinetic analyses will be provided in 
the statistical analysis plan. 
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8.9. 
Sample Size 
Final 
Amendment3 
Due to the explorato1y nature of this study, the sample size was not detennined by any fo1mal 
power calculation. The nmnber of subjects in each treatment group was decided based on clinical 
expenence. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. 
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IEC. The investigator will not begin any study subject activities until 
approval from the IEC has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IEC any modifications made to the protocol or any accompanying material to be provided to 
the subject after initial IEC approval, with the exception of those necessary to reduce immediate 
risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IEC -approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IEC or local 
requirements. 
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 Year 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, IEC, or laboratory. Laboratory specimens must be labeled in 
such a way as to protect subject identity while allowing the results to be recorded to the proper 
subject. Refer to specific laboratory instructions in lab manual. 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. 


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The investigator agrees that all information received from Gilead, including but not limited to the 
Investigator’s Brochure, this protocol, 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, eCRF and query forms, IEC
and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, Year of birth, gender);

Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.


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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 (i.e., 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 casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs 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. 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). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock 
(as instructed by Gilead), the investigator will use his/her log in credentials to confirm that the 
forms have been reviewed, and that the entries accurately reflect the information in the source 
documents. 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
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files.


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If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IEC, 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 IEC
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 


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
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 
eCRF.
The monitor is responsible for routine review of the 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 eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
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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10.
REFERENCES
Benias P, Min A. Goals of Antiviral Therapy for Hepatitis B: HBeAg Seroconversion, HBsAg 
Seroconversion, Histologic Improvement, and Possible Impact on Risk of 
Hepatocellular Carcinoma. Curr Hepatitis Rep 2011;10.
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.
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 Gastroenterol Hepatol 2016;1:185-95.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Debes JD, Ricci P. Acute liver failure during hepatitis C treatment with sofosbuvir and ledipasvir 
[Article in Press]. Dig Liver Dis 2015.
Dienstag JL, Goldin RD, Heathcote EJ, Hann HWL, Woessner M, Stephenson SL, et al. 
Histological outcome during long-term lamivudine therapy. Gastroenterology 
2003;124 (1):105-17.
EASL. European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol 2012. 2012.
European Association For The Study Of The Liver. EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B. J Hepatol 2009;50 (2):227-42.
European Association for the Study of the Liver (EASL). EASL 2017 Clinical Practice 
Guidelines on the management of hepatitis B virus infection. [Article In Press]. J 
Hepatol 2017:1-29.
Fattovich G, Giustina G, Sanchez-Tapias J, Quero C, Mas A, Olivotto PG, et al. Delayed 
clearance of serum HBsAg in compensated cirrhosis B: relation to interferon 
alpha therapy and disease prognosis. Am J Gastroenterol 1998;93 (6):896-900.
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.


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Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of 
hepatitis C: an update. Hepatology 2009;49 (4):1335-74.
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.
Idilman R, Cinar K, Seven G, Bozkus Y, Elhan A, Bozdayi M, et al. Hepatitis B surface antigen 
seroconversion is associated with favourable long-term clinical outcomes during 
lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral 
Hepat 2012;19 (3):220-6.
Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside 
analogue therapy in patients with chronic hepatitis B: clinical outcomes and 
durability. Gut 2013;63:1325-32.
Kwon H, Lok AS. Hepatitis B therapy. Nature reviews. Gastroenterology & hepatology 2011;8 
(5):275-84.
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.
Liaw YF. Impact of hepatitis B therapy on the long-term outcome of liver disease. Liver Int 
2011;31 Suppl 1:117-21.
Lok AS. Evolution of nucleoside/tide analogues for hepatitis B: is the ideal drug here yet? J 
Hepatol 2009;51 (2):416-8.
Lok AS. Hepatitis: Long-term therapy of chronic hepatitis B reverses cirrhosis. Nature reviews. 
Gastroenterology & hepatology 2013;10 (4):199-200.
Maini MK, Schurich A. The molecular basis of the failed immune response in chronic HBV: 
therapeutic implications. J Hepatol 2010;52 (4):616-9.
Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, et al. High 
rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients 
responding to interferon: a long-term follow-up study. J Hepatol 2009;50 
(6):1084-92.
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.
Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, et al. Up-regulation of a death 
receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp 
Med 2013;210 (1):99-114.


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Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C, et al. Blockade of 
immunosuppressive cytokines restores NK cell antiviral function in chronic 
hepatitis B virus infection. PLoS pathogens 2010;6 (12):e1001227.
Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology 2009;49 (5 
Suppl):S103-11.
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(3):201-13.
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Nature reviews 2005;5 (3):215-29.
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(1):1-98.
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.
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hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort 
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http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index1.html. 
Accessed: 03 August 2015.
Wright TL. Introduction to chronic hepatitis B infection. Am J Gastroenterol 2006;101:6.
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Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 4.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements


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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Open-Label, Active-Controlled Study to Evaluate the Safety and 
Antiviral Activity of GS-9992 Plus Tenofovir Alafenamide for 12 Weeks in Chronic Hepatitis B 
Subjects 
GS-US-464-4437, Amendment 3, 11 March 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
[PPD 
PPD 
Author 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Study Procedures Table
Procedures
Screening
(45 days)
Baseline 
Day 1
Weeks (± 3 Days)
Early 
Discontinuationa
24 Week 
Treatment-Free 
Follow-up (± 5 Days)
(End of Weeks 4, 8, 
12, 16, 20, and 24)
1
2
4
8
12
16
24
36
48
Informed Consent (at, or 
prior to, screening visit) n
X
Review of Inclusion/
Exclusion Criteria
X
X
Medical History
X
X
AEs and Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Complete Physical 
Examination 
X
X
X
X
Xc
Symptom-directed physical 
examinationb
X
X
X
X
X
X
X
X
X
Height 
X
Body Weight
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
Pregnancy Testf
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug Screen
X
X
Safety laboratory tests 
(hematology and chemistry,
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X
X
X


GS-9992 
Protocol GS-US-464-4437 
Final 
Gilead Sciences, Inc. 
Amendment3 
Weeks(± 3 Days) 
24 Week 
Treatment-Free 
Follow-up (± 5 Days) 
Screening 
Baseline 
Early 
(End of Weeks 4, 8, 
Procedures 
(45 days) 
Day 1 
1 
2 
4 
8 
12 
16 
24 
36 
48 
Discontinuation• 
12, 16, 20, and 24) 
Quantitative plasma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBVDNA 
FibroScan 
X 
HCC imaging 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative HBV serologyg 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of PBMC, whole 
blood, serum, and plasma 
X 
X 
X 
X 
X 
X 
X 
Xh 
samples for biomarker 
analysis 
HBV Genotyping 0 
X 
Serum sample for HBV viral 
sequencing (resistance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
surveillance) or ddPCR P 
Single Plasma PKi 
X 
)Ci 
X 
)Ci 
X 
X 
X 
X 
X 
X 
Other Viral Serology 
X 
(HCV, HIV, HDV) 1 
Creatinine Clearance 
X 
X 
X 
X 
X 
Randomization 
X 
Dispense T AF 
X 
X 
X 
X 
X 
X 
X 
Dispense GS-9992 
X 
X 
X 
CONFIDENTIAL 
Page 102 
11 March 2019 


GS-9992 
Protocol GS-US-464-4437 
Final 
Gilead Sciences, Inc. 
Amendment3 
Weeks (± 3 Days) 
24 Week 
Treatment-Free 
Follow-up (± 5 Days) 
Screening 
Baseline 
Early 
(End of Weeks 4, 8, 
Procedures 
(45 days) 
Day 1 
1 
2 
4 
8 
12 
16 
24 
36 
48 
Discontinuation• 
12, 16, 20, and 24) 
In-Clinic Dose with GS-9992 
X 
xm 
xm 
xm 
In-Clinic dose with TAF 
X 
GS-9992 Accountability 
X 
X 
X 
X 
X 
X 
T AF Accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
TI1e Early Discontinuation (ED) visit should be performed within 14 days from notification of study discontinuation. 
b 
Symptom-directed physical exam will only be pe1fon11ed when subject is experiencing symptoms. 
c 
To completed at Treatment-Free Follow up Week 4 only: AE review, complete physical examination, and mine pregnancy test. 
d 
Vital signs include blood pressm·e, pulse, respiration rate and temperature. 
e 
QTc interval will be repo1ted using Fridericia's coll'ection: QTcF=QT!RR0333. Subjects must rest quietly in die supine position for a minimum of 5 minutes prior to die 
recording. 
f 
For female subjects of childbea1ing potential, the serum pregnancy test will be pe1fon11ed at Screening. U1ine test will be pe1fon11ed at all other visits as indicated. Positive 
mine test will be confomed with serum test. Pregnancy testing should include prevention counseling. 
g 
Qualitative HBV serology: (HBeAg [reflex HBeAb ifHBeAg is negative] and HBsAg [reflex HBsAb ifHBsAg is negative]). Collected eve1y 12 weeks dming the study. 
Post-Treatment visit Weeks 12 and 24. 
h 
PBMCs to be collected at Weeks 4, 8, 12, and 24 only. PBMC sample collection is only re uired at die sites diat have access to PBMC 
Weeks 2 and 8 PK samples will be collected between 15 minutes and 4 hom·s post-dose. 
r 
m 
r 
0 
p 
CONFIDENTIAL 
Page 103 
11 March 2019 


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 104
11 March 2019
Appendix 3.
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 105
11 March 2019
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.


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 106
11 March 2019
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 mmol/L
2.0 to 2.5 mEq/L
2.0 to <2.5 mmol/L
2.0 mEq/L
<2.0 mmol/L
Hyperkalemia 
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant  <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 107
11 March 2019
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 mmol/L
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmol/L
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 108
11 March 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 109
11 March 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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. 


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 110
11 March 2019
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


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Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick) 
1
2
3-4+
NA
Hematuria (Quantitative) 
See Note below
                              Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
                              Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour 
Collection
Adult and Pediatric 
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes: 

Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.

With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.

If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.


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Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 112
11 March 2019
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, 
non-life-threatening AND 
Non-urgent medical 
intervention indicated 
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia 
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant 
acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated 
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic 
OR 
90–99 mmHg diastolic
159–179 mmHg systolic 
OR 
99–109 mmHg diastolic
179 mmHg systolic 
OR 
109 mmHg diastolic
Life-threatening 
consequences (e.g., malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening
consequences (e.g., malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with 
non-life-threatening 
physiologic consequences 
OR Effusion with nonurgent 
intervention indicated
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated


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Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 113
11 March 2019
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV block 
OR Ventricular pause 
3.0 sec
Complete AV block 
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, e.g., Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Embolic event 
(e.g., pulmonary embolism, 
life-threatening thrombus) 
Vasovagal Episode 
(associated with a procedure 
of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 114
11 March 2019
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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Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 115
11 March 2019
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 116
11 March 2019
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Anorexia
Loss of appetite without 
decreased oral intake
Loss of appetite associated 
with decreased oral intake 
without significant weight 
loss 
Loss of appetite associated 
with significant weight loss 
Life-threatening 
consequences OR Aggressive 
intervention indicated 
[e.g., tube feeding or total 
parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences (e.g., sepsis or 
perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(e.g., obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more unformed 
than usual) but usual number 
of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 117
11 March 2019
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, Dysphagia-
Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal 
bleeding OR Life-threatening 
consequences 
(e.g., aspiration, choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no or 
minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 
48 hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences (e.g., sepsis, 
circulatory failure, 
hemorrhage)
Proctitis 
(functional-symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Medical intervention 
indicated 
Symptoms causing inability 
to perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake
Frequent episodes of 
vomiting with no or mild 
dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening 
consequences 
(e.g., hypotensive shock)


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 118
11 March 2019
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 
(e.g., suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, 
OR coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual
social & functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Specialized resources on 
part-time basis indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 119
11 March 2019
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting 
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting 
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing inability 
to perform usual social & 
functional activities
Symptoms causing inability 
to perform basic self-care 
functions OR Hospitalization 
indicated (other than ER 
visit) OR Headache with 
significant impairment of 
alertness or other neurologic 
function 
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic 
self-care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle 
weak-ness causing no or 
minimal interference with 
usual social & functional 
activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 120
11 March 2019
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Seizure: (new onset) 
NA
1 seizure 
2–4 seizures 
Seizures of any kind that are 
prolonged, repetitive 
(e.g., status epilepticus), or 
difficult to control 
(e.g., refractory epilepsy)
Seizure: (pre-existing) 
For Worsening of Existing 
Epilepsy the Grades Should 
Be Based on an Increase from 
Previous Level of Control to 
Any of These Levels
NA
Increased frequency of 
pre-existing seizures 
(non-repetitive) without 
change in seizure character 
OR infrequent breakthrough 
seizures while on stable meds 
in a previously controlled 
seizure disorder
Change in seizure character 
from baseline either in 
duration or quality 
(e.g., severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(e.g., status epilepticus), or 
difficult to control 
(e.g., refractory epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated with 
a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 121
11 March 2019
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


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 122
11 March 2019
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR laryngeal 
edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities 
Symptoms causing inability 
to perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Symptoms causing inability 
to perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site Pain, 
Headache, Arthralgia, and 
Myalgia
Pain causing no or minimal 
interference with usual social 
& functional activities
Pain causing greater than 
minimal interference with 
usual social & functional 
activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than 
ER visit) indicated
Unintentional Weight Loss
NA
5% to 9% loss in body weight 
from baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  
Aggressive intervention 
indicated [e.g., tube feeding 
or total parenteral nutrition]


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 123
11 March 2019
INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain (pain 
without touching)
Or Tenderness (pain when 
area is touched) 
Pain/tenderness causing no or 
minimal limitation of use of 
limb
Pain/tenderness limiting use 
of limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than 
ER visit) indicated for 
management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm 
(or 2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment 
(e.g., upper arm/thigh)
Erythema OR Induration OR 
Edema involving 50% 
surface area of the extremity 
segment (e.g., upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile abscess 
OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 48 h 
treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h 
treatment 
Generalized itching causing 
inability to perform usual 
social & functional activities
NA


GS-9992
Protocol GS-US-464-4437
Final 
Gilead Sciences, Inc. 
Amendment 3
CONFIDENTIAL
Page 124
11 March 2019
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (e.g., back of 
neck, breasts, abdomen)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to 
initiate medication OR 
Modification of current meds 
to regain glucose control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite 
treatment modification
Life-threatening 
consequences 
(e.g., ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., thyroid 
storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences 
(e.g., myxedema coma)
Lipoatrophy (e.g., fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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


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Amendment 3
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Appendix 4.
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 orchiectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9992
The risk of treatment with GS-9992 has not been evaluated in pregnant women. Relevant 
non-clinical reproductive toxicity studies for human pregnancy do not indicate a strong suspicion 
of human teratogenicity/fetotoxicity. Non-clinical early embryonic development and fertility 
studies with GS-9992 have not been conducted to date. GS-9992 has insufficient data to exclude 
the possibility of a clinically relevant interaction with hormonal contraception that results in 
reduced contraception efficacy. Therefore, contraceptive steroids are not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Pregnancy tests will 
be performed regularly throughout this study. Please refer to the latest version of the 
investigator’s brochure for additional information.
TAF
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 or 
embryo-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.


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Amendment 3
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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective or
an acceptable contraceptive measures. They must also not rely on hormone-containing 
contraceptives as a form of birth control during the study. They must have a negative serum 
pregnancy test at Screening and a negative pregnancy test on the Baseline/Day 1 visit prior to 
randomization. At minimum, a pregnancy test will be performed at 4 weeks post-treatment. 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. Female subjects must agree to one of the following 
from Screening until 7 days after the last dose of TAF and until 90 days after the last dose of 
GS-9992.
Highly effective contraceptive measures:

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
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)
Or, Acceptable contraceptive measures:

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)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until 7 days after the last dose of TAF and until 90 days after the last dose of GS-9992.


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Amendment 3
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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 during treatment with TAF and 
for 90 days after the last dose of GS-9992.
Male subjects must also refrain from sperm donation during treatment with GS-9992 and until 
90 days after the end of last dose of GS-9992.
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.
4) 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 7.7.2.1.

SAP_001.pdf: 
Study Title: 
Name of Test Drug: 
Study Number: 
Protocol Version (Date): 
Analysis Type: 
Analysis Plan Version: 
Analysis Plan Date: 
Analysis Plan Author: 
(!") GI LEAU 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Randomized, Open-Label, Active-Controlled Study to 
Evaluate the Safety and Antiviral Activity of GS-9992 Plus 
Tenofovir Alafenamide (TAF) for 12 Weeks in Chronic Hepatitis B 
(CHB) Subjects 
GS-9992 
GS-US-464-4437 
Original: 
22 August 2017 
Amendment 1: 
05 December 2017 
Amendment 2: 
24 May 2018 
Amendment 3: 
11 March 2019 (Hong Kong) 
Final Analysis 
Version 1.0 
22September2020 
PPD 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
Interim Analysis.....................................................................................................................................12
2.1.1.
Analysis for 12 Week Regimen............................................................................................12
2.1.2.
Analysis for 48 Week Regimen............................................................................................12
2.1.3.
TFFU Analysis .....................................................................................................................12
2.2.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Randomized/Enrolled Analysis Set................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Safety Analysis Set...............................................................................................................13
3.1.4.
TFFU Analysis Set...............................................................................................................14
3.1.5.
Biomarker Analysis Set........................................................................................................14
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subsets.............................................................................................................14
3.5.
Multiple Comparisons............................................................................................................................14
3.6.
Missing Data and Outliers......................................................................................................................15
3.6.1.
Missing Data ........................................................................................................................15
3.6.2.
Outliers.................................................................................................................................15
3.7.
Data Handling Conventions and Transformations .................................................................................15
3.8.
Analysis Visit Windows.........................................................................................................................17
3.8.1.
Definition of Study Day .......................................................................................................17
3.8.2.
Analysis Visit Windows.......................................................................................................17
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis
Window................................................................................................................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................22
4.1.
Subject Enrollment and Disposition.......................................................................................................22
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................24
4.2.1.
Duration of Exposure to Study Drug....................................................................................24
4.2.2.
Adherence to Study Drug.....................................................................................................24
4.3.
Protocol Deviations................................................................................................................................26
5.
BASELINE CHARACTERISTICS....................................................................................................................28
5.1.
Demographics and Baseline Characteristics ..........................................................................................28
5.2.
Other Baseline Characteristics ...............................................................................................................28
5.3.
Medical History......................................................................................................................................29


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6. 
EFFICACY ANALYSES ................................................................................................................................... 30 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 30 
6.1.1. 
Definition of the Primary Efficacy Endpoint ....................................................................... 30 
6.1.2. 
Statistical Hypothesis for the Primary Efficacy Endpoint .................................................... 30 
6.1.3. 
Analysis of the Primary Efficacy Endpoint .......................................................................... 30 
6.1 .4. 
Subgroup Analysis of the Primary Efficacy Endpoint ......................................................... 31 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 3 1 
6.2.1. 
Definition of Secondary Efficacy Endpoints ........................................................................ 31 
6.2.2. 
Anal sis Methods for Seconda 
Efficac End oints .......................................................... 32 
6.4. 
7. 
SAFETY ANALYSES ........................................................................................................................................ 35 
7.1. 
Adverse Events and Deaths .................................................................................................................... 35 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 35 
7.1.2. 
Adverse Event Severity ........................................................................................................ 35 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 35 
7.1 .4. 
Serious Adverse Events ........................................................................................................ 35 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 36 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 37 
7 .2. 
Laboratory Evaluations .......................................................................................................................... 39 
7 .2.1. 
Summaries of On Treatment Numeric Laboratory Results .................................................. 39 
7.2.2. 
Summaries of Numeric Laboratory Results during TFFU Period ........................................ 40 
7.2.3. 
Graded Laboratory Values ................................................................................................... 40 
7 .2.4. 
Liver-related Laboratory Evaluations ................................................................................... 42 
7.3. 
Body Weight, Body Mass Index and Yitai Signs ................................................................................... 43 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 43 
7.4.1. 
Prior Medications ................................................................................................................. 44 
7.4.2. 
Concomitant Medications ..................................................................................................... 44 
7.5. 
Electrocardiogram Results ..................................................................................................................... 45 
7.6. 
Other Safety Measures ........................................................................................................................... 45 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 45 
8. 
PHARMACOKINETIC ANALYSES ................................................................................................................ 46 
9. 
REFERENCES ................................................................................................................................................... 47 
10. SOFTWARE ....................................................................................................................................................... 48 
11. SAP REYISION .................................................................................................................................................. 49 
12. APP ENDICES .................................................................................................................................................... 50 
Appendix I. 
Table 3-1. 
Table 3-2. 
Table 3-3. 
CONFIDENTIAL 
Schedule of Assessments ........................................................................................................ 51 
LIST OF IN-TEXT TABLES 
sis Visit Windows for On-treatment gHBsAg, HBV DNA, ddPCR , 
Yitai Signs and Safety Laboratory Data ........... I 8 
Ana ys1s V1s1t Wm ows or n-treatment ualitative HBV Serology .................................. 18 
Analysis Visit Windows for On-treatment Electrocardiogram (ECG), and 
Coagulation ............................................................................................................................ 18 
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Table 3-4.
Analysis Visit Windows for On-treatment Creatinine Clearance and Body Weight 
Data ........................................................................................................................................19
Table 3-5.
Analysis Visit Windows for Posttreatment qHBsAg, HBV DNA, ddPCR, 
, Vital Signs and Safety Laboratory Data ...........19
Table 3-6.
Analysis Visit Windows for Posttreatment Qualitative HBV Serology .................................20
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema.........................................................................................................................10
CCI


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
BLQ
below the limit of quantitation
BMI
body mass index
BPM
beats per minute
CHB
chronic hepatitis B
CI
confidence interval
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FU
follow-up
GLPS
Global Product Safety 
HBcrAg
hepatitis B core-related antigen
HBV
hepatitis B virus
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HLGT
high level group term
HLT
high level term
ID
Identification
IMP
Investigational Medicinal Product
LLT
lower level term
LLOQ
lower limit of quantitation
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NUC
nucleos(t)ide
INR
international normalized ratio
Peg-IFN
pegylated interferon
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
RBC
red blood cell


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RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SOC
system organ class
TAF
tenofovir alafenamide
TE
treatment-emergent
TFFU
treatment-free follow-up
TFLs
tables, figures, and listings
TND
target not detected
ULN
upper limit of the normal range
WBC
white blood cell
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 tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-464-4437. This SAP is based on the study protocol amendment 3 dated 
11 March 2019 and the electronic case report form (eCRF). The SAP will be finalized before 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 safety and tolerability of the 12 week treatment regimens of GS-9992 plus 
tenofovir alafenamide (TAF) or commercially available nucleos(t)ides (NUCs)

Groups 1-3 and 5
To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in 
viremic chronic hepatitis B (CHB) subjects as measured by the proportion of subjects 
with ≥ 0.5 log10 IU/mL decline from baseline at Week 12 in circulating serum 
quantitative hepatitis B surface antigen (qHBsAg)

Group 4
To evaluate the antiviral activity of 12 weeks of GS-9992 with commercially available 
NUC(s) in virally suppressed CHB subjects as measured by the proportion of subjects 
with ≥ 0.5 log10 IU/mL decline from baseline at Week 12 in circulating serum qHBsAg
The secondary objectives of this study are as follows:

Groups 1-3 and 5
To evaluate the safety and tolerability of the 48 week treatment regimens as assessed by 
review of the accumulated safety data
To evaluate the antiviral activity of 12 weeks of GS-9992 plus TAF versus TAF alone in 
CHB subjects as measured by the proportion of subjects with ≥ 1 log10 IU/mL decline 
from baseline at Week 12 in circulating qHBsAg
To evaluate the proportion of hepatitis B e antigen (HBeAg) positive CHB subjects who 
achieve HBeAg loss and seroconversion during 12 weeks of GS-9992 plus TAF versus 
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To evaluate the proportion of CHB subjects who achieve hepatitis B surface antigen 
(HBsAg) loss during 12 weeks of GS-9992 plus TAF versus TAF alone and after 
GS-9992 discontinuation through 48 weeks 
To evaluate the incidence of drug resistance mutations during 48 weeks of treatment 
To characterize steady-state phannacokinetics (PK) of study drugs 
To evaluate the change from baseline in hepatitis B virus (HBV) deoxyribonucleic acid 
(DNA) and qHBsAg in CHB subjects during 12 weeks of GS-9992 plus TAF versus TAF 
alone and after GS-9992 discontinuation through 48 weeks 
• 
Group 4 
I 
I 
I 
I 
To evaluate the proportion of subjects experiencing HBV virologic breakthrough 
(2 consecutive visits ofHBV DNA ~ 69 IU/mL) during 12 weeks of GS-9992 treatment 
To evaluate the antiviral activity of 12 weeks of GS-9992 in CHB subjects as measured 
by the proportion of subjects with~ 1 log10 IU/mL decline from baseline at Week 12 in 
circulating qHBsAg 
To evaluate the proportion of HBeAg-positive CHB subjects who achieve HBeAg loss 
and seroconversion during 12 weeks of GS-9992 and after GS-9992 discontinuation 
through 48 weeks 
To evaluate the proportion of CHB subjects who achieve HBsAg loss during 12 weeks of 
GS-9992 and after GS-9992 discontinuation though 48 weeks 
To characterize steady-state PK of study drugs 
To evaluate the change from baseline in qHBsAg in CHB subjects during 12 weeks of 
GS-9992 and after GS-9992 discontinuation through 48 weeks 
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1.2.
Study Design
This is a Phase 2, randomized, open-label, active-controlled study to evaluate the safety and 
antiviral activity of GS-9992 plus TAF or commercially available NUC in CHB subjects.
Approximately 120 chronic, immune-active, HBV-infected adults without cirrhosis will be
enrolled; including 100 viremic subjects not currently on HBV NUC and 20 virally suppressed 
subjects on a commercially available NUC.
Groups 1 and 2: Approximately 40 viremic subjects will be randomized in a 3:1 ratio to the 
following:

Group 1: Approximately 30 subjects will be administered GS-9992 50 mg (2 × 25 mg
capsules) once daily one hour before or one hour after a meal plus TAF 25 mg once daily
with food for 12 weeks then TAF 25 mg once daily with food for 36 weeks

Group 2: Approximately 10 subjects will be administered TAF 25 mg once daily with food
for 48 weeks
Randomization will be stratified by HBeAg status (positive or negative) at screening with
approximately 40% of HBeAg negative subjects enrolled.
Group 3: Approximately 30 viremic subjects will be administered GS-9992 200 mg (2 x 100mg)
once daily one hour before or one hour after a meal plus TAF 25 mg once daily with food for
12 weeks then TAF 25 mg once daily with food for 36 weeks.
Approximately 40% of subjects enrolled in Group 3 will be HBeAg negative.
Group 4: Approximately 20 virally suppressed subjects currently being treated with a 
commercially available NUC(s) for CHB will be administered GS-9992 100 mg tablet once daily 
one hour before or one hour after a meal for 12 weeks.
Approximately 50% of subjects enrolled in Group 4 will be HBeAg negative. Subjects will 
remain on their current commercially available NUC(s) therapy for the duration of the study. All 
subjects will be followed through Week 48.
Group 5 (Hong Kong): Approximately 30 viremic subjects may be enrolled and assigned:
GS-9992 400 mg (2 x 200 mg tablets) once daily one hour before or one hour after a meal plus
TAF 25 mg once daily with food for 12 weeks then TAF 25 mg once daily with food for 
36 weeks.


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Figure 1.
Study Schema
24 Week Treatment-Free Follow-up (TFFU)
Subjects that meet any one of the following criteria will be followed for 24 weeks or until the 
initiation of alternative CHB therapy, whichever comes first:

Subjects that discontinue all HBV therapy (eg, GS-9992 and/or TAF or commercially 
available NUC), for any reason;

Subjects with HBsAg loss confirmed at least 12 weeks apart should discontinue all HBV
therapy following confirmation.
Week 
Group 1 
n.=30 
Group 2 
n.=10 
Group J. 
n=30 
Group4 
n=20 
Group 5 
ll""30 
0 
GS-9992 50 mg QD 
TAF 25 mg QD 
TAF 25 mg QD 
GS-9992 200 mg &; 
TAF 25 mg QD 
GS-9992 100 mg QD + 
Commercially available 
NUC 
GS-9992 400 mg QD (2 X 
200mg OD) 
TAF 25 mg QD 
12 
48 
] 
TAF 25 mg 
TAF 25 mg 
H 
Commercial NUC" 
I 
TAF 25 mg 
*Group 4: S11b;ects 11'ho discontinue NUCs should befolloffed in Treatment-Free Follow-11p 
FU24 


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The total time to complete all study visits is up to approximately 79 weeks including the
following periods:

Up to 45 day (6 to 7 weeks) screening period

A 48-week study period
Groups 1, 3 and 5: 12 week treatment of GS-9992 plus TAF followed by TAF only 
treatment
Group 2: 48 weeks of TAF only treatment
Group 4: 12 week treatment of GS-9992 plus commercially available NUC followed by 
NUC only

Up to 24-week TFFU period
The schedule of assessments is provided as an appendix to the SAP (Appendix 1).
1.3.
Sample Size and Power
Due to the exploratory nature of this study, the sample size was not determined by any formal 
power calculation. The number of subjects in each treatment group was decided based on clinical 
experience.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
After all subjects in Group 3 have completed the study, all the data including Groups 1-4 through 
TFFU and Group 5 through Week 12 have been cleaned and finalized, the interim analysis of the 
data will be performed into three parts as follows:
2.1.1.
Analysis for 12 Week Regimen
The Analysis for 12 Week Regimen will include data collected through 30 days after the last 
dose of GS-9992 (Groups 1, 3-5) or 30 days after 12 weeks treatment of TAF (Group 2). 
2.1.2.
Analysis for 48 Week Regimen
The Analysis for 48 Week Regimen will include data collected to the end of the completion of 
48 Week study period.
2.1.3.
TFFU Analysis 
The TFFU analysis will be conducted for subjects who entered the 24-week TFFU period. 
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the final analysis of 
the data will be performed. The final analysis consists of three parts: analysis for
12 Week regimen, analysis for 48 Week regimen, and TFFU 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 All Randomized/Enrolled Analysis 
Set and sorted by subject ID, 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 (Group 1 and 2) or enrolled (Group 3-5) will 
be used in the listings. Age, sex at birth, race, and ethnicity will be included in the listings, if
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 eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized/Enrolled Analysis Set
The All Randomized/Enrolled Analysis Set includes all subjects who were randomized
(Group 1 and 2) or enrolled (Group 3-5) in the study. Subjects are grouped within the All 
Randomized/Enrolled Analysis Set by the treatment group to which they were randomized
(Group 1 and 2) or enrolled (Group 3-5). 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized to Groups 1 or 2, or 
enrolled in Group 3-5, and who took at least 1 dose of any study drug. The study drugs in this 
study are GS-9992 and TAF. Subjects are grouped within FAS by treatment group to which they 
were randomized or enrolled.
This is the primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of any study drug. Subjects 
are grouped within the Safety Analysis Set according to the treatment they actually received. 
This is the primary analysis set for safety analyses.


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3.1.4.
TFFU Analysis Set
The TFFU Analysis Set includes all subjects who continued in the study following the 
discontinuation of TAF (Groups1-3, and 5) or commercially available NUC(s) (Group 4), during 
the Treatment-Free Follow-Up (TFFU) Phase. Subjects are grouped within the TFFU Analysis 
Set by the treatment group to which they were randomized.
3.1.5.
Biomarker Analysis Set
The Biomarker Analysis Set includes all subjects who were randomized to Groups 1 or 2 or 
enrolled in Group 5, and who took at least 1 dose of any study drug and have at least 
1 nonmissing biomarker value for each respective biomarker.
3.2.
Subject Grouping
For analyses based on the All Randomized/Enrolled Analysis Set or FAS, subjects will be 
grouped according to the treatment to which they were randomized or enrolled. For analyses 
based on the Safety Analysis Set, PK Analysis Set
, subjects will 
be grouped according to the actual treatment received. The actual treatment received will differ 
from the randomized or enrolled treatment only when their actual treatment differs from 
randomized or enrolled treatment for the entire treatment duration.
3.3.
Strata and Covariates
Approximately 40 subjects will be randomly assigned to Group 1 or Group 2 via the interactive
voice or web response system (IXRS) in a 3:1 ratio using a stratified randomization schedule. 
Approximately 30 subjects will be enrolled to Group 3, 20 subjects to Group 4 and 30 subjects to 
Group 5. Stratification will be based on the following variable: 

HBeAg (positive, negative)
If there are discrepancies in stratification factor values between the IXRS and the clinical
database, the values recorded in the clinical database will be used for analyses.
Efficacy endpoints will be evaluated by baseline HBeAg status and overall for each treatment 
group.
3.4.
Examination of Subject Subsets
Due to the exploratory nature and the small sample size of this study, subgroup analyses based 
on the presumed prognostic baseline characteristics will not be performed for analysis of efficacy 
endpoints.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical hypothesis testing 
will be performed in this study. 
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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
A missing baseline laboratory result will be treated as normal (ie, no toxicity grade) for the 
laboratory abnormality summary.
Both the baseline and post-baseline borderline results for HBeAg, hepatitis B e antibody 
(HBeAb), HBsAg, and hepatitis B surface antibody (HBsAb) will be imputed following the rules 
below:

HBsAb/HBeAb borderline HBsAb/HBeAb negative

HBsAg/HBeAg borderline HBsAg/HBeAg positive
For missing last dose date of study drug, imputation rules are described in Section 3.8.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis. 
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a subject, then age derived based on date of birth and the Day 1 
visit date will be used instead. If an enrolled (or randomized) subject was not dosed with any 
study drug, the enrollment (or randomization) date will be used instead of the Day 1 visit 
date. For screen failures, the date the first informed consent was signed will be used for the age 
derivation. Age required for longitudinal and temporal calculations and analyses (eg, estimates of 
creatinine clearance, age at date of AE) will be based on age derived from date of birth and the 
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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the 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).
For HBV DNA, if the value in IU/mL is above the upper LOQ, the corresponding diluted HBV 
DNA value, if available, will be used.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data, eg, log-transformed data, or nonparametric
analysis methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 
0 at predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”.

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ”.

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ”.

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ”.

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”.
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dose date of any study drug and derived as follows:

For postdose study days: Assessment Date First Dose Date of Any Study Drug + 1

For days prior to the first dose: Assessment Date First Dose Date of Any Study Drug
Therefore, study Day 1 is the day of first dose of study drug administration.
The last dose date of an individual study drug will be the stop date on the study drug
administration eCRF for the record where the “study drug was permanently withdrawn” flag is 
“Yes”.
If the last study drug dosing date is missing, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.

For Groups 1-3 and 5
Data collected up to 3 days after the last dose date of GS-9992 or TAF, whichever comes last, 
will be considered as on-treatment data whereas data collected afterwards will be considered as 
posttreatment data.

For Group 4
Data collected up to 3 days after the last dose date of GS-9992 or 3 days after the subjects have 
discontinued commercially available NUC(s), whichever comes last, will be considered as 
on-treatment data whereas data collected afterwards will be considered as posttreatment data.
On-treatment data will be mapped to the analysis windows defined in Table 3-1, Table 3-2, 
Table 3-3 and Table 3-4.


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Table 3-1.
Analysis Visit Windows for On-treatment qHBsAg, HBV DNA,
ddPCR , 
 Vital Signs and 
Safety Laboratory Data
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 1
8
2
11
Week 2
15
12
22
Week 4
29
23
43
Week 8
57
44
71
Week 12
85
72
99
Week 16
113
100
141
Week 24
169
142
211
Week 36
253
212
295
Week 48
337
296
≥ 337
Note: For Group 4, subjects were treated with GS 9992 through Week 12 and continued on NUC afterwards.
Table 3-2.
Analysis Visit Windows for On-treatment Qualitative HBV Serology
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
127
Week 24
169
128
211
Week 36
253
212
295
Week 48
337
296
≥ 337
Note: For Group 4, subjects were treated with GS 9992 through Week 12 and continued on NUC afterwards.
Table 3-3.
Analysis Visit Windows for On-treatment Electrocardiogram (ECG), 
and Coagulation 
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
≥ 85
Note: ECGs are to be collected at screening, baseline, Week 12 or Early Discontinuation. For purpose of analysis, baseline value 
will be the last available value prior to the first dose of any study drug. The Early Discontinuation value will be the last available 
value on or prior to the last dose date of any study drug + 3 days.
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Table 3-4.
Analysis Visit Windows for On-treatment Creatinine Clearance and 
Body Weight Data
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
211
Week 48
337
212
≥ 337
Note:
a.
For Group 4, subjects were treated with GS 9992 through Week 12 and continued on NUC afterwards.
b.
Creatinine clearance data are to be collected at screening, baseline, Week 12, Week 48 or early discontinuation. For purpose 
of analysis, baseline value will be the last available value prior to the first dose of any study drug. The Early Discontinuation 
value will be the last available value on or prior to the last dose date of any study drug + 3 days.
Posttreatment data will be mapped to the posttreatment follow-up (FU) analysis windows, which
will be defined by FU Day.

For Groups 1-3
FU Day  Assessment Date Last Dose Date of GS-9992 or TAF (whichever comes last)

For Group 4
FU Day  Assessment Date Last Dose Date of GS-9992 or Date Subject Discontinued NUC
(whichever comes last)
Posttreatment FU analysis windows are presented in Table 3-5 and Table 3-6.
Table 3-5.
Analysis Visit Windows for Posttreatment qHBsAg, HBV DNA,
ddPCR, 
Vital Signs and 
Safety Laboratory Data
Analysis Visit
FU Day
Lower Limit
Upper Limit
FU Week 4
29
4
43
FU Week 8
57
44
71
FU Week 12
85
72
99
FU Week 16
113
100
127
FU Week 20
141
128
155
FU Week 24
169
156
≥ 169
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Table 3-6.
Analysis Visit Windows for Posttreatment Qualitative HBV Serology
Analysis Visit
FU Day
Lower Limit
Upper Limit
FU Week 12
85
4
127
FU Week 24
169
128
≥ 169
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dose 
date of any study drug, unless specified differently. If multiple measurements occur on the 
same day, the last nonmissing value prior to the time of first dosing of any study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the average of these measurements will be considered the baseline 
value.

For postbaseline values (except for ALT): 
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken except for 
qHBsAg (IU/mL) and HBV DNA (IU/mL), HBeAg (IU/mL), HBcrAg (U/mL), HBV 
RNA (Copies/mL) as for which the geometric mean will be taken.

For postbaseline ALT values: 
The record with the largest value within the same analysis window will be selected
If there is more than 1 record with the largest value, the latest record will be selected.
If there are multiple largest records with the same time or no time recorded on the same 
day, any one of these measurements can be selected as the analysis value. 


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If multiple valid, nonmissing, categorical measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

For baseline, the last available record on or prior to the date of the first dose of any study 
drug will be selected. If there are multiple records with the same time or no time recorded on 
the same day, the value with the lowest severity will be selected for safety data (eg, normal 
will be selected over abnormal for safety ECG findings) and the most conservative value will 
be selected for efficacy data (eg, negative will be selected over positive for HBeAg and 
HBsAg whereas positive will be selected over negative for HBeAb and HBsAb).

For postbaseline values:
The most conservative value (eg, abnormal will be selected over normal for safety ECG)
within the window will be selected except for HBV serology (HBsAg, HBsAb, HBeAg, 
and HBeAb), for which the most favorable value (ie, negative will be selected over 
positive for HBsAg and HBeAg, whereas positive will be selected over negative for 
HBsAb and HBeAb) will be selected. 
In the event that more than 1 value within a window are the value collected closest to the 
nominal day will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the latest record will be selected; if 
these measurements were recorded at the same time or no time recorded, any one of these 
measurements can be selected as the analysis value. 


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
Key study dates (i.e., (first subject screened, first subject enrolled, last subject 
enrolled/randomized, last subject last visit for the primary endpoint, and last subject last visit for 
the clinical study report) will be provided. Last subject last visit for the primary endpoint in this 
study is the last subject who completed Week 12 qHBsAg collection. Last subject last visit for 
the clinical study report in this study is the last subject who completes TFFU period.
A summary of subject enrollment will be provided by treatment group for each country and
investigator within a country and overall. The summary will present the number and percentage 
of subjects enrolled. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column. 
A similar enrollment table will be provided by randomization stratum, ie, HBeAg status 
(positive, negative). The denominator for the percentage of subjects in the stratum will be the 
total number of enrolled subjects. If there are discrepancies in the value used for stratification 
assignment between the IXRS and the clinical database, the value collected in the clinical 
database will be used for the summary. A listing of subjects with discrepancies in the value of 
HBeAg used for stratification assignment between the IXRS and the clinical database at the time 
of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by treatment group and study overall. This
summary will present the number of subjects screened and the number of subjects in each of the 
categories listed below:

All Enrolled/Randomized Analysis Set 

Safety Analysis Set 

FAS

Biomarker Analysis Set

TFFU Analysis Set

GS-9992 completion status
Completed GS-9992
Prematurely discontinued GS-9992


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
Reason for premature discontinuation of GS-9992

TAF completion status
Completed TAF
Prematurely discontinued TAF

Reason for premature discontinuation of TAF

TFFU completion status
On TFFU
Completed TFFU
Prematurely discontinued TFFU

Reason for premature discontinuation of TFFU

Study completion status
On Study
Completed study 
Prematurely discontinued study 

Reason for premature discontinuation of study
For the status of study drug and study completion and the reasons for premature discontinuation, 
the number and percentage of subjects in each category will be provided. The denominator for 
the percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation

Reason for premature discontinuation from TFFU

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and kit ID (if applicable)


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4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative to the study drug regimen specified in the protocol. 
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dose date is 
missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date that occurred during the on-treatment period will 
be used.
The total duration of exposure to GS-9992 and TAF will be summarized using descriptive 
statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number
(ie, cumulative counts) and percentage of subjects exposed through the following time periods:
Baseline, Week 1, Week 2, Week 4, Week 8, Week 12 for both GS-9992 and TAF, and 
additionally Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44 and 
Week 48 for TAF.
A 3-day window is applied to the last planned on-treatment visit to match with the 
protocol-specified visit window. Summaries will be provided for each treatment group for the 
Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The presumed number of doses taken by a subject will be determined by the data collected on the 
drug accountability eCRF using the following formula:
Total Number of Doses Administered 
No. of Doses Dispensed
No. of Doses Returned














4.2.2.1.
Prescribed Adherence to GS-9992
The level of prescribed adherence to GS-9992 will be determined by the total amount of study 
drug taken relative to the total amount of study drug specified by the protocol for a subject who 
completes treatment in the study. 


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The level of adherence will be expressed as a percentage using the following formula:
%
100
  
Protocol
by 
Specified
  
Drug
Study 
of
Amount 
Total
Taken  
Drug
Study 
of
Amount 
Total
(%)
  
9992
-
GS
 to
Adherence








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
For a record where the number of capsules/tablets returned was missing (with “Yes” answered 
for “Was bottle returned?” question), it is assumed the number of capsules/tablets returned was 
0. If the number of capsules/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 the 
capsules/tables will be treated as not taken.
In this study, the total amount of GS-9992 prescribed for 12 weeks would require 168 capsules
for Group 1 (dosed with 2 capsules of GS-9992 25 mg QD); 168 tablets for Group 3 (dosed with 
2 tablet of GS-9992 100 mg QD); 84 tablets for Group 4 (dosed with 1 tablet of GS-9992 100 mg 
QD); 168 tablets for Group 5 (dosed with 2 capsules of GS-9992 200 mg QD) respectively.
Descriptive statistics for the level of prescribed adherence to GS-9992 (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) along with the number and percentage of subjects belonging 
to adherence categories (< 80%, ≥ 80 to < 90%, ≥ 90%) will be provided for Group 1, 3 , 4 and 5 
by treatment group for the Safety Analysis Set. No inferential statistics will be provided.
4.2.2.2.
Adherence to TAF
The level of adherence to TAF will be determined by the total amount of study drug taken 
relative to the total amount of study drug prescribed, where each total amount is obtained by 
summing up the corresponding amount at each dispensing period over all evaluable dispensing 
periods. 
The level of adherence will be expressed as a percentage using the following formula:
%
100
Period
Dispensing
Each 
at 
Prescribed
Tablets
of
No.
Period
Dispensing
Each 
at 
Taken 
Tablets
of
No.
(%)
TAF
 to
Adherence











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1) Number of tablets taken at a distinct dispensing period is calculated as the minimum of 
(a) the daily number of tablets prescribed for TAF multiplied by the duration of treatment 
at the dispensing period of the same dispensing date, and (b) the number of tablets taken 
(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 is calculated as the daily number 
of tablets prescribed for TAF 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.
Note: If calculated adherence is greater than 100%, the result will be set to 100%.
For TAF, a record where the number of capsules/tablets returned was missing (with “Yes” 
answered for “Was bottle returned?” question); it is assumed the number of capsules/tablets 
returned was 0. If the number of capsules/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.
Descriptive statistics for the level of prescribed adherence to TAF (n, mean, SD, median, Q1, 
Q3, minimum, and maximum) along with the number and percentage of subjects belonging to 
adherence categories (< 80%, ≥ 80 to < 90%, ≥ 90%) will be provided for Group 1, 2 , 3 and 5 by 
treatment group for the Safety Analysis Set. No inferential statistics will be provided.
A by-subject listing of study drug administration and drug accountability will be provided
separately by subject ID number and visit (in chronological order).
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility (inclusion or 
exclusion) criterion and the number of subjects who did not meet specific criteria by treatment 
group based on All Randomized/Enrolled Analysis Set. A by-subject listing will be provided for 
those subjects who did not meet at least 1 eligibility criterion. The listing will present the 
eligibility criterion (or criteria if more than 1 deviation) that subjects did not meet and related 
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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 (e.g., nonadherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized by treatment group for All Randomized/Enrolled Analysis Set. A 
by-subject listing will be provided for those subjects with important protocol deviation.
Subjects who received study drug other than their treatment assignment at randomization or 
enrollment will be listed with the start and stop dates that they received incorrect study treatment.
A by-subject listing will be provided for subjects with important protocol deviation related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviation related to COVID-19.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
Subject demographic variables (ie, age, sex, race, ethnicity and region [South Korea, 
Hongkong]) and baseline characteristics (body weight [in kg], height [in cm], body mass index 
[BMI; in kg/m2]) will be summarized by HBeAg status (positive, negative) and overall for each 
treatment group and Group 1, 3, and 5 GS-9992 overall using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) for continuous variables, and using number and 
percentage of subjects for categorical variables (Age : < 50 years, ≥50 years; BMI: 
< 18.5 kg/m2, ≥ 18.5 kg/m2 25 kg/m2, ≥ 25 kg/m2
30 kg/m2, ≥ 30 kg/m2). The summary of 
demographic data will be provided for the Safety Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include

HBV genotype

cirrhosis (yes, no, indeterminate) and its determination method

APRI as categories (≤ 1, > 1)

FibroTest score as a continuous variable and fibrosis stage by FibroTest score as a 
categorical variable (0.00  0.48, 0.49  0.74, 0.75  1.00)

HBsAg (log10 IU/mL) as a continuous variable and as categories (≤ 4 log10 IU/mL, 
> 4 log10 IU/mL)

HBV DNA (log10 IU/mL) as a continuous variable and as categories (< LLOQ, ≥ LLOQ; and 
also < 7 log10 IU/mL, ≥7 log10 IU/mL
8 log10 IU/mL, ≥ 8 log10 IU/mL)

HBeAb (positive, negative)

ALT (U/L) as a continuous variable and as categories based on central laboratory normal 
range (≤ ULN, > ULN 5 × ULN, > 5 × ULN 10 × ULN, > 10 ULN)

ALT level as categories based on American Association for the Study of Liver Diseases 
(AASLD) normal range with the ULN as 25 U/L for female and 35 U/L for male 
(≤ULN, > ULN 5 × ULN, > 5 × ULN 10 × ULN, > 10 ULN)

current oral nucleoside/nucleotide treatment (Group 4 only) 


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
previous oral nucleoside/nucleotide treatment experience (yes, no)

previous interferon experience to treat HBV (yes, no)

duration of being HBV positive (years) as a continuous variable

mode of HBV infection

estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault equation (mL/min)
eGFR will be calculated by the Cockcroft-Gault method: 
eGFRCG (mL/min)
[(140 - age (years)) × weight (kg) × (0.85 if female)] / 
(serum creatinine (mg/dL) × 72), where weight is total body mass in kilograms.
These baseline characteristics will be summarized by HBeAg status (positive, negative) and 
overall for each treatment group and Group 1- 3, and 5 overall using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) for continuous variables and using 
number and percentage of subjects for categorical variables. The summary of baseline 
characteristics will be provided for the Safety Analysis Set.
A by-subject listing of baseline characteristics will be provided by subject ID number in 
ascending order.
A by-subject data listing for HBV treatment history will be provided for the Safety Analysis Set. 
The listing will display the previous HBV treatment experience, previous HBV regimen and 
treatment, the treatment duration, and the reason for treatment discontinuation for treatment 
experienced subjects. For Group 4, a separate by-subject listing for current HBV treatment will 
be provided. The listing will present the current HBV treatment, regimen, and the start date of 
the current HBV treatment. 
5.3.
Medical History
Medical history was collected at screening.
Data will be coded using the current version of Medical Dictionary for Regulatory Activities
(MedDRA). Medical history will be summarized by system organ class (SOC) and preferred 
term (PT) by treatment group. Subjects who reported 2 or more medical history items that are 
coded to the same SOC and/or PT will be counted only once by the unique coded term in the 
summary. The summary will be provided for the Safety Analysis Set. No formal statistical 
testing is planned. 
A by-subject listing will also be provided. 


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with ≥ 0.5 log10 IU/mL decline in 
qHBsAg from baseline at Week 12.
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
No statistical hypothesis testing will be performed. 
6.1.3.
Analysis of the Primary Efficacy Endpoint
Proportion point estimates and the 2-sided 95% exact confidence intervals (CIs) of the primary 
efficacy endpoint will be provided by HBeAg status (positive, negative) and overall for each 
treatment group. CIs of the proportion point estimates will be constructed based on the 
Clopper-Pearson method {Clopper 1934}. CIs for the proportion differences by HBeAg status
will be constructed based on the standardized statistic and inverting two 1 sided tests 
{Chan 1999}.
In addition, the proportion differences (Group 1 Group 2, Group 3 Group 2, 
Group 5 - Group 2) and the corresponding 2-sided 95% CIs will be reported. CIs of the 
proportion differences will be calculated by using stratum-adjusted Mantel-Haenszel (MH) 
proportions {Koch 1989}, stratified by the randomization stratification factor HBeAg status 
(positive, negative), as follows: 
P1
P2 Z(1 α/2 ) * SE(P1
P2),
where

(P1
P2)  

h
h
h
w
d
w
, is the stratum-adjusted MH proportion difference, where 
h
d
h
h
p
p
2
1
is the proportion difference Groups 1 and 2 in stratum h (h
1 and 2).

h
w
h
h
h
h
n
n
n
n
2
1
2
1

, is the weight based on the harmonic mean of sample size per treatment 
group for each stratum where 
h
n1 and 
h
n2 are the sample sizes of Groups 1 and 2 in stratum h.


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
SE(P1
P2)  
2
2
*
2
*
2
1
*
1
*
1
)
(
1
)
1(
1
)
1(





h
h
h
h
h
h
h
w
n
p
p
n
p
p
w
, where 
1
5.0
1
1
*
1


h
h
h
n
m
p
and 
1
5.0
2
2
*
2


h
h
h
n
m
p
and 
h
m1 and 
h
m2 are the number of subjects with ≥ 0.5 log10 IU/mL decline 
in HBsAg from baseline at Week 12 in Groups 1 and 2 in stratum h.

α  0.05 for this study 

Z(1 α/2)
 Z0.975
 1.96 is the 97.5th percentile of the normal distribution
If the computed lower confidence bound is less than 1, the lower bound is defined as 1. If the 
computed upper confidence bound is greater than 1, then the upper bound is defined as 1.
6.1.4.
Subgroup Analysis of the Primary Efficacy Endpoint
No subgroup analysis will be performed.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoints include the following:

Proportion of subjects with ≥ 1 log10 IU/mL decline in qHBsAg from baseline at Week 12

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion through 
48 weeks of treatment

Proportion of subjects who achieve HBsAg loss through 48 weeks of treatment

Proportion of subjects with drug resistance mutations during 48 weeks of treatment
(Group 1
3, and 5)

Change from baseline in HBV DNA and qHBsAg through 48 weeks of treatment
(Group 1 - 3, and 5)

Change from baseline in qHBsAg through 48 weeks of treatment (Group 4)

Proportion of subjects experiencing HBV virologic breakthrough (2 consecutive visits of 
HBV DNA ≥ 69 IU/mL) during 12 weeks of GS-9992 treatment (Group 4)
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HBV Serology definitions:

HBsAg loss: HBsAg changing from positive at baseline to negative at any postbaseline visit.

Confirmed HBsAg loss: HBsAg loss confirmed by any 2 consecutive results.

HBsAg loss reversion: Any postbaseline HBsAg positive result following HBsAg loss.

HBsAb seroconversion: HBsAb changing from negative or missing at baseline to positive at 
any postbaseline visit.  

Confirmed HBsAb seroconversion: HBsAb changing from negative or missing at baseline 
to positive at any postbaseline visit confirmed by any 2 consecutive results.

HBsAb seroreversion: Any postbaseline HBsAb negative result following HBsAb 
seroconversion.
HBeAg-related terminology is defined similarly.
Lower LOQ (LLOQ) for HBV DNA is defined as 20 IU/mL. LLOQ for qHBsAg is defined as 
0.05 IU/mL. LLOQ for qHBeAg is defined as 0.11 IU/mL.
Missing data will be treated as a non-event unless otherwise specified (eg, no HBsAg loss, no 
seroconversion, etc.)
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
The proportion of subjects with ≥ 1 log10 IU/mL decline in HBsAg from baseline at Week 12 will 
be analyzed on FAS similarly to the primary efficacy endpoint. Proportion point estimates and 
the 2-sided 95% exact CIs will be provided by HBeAg status (positive, negative) and overall for 
each treatment group. CIs of the proportion point estimates will be constructed based on the
Clopper-Pearson method. In addition, the proportion differences (Group 1 Group 2, 
Group 3 - Group 2, and Group 5
Group 2) and the corresponding 2-sided 95% CIs will be 
reported. CIs of the proportion differences will be calculated by using stratum-adjusted MH 
proportions, stratified by HBeAg status (positive, negative).
A summary table will be provided for HBsAg-related serology results. The proportion of 
subjects who have ever had HBsAg loss, confirmed HBsAg loss, on-treatment HBsAg loss, 
posttreatment HBsAg loss (for subjects with positive HBsAg at the end of the on-treatment 
period), HBsAg loss with HBsAb seroconversion, HBsAg loss with HBsAb seroreversion, and 
HBsAg loss reversion with or without HBsAb seroconversion will be summarized by HBeAg 
status (positive, negative) and overall for each treatment group. 


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Additional smmnary tables may be provided for the following: 
If~ 3 subjects achieved HBsAg loss, 
Versionl.0 
• 
The proportion of subjects with HBsAg loss will be smmnarized by visit through Week 48; 
If~ 3 subjects achieved HBsAg loss with HBsAb seroconversion, 
• 
The proportion of subjects with HBsAb seroconversion will be smmnarized by visit through 
Week 48 
• 
The proportion of subjects who have ever had HBsAg loss with HBsAb seroconversion, 
confinned HBsAb seroconversion, on-treatment HBsAb seroconversion, posttreatment 
HBsAb seroconversion (for subjects with negative or missing HBsAb at the end of the 
on-treatment period) will be smmnarized. 
For subjects in the FAS with baseline HBeAg status positive, similar summary tables will be 
provided for HBeAg-related serology results. 
Smmnary statistics will be presented by HBeAg status (positive, negative) and overall for each 
treatment group for absolute values and change from baseline in HBV DNA (log1 o IU/mL) 
(Group 1- 3, and 5) and qHBsAg (log10 IU/mL) by visit (Group 1- 5). 
For Group 4, the proportion of subjects who experienced HBV virologic breakthrough 
(2 consecutive visits ofHBV DNA~ 69 IU/mL) during 12 weeks of GS-9992 treatment will be 
evaluated by HBeAg status (positive, negative) and overall. Proportion point estimates and the 
2-sided 95% exact Cls will be calculated based on the Clopper-Pearson method. 
Imputation rules described in Section 3.6.1 will be used to assign HBeAg and HBsAg status for 
borderline results. Otherwise, a Missing 
Excluded analysis will be perfonned. 
Plots of the mean ± SD and median (Q 1, Q3) of absolute values and changes from baseline in 
HBV DNA (Group 1- 3, 5) and qHBsAg will be presented (Group 1-5). 
Drug resistance mutations will be analyzed as part of the Virology Study Report. 
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6.4. 
Changes From Protocol-Specified Efficacy Analyses 
One of the secondary objectives of this study for Groups 1-3 and 5: 
To characterize steady-state phannacokinetics (PK) of study drugs 
Versionl.0 
GS-9992 drug development was stopped by Spring Banks and the study team decided not to 
perfonn PK analysis and the collected PK samples will be stored. 
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of
MedDRA. System organ class (SOC), high level group term (HLGT), high level term (HLT), 
preferred term (PT), and lower level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria
specified in the 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. The missing 
category will be listed last in summary presentation.
Severity of adverse events will be determined by the investigator as mild, moderate, or severe. 
The severity of events for which the investigator did not record severity will be categorized as 
“missing” for tabular summaries and data listings. The missing category will be listed last in 
summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAEs that were specified in the study protocol. SAEs captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Global Product Safety 
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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
For the Analysis for 12 Week Regimen, treatment-emergent adverse events (TEAEs) are 
defined as follows:

For subjects treated with GS-9992 and TAF or commercially available NUC(s) (ie, Group 1, 
3 , 4 and 5): 
Any AEs with an onset date on or after the first dose date of any study drug and no later 
than 30 days after permanent discontinuation of GS-9992
Any AEs leading to premature discontinuation of any study drug during the 
first 12 weeks (ie, from Day 1 to Day 84).

For subjects treated with TAF only (ie, Group 2):
For those who remained on TAF treatment for the first 12 weeks plus 30 days
(ie, from Day 1 to Day 114):
■
Any AEs with an onset date on or after the first dose of TAF and no later than 
30 days after the first 12 weeks treatment of TAF (ie, no later than Day 114) 
For those who prematurely discontinued TAF during the first 12 weeks plus 30 days
(ie, from Day 1 to Day 114):  
■
Any AEs with an onset date on or after the first dose of TAF and no later than 3 days 
after permanent discontinuation of TAF or up to Day 114, whichever comes earlier
■
Any AEs leading to premature discontinuation of TAF
For the Analysis for 48 Week Regimen, TEAEs are defined as follows:

For subjects treated with GS-9992 and TAF (ie, Group 1 , 3 and 5): 
Any AEs with an onset date on or after the first dose date of any study drug and no later
than 3 days after permanent discontinuation of TAF or 30 days after permanent 
discontinuation of GS-9992, whichever comes last
Any AEs leading to premature discontinuation of any study drug during the 48 weeks 
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
For subjects treated with TAF only (ie, Group 2):
Any AEs with an onset date on or after the first dose date of TAF and no later than 3 days 
after permanent discontinuation of TAF
Any AEs leading to premature discontinuation of TAF during the 48 weeks treatment 

Subjects treated with GS-9992 and commercially available NUC(s) (ie, Group 4) are not 
included in treatment-emergent Analysis for 48 Week Regimen.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dose date of
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to the cutoff day in the TEAE definition in Section 7.1.5.1.
An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dosing date of any study drug, will be considered to be treatment
emergent in both the Analysis for 12 Week Regimen and Analysis for 48 Week Regimen. In
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of any study drug 
will be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
AEs will be summarized based on the Safety Analysis Set.
3 sets of summaries will be generated: (1) all TEAEs for 12 Week Regimen (2) all TEAEs for 
48 Week Regimen (Group1-3, and 5). (3) all AEs during TFFU period (AEs that occur during 
TFFU after Week 48) will be listed, and summary tables will be presented using the TFFU 
Analysis Set as appropriate.
A brief, high-level summary of the number and percentage of subjects who experienced at least 
1 TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary.
The number and percentage of subjects who experienced at least 1 TEAE will be provided and
summarized by SOC, PT and treatment group:

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For the AE categories described below, summaries will be provided by PT and treatment group:

TEAEs

TEAEs of Grade 3 or higher

TE treatment-related AEs 

GS-9992 only TE treatment-related AEs (Group 1, 3-5)

TE treatment-related AEs of Grade 3 or higher

TE SAEs

TE treatment-related SAEs 

TEAEs leading to premature discontinuation of GS-9992

TEAEs leading to premature discontinuation of TAF

TEAEs leading to dose modification or temporary interruption of GS-9992

TEAEs leading to dose modification or temporary interruption of TAF
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order by SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study. 
In addition to the by-treatment summaries described above, data listings will be provided for the 
following AEs:

All AEs, indicating whether the event is treatment-emergent

All AEs of Grade 3 or higher

SAEs

All deaths

AEs leading to premature discontinuation of any study drug

AEs leading to dose modification or temporary interruption of any study drug


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For subjects in the TFFU Analysis Set, by-subject listings will be provided as follows:

All AEs

AEs of Grade 3 or higher

All SAEs

All deaths
The listings will indicate whether an event is treatment-emergent, and whether the event 
occurred during TFFU.
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 the 
Safety Analysis Set and will include all available data.
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. Hemolyzed test results will not be 
included in the analysis, but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum 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.
No inferential statistics will be generated.
7.2.1.
Summaries of On Treatment Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided
using all available data by treatment group for chemistry (including alanine aminotransferase
[ALT], albumin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], creatine kinase,
fasting glucose, total bilirubin, fasting total cholesterol, lactate dehydrogenase [LDH]),
hematology (including hemoglobin, lymphocytes, neutrophils, white blood cells and platelets), 
and estimated creatinine clearance calculated by the Cockcroft-Gault method as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit


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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of any study drug. Change from baseline to a postbaseline visit will be 
defined as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and 
maximum will be displayed to the reported number of digits; SD values will be displayed to the 
reported number of digits plus 1.
Median (Q1, Q3) of the observed values for albumin, ALT, ALP, lipase, estimated creatinine 
clearance, total bilirubin, triglycerides, total cholesterol, hemoglobin, lymphocytes, neutrophils, 
platelets, and white blood cells will be plotted using a line plot by treatment group and visit. In 
the case of multiple values in an analysis window, data will be selected for analysis as described 
in Section 3.8.3.
7.2.2.
Summaries of Numeric Laboratory Results during TFFU Period
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided
using all available data for chemistry (including albumin, ALT, ALP, AST, total bilirubin, 
creatine kinase, fasting glucose, fasting total cholesterol and LDH), hematology (including 
hemoglobin, lymphocytes, neutrophils, white blood cells and platelets), and estimated creatinine 
clearance calculated by the Cockcroft-Gault method as follows:

Baseline values 

Value at last on-treatment visit (TFFU baseline)

Values at each TFFU visit

Change from TFFU baseline at each TFFU visit
Last on-treatment laboratory value (TFFU baseline) is defined as the last measurement obtained 
on or prior to the date/time of last dose of any study drug including GS-9992, TAF and NUC 
treatment. Change from TFFU baseline value to a post treatment visit will be defined as the visit 
value minus the last on-treatment value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD values will be displayed to the reported 
number of digits plus 1.
Mean ± SD of the observed values for total bilirubin will be plotted using a line plot by HBeAg 
status and treatment group and visit. In the case of multiple values in an analysis window, data 
will be selected for analysis as described in Section 3.8.3.
7.2.3.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used to assign toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all 
values that do not meet the criteria for an abnormality of at least Grade 1. For laboratory tests 
with criteria for both increased and decreased levels, analyses for each direction (ie, increased, 
decreased) will be presented separately.


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7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
TE laboratory abnormalities are defined as values that increase at least 1 toxicity grade from 
baseline at any postbaseline time point, up to and including the cutoff day defined as follows:
For the Analysis for 12 Week Regimen:

For subjects treated with GS-9992 and TAF or commercially available NUC(s) (ie, Group 1, 
3 -5): 
30 days after permanent discontinuation of GS-9992

For subjects treated with TAF only (ie, Group 2):
For those who remained on TAF treatment for the first 12 weeks plus 30 days (ie, from 
Day 1 to Day 114):
■
30 days after the first 12 weeks treatment of TAF (ie, no later than Day 114)
For those who prematurely discontinued TAF during the first 12 weeks plus 30 days 
(ie, from Day 1 to Day 114):
■
3 days after permanent discontinuation of TAF or up to Day 114, whichever comes 
earlier
For the Analysis for 48 Week Regimen:

For subjects treated with GS-9992 and TAF (ie, Group 1 , 3 and 5): 
3 days after permanent discontinuation of TAF or 30 days after permanent 
discontinuation of GS-9992, whichever comes last

For subjects treated with TAF only (ie, Group 2):
3 days after permanent discontinuation of TAF

Subjects treated with GS-9992 and commercially available NUC(s) (ie, Group 4) are not 
included in treatment-emergent Analysis for 48 Week Regimen.
If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed
within the time frame specified above will be considered treatment-emergent.
7.2.3.2.
Laboratory Abnormalities during TFFU Period
Laboratory abnormalities during TFFU Period are defined as values that increase at least 
1 toxicity grade from TFFU baseline at any post treatment time point, up to the end of the study.


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7.2.3.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit for 
treatment emergent laboratory abnormalities. Laboratory abnormalities during TFFU period will 
be summarized using the number and percentage of subjects in the study with the given response 
at TFFU baseline and each scheduled post treatment visit. 
3 sets of summaries will be generated: (1) all TE laboratory abnormalities for 12 Week Regimen
(2) all TE laboratory abnormalities for 48 Week Regimen for Groups 1-3, 5. (3) all laboratory 
abnormalities during TFFU after Week 48 for subjects in the TFFU Analysis Set will be listed, 
and summary tables will be presented using the TFFU Analysis Set as appropriate. 
The following summaries (number and percentage of subjects) for laboratory abnormalities will 
be provided by lab test and by treatment group; subjects will be categorized according to the 
most severe postbaseline or post TFFU baseline abnormality grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline or post TFFU baseline values. A by-subject listing of Grade 3 or 
4 laboratory abnormalities, and all graded laboratory abnormalities will be provided by subject 
ID number and visit in chronological order. This listing will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades or 
abnormal flags displayed.
7.2.4.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for any postbaseline or post TFFU baseline measurements (based on central lab 
normal range):
1) ALT > 1.5 nadir and one of the following: 
ALT ≥ 2 baseline 
ALT ≥ 10 ULN
ALT ≥ 3 ULN and total bilirubin ≥ 2 ULN
ALT ≥ 3 ULN and INR ≥ 1.7


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ALT flare, AASLD Hepatitis flare and ALT elevation will also be summarized using the number 
and percentage of subjects for any postbaseline or post TFFU baseline measurements as follows 
(based on both central lab and AASLD normal range):

ALT flare: ALT > 2 baseline and ≥ 5 ULN

AASLD Hepatitis flare: ALT ≥ 3 baseline and > 100 U/L
2) ALT elevation: ALT > 1.5 nadir and one of the following: 
ALT ≥ 2 baseline
ALT ≥ 2.5 ULN and < 5 ULN
ALT ≥ 5 ULN and < 10 ULN
ALT ≥ 10 ULN
2 sets of summaries will be generated: (1) all liver-related TE laboratory abnormalities and ALT 
flare/elevation for Week 48 Regimen. (2) all liver-related laboratory abnormalities and ALT 
flare/elevation during TFFU will be listed, and summary tables will be presented using the TFFU 
Analysis Set as appropriate.
7.3.
Body Weight, Body Mass Index and Vital Signs
Descriptive statistics will be provided by treatment group for vital signs as follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. A listing of body weight and BMI will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. 


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7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
Only prior HBV medications will be summarized. A by-subject listing of prior HBV medications 
will also be provided.
Prior HBV medications will be summarized by preferred name using the number and percentage 
of subjects by treatment group. A subject reporting the same medication more than once will be 
counted only once when calculating the number and percentage of subjects who received that 
medication. The summary will be ordered by preferred name in order of descending overall 
frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects by treatment group. A subject reporting the same medication more than 
once will be counted only once when calculating the number and percentage of subjects who 
received that medication. The summary will be ordered by preferred name in descending overall 
frequency. For drugs with the same frequency, sorting will be done alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.


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7.5.
Electrocardiogram Results
ECG analysis results are intended to identify meaningful abnormalities. If potential abnormalities 
of interest are identified, further analyses may be conducted.
A shift table of the investigators’ assessment of ECG results at Week 12 compared with baseline 
values will be presented by treatment group using the following categories: normal; abnormal, 
not clinically significant; abnormal, clinically significant; or missing. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline or postbaseline will not be included in the denominator 
for percentage calculation. No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
PK samples were collected and stored at Covance. A decision was made that PK analysis will 
not be performed.


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9.
REFERENCES
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics 1999;55 (4):1202-9.
Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Biometrika 1934;26 (4):404-13.
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.).  Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21. 


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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


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12.
APPENDICES
Appendix 1.
Schedule of Assessments


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Appendix 1.
Schedule of Assessments
Procedures
Screening
(45 days)
Baseline
Day 1
Weeks (± 3 Days)
Early
Discontinuationa
24 Week 
Treatment-Free 
Follow-up 
(± 5 Days) (End of 
Weeks 4, 8,
12, 16, 20, and 24)
1
2
4
8
12
16
24
36
48
Informed Consent (at, or 
prior to, screening visit) n
X
Review of Inclusion/ 
Exclusion Criteria
X
X
Medical History
X
X
AEs and Concomitant
Medications
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Complete Physical
Examination
X
X
X
X
Xc
Symptom-directed physical 
examinationb
X
X
X
X
X
X
X
X
X
Height
X
Body Weight
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
Pregnancy Testf
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug Screen
X
X
Safety laboratory tests
(hematology and chemistry,
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X
X
X
Quantitative plasma
X
X
X
X
X
X
X
X
X
X
X
X


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Weeks (± 3 Days) 
24 Week 
Treatment-Free 
Follow-up 
(± 5 Days) (End of 
Screening 
Baseline 
Early 
Weeks 4, 8, 
Procedures 
(45 days) 
Day 1 
1 
2 
4 
8 
12 
16 
24 
36 
48 
Discontinuation• 
12, 16, 20, and 24) 
HBV DNA 
FibroScan 
X 
HCC imaging 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualitative HBV serology: 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of PBMC, whole 
blood, serum, and plasma 
X 
X 
X 
X 
X 
X 
X 
Xh 
samples for biomarker 
analysis 
HBV Genotyping 
0 
X 
Serum sample for HBV viral 
sequencing (resistance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
surveillance) or ddPCR r 
Single Plasma PKi 
X 
Xi 
X 
Xi 
X 
X 
X 
X 
X 
X 
Other Viral Serology(HCV, 
X 
HJ V, HOV) 1 
Creatinine Clearance 
X 
X 
X 
X 
X 
Randomization 
X 
Dispense TAF 
X 
X 
X 
X 
X 
X 
X 
Dispense GS-9992 
X 
X 
X 
ln-Clinic Dose with GS-9992 
X 
xm xm xm 
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GS-9992 
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Statistical Analysis Plan 
Procedures 
ln-Clinic dose with TAF 
GS-9992 Accountability 
TAF Accountability 
Screening 
(45 days) 
Baseline 
Day 1 
X 
1 
2 
4 
X 
X 
X 
X 
X 
X 
Weeks (± 3 Days) 
8 
12 
16 
24 
36 
X 
X 
X 
X 
X 
X 
X 
The Early Discontinuation (ED) visit should be perfom1ed within 14 days from notification of study discontinuation. 
Symptom directed physical exam will only be perfom1ed when subject is experiencing symptoms. 
48 
X 
Early 
Discontinuation• 
X 
X 
To completed at Treatment Free Follow up Week 4 only: AE review, complete physical examination, and urine pregnancy test. 
Vital signs include blood pressure, pulse, respiration rate and temperature. 
Version 1.0 
24 Week 
Treatment-Free 
Follow-up 
(± 5 Days) (End of 
Weeks 4, 8, 
12, 16, 20, and 24) 
a. 
b. 
C. 
d. 
e. 
QTc interval will be reported using Fridericia 's correction: QTcF QT/RR0333. Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the 
recording. 
f. 
g. 
h. 
i. 
j. 
I 
For female subjects of childbearing potential, the semm pregnancy test will be perfom1ed at Screening. Urine test will be perfom1ed at all other visits as indicated. 
Positive urine test will be confim1ed with semm test. Pregnancy testing should include prevention counseling. 
Qualitative HBV serology: (HBeAg (reflex 1-lBeAb ifHBeAg is negative] and HBsAg (reflex 1-lBsAb ifHBsAg is negative]). Collected every 12 weeks during the study. 
Post Treatment visit Weeks 12 and 24. 
PBMCs to be collected at Weeks 4, 8, 12, and 24 only. PBMC sample collection is only re. 
-
les will be collected between 15 minutes and 4 hours post dose. 
Single PK sample will be collected at any time on all other Post Day I visit 
. For Group 4, single PK will be 
collected throu h Week 12 onl . 
I. 
In the event of a positive result and/or antigen testing for HIV, HOV 
111. 
In clinic dose re. uired for Weeks 2 and 8 single PK samples 
I 
0. 
p. 
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GS-US-464-4437 Week 48 SAP v 1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
21-Sep-2020
16:22:51
Clinical Research eSigned 23-Sep-2020
20:46:08
PPD
PPD-